taxane and Breast-Neoplasms

The current standard of care for resected early-stage triple negative breast cancer (TNBC) patients who did not receive systemic preoperative therapy is adjuvant anthracycline- and taxane-based chemotherapy (CT). A network meta-analysis (NMA) of randomized controlled trials (phase III) enrolling patients with resected stage I-III TNBC comparing adjuvant regimens was performed. Overall survival (OS) and disease-free survival (DFS) data were extracted. A total of 27 phase III clinical trials were selected including 15,242 TNBC patients. This NMA showed an OS benefit from the incorporation of capecitabine into classic anthracycline/taxane-based combinations compared to anthracyclines with or without taxanes alone.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Network Meta-Analysis; Triple Negative Breast Neoplasms

Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.. We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs.. 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade.. Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials.. Cancer Research UK, UK Medical Research Council.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Female; Humans; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Receptors, Estrogen

Breast cancer is a common cancer in women and a leading cause of mortality. With the early diagnosis and development of therapeutic drugs, the prognosis of breast cancer has markedly improved. Chemotherapy is one of the predominant strategies for the treatment of breast cancer. Taxanes, including paclitaxel and docetaxel, are widely used in the treatment of breast cancer and remarkably decrease the risk of death and recurrence. However, taxane resistance caused by multiple factors significantly impacts the effect of the drug and leads to poor prognosis. Long noncoding RNAs (lncRNAs) have been shown to play a significant role in critical cellular processes, and a number of studies have illustrated that lncRNAs play vital roles in taxane resistance. In this review, we systematically summarize the mechanisms of taxane resistance in breast cancer and the functions of lncRNAs in taxane resistance in breast cancer. The findings provide insight into the role of lncRNAs in taxane resistance and suggest that lncRNAs may be used to develop therapeutic targets to prevent or reverse taxane resistance in patients with breast cancer.

Topics: Breast Neoplasms; Female; Humans; Paclitaxel; RNA, Long Noncoding; Taxoids

Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy.. Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models.. AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology.. For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Female; Humans; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids

Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

Topics: Breast Neoplasms; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Female; Genetic Markers; Humans; Liver-Specific Organic Anion Transporter 1; Neurotoxicity Syndromes; Paclitaxel; Peripheral Nervous System Diseases; Pharmacogenetics; Polymorphism, Single Nucleotide; Taxoids

Evidence for the preferred neoadjuvant therapy regimen in triple-negative breast cancer (TNBC) is not yet established.. Literature search was conducted from inception to February 12, 2022. Phase 2 and 3 randomized controlled trials (RCTs) investigating neoadjuvant therapy for TNBC were eligible. The primary outcome was pathologic complete response (pCR); the secondary outcomes were all-cause treatment discontinuation, disease-free survival or event-free survival (DFS/EFS), and overall survival. Odd ratios (OR) with 95% credible intervals (CrI) were used to estimate binary outcomes; hazard ratios (HR) with 95% CrI were used to estimate time-to-event outcomes. Bayesian network meta-analysis was implemented for each endpoint. Sensitivity analysis and network meta-regression were done.. 41 RCTs (N = 7109 TNBC patients) were eligible. Compared with anthracycline- and taxane-based chemotherapy (ChT), PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with a significant increased pCR rate (OR 3.95; 95% CrI 1.81-9.44) and a higher risk of premature treatment discontinuation (3.25; 1.26-8.29). Compared with dose-dense anthracycline- and taxane-based ChT, the combined treatment was not associated with significantly improved pCR (OR 2.57; 95% CrI 0.69-9.92). In terms of time-to-event outcomes, PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with significantly improved DFS/EFS (HR 0.42; 95% CrI 0.19-0.81).. PD-1 inhibitor plus platinum and anthracycline- and taxane-based ChT was currently the most efficacious regimen for pCR and DFS/EFS improvement in TNBC. The choice of chemotherapy backbone, optimization of patient selection with close follow-up and proactive symptomatic managements are essential to the antitumor activity of PD-1 inhibitor.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Immune Checkpoint Inhibitors; Neoadjuvant Therapy; Network Meta-Analysis; Platinum; Taxoids; Triple Negative Breast Neoplasms

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Female; Humans; Paclitaxel; Taxoids

Cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent approximately 15% to 20% of all breast cancers. Historically, this subtype of breast cancer was associated with an increased risk for the development of systemic and brain metastases and poor overall survival. The introduction of trastuzumab dramatically changed the outcomes of patients with HER2-positive disease, with many demonstrating outcomes similar to those of patients with luminal tumors. Currently, the first-line standard of care for patients with HER2-positive metastatic breast cancer is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. After progression, the standard of care is trastuzumab emtansine (T-DM1). Although the treatment choices for patients whose disease has progressed on these agents are more limited, promising new drugs have emerged as effective options, including tucatinib and trastuzumab deruxtecan, which were recently approved by the US Food and Drug Administration. Finding the best treatment sequencing for each patient, developing reliable predictive biomarkers, and understanding the mechanisms of resistance to these drugs are necessary to maximize patient outcomes and quality of life. In this review, we analyze the management strategies for metastatic HER2-positive breast cancer, address specific situations, such as the treatment of patients with brain metastases, and discuss future directions in the treatment of this subtype.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Camptothecin; Female; Humans; Immunoconjugates; Neoplasm Metastasis; Oxazoles; Pyridines; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

We performed a network meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of HER2-targeted agents in combination with taxanes and to identify the best strategy for HER2. Pubmed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials that evaluated any taxanes+HER2-targeted agents in the treatment of HER2. A total of 13 RCTs were eligible, involving 4941 patients and 10 regimens. The result showed that single-HER2-targeted agent+a taxane did improve the effect on ORR and PFS than taxane alone, but only trastuzumab+a taxane had a significant improvement in OS outcomes. Single-HER2-targeted agent (trastuzumab) combined with taxane-based doublets (taxane+carboplatin/capecitabine/doxorubicin/bevacizumab) showed no further benefit than trastuzumab+a taxane. Doublet-HER2-targeted agents combined with a taxane(trastuzumab+pertuzumab+a taxane) showed further improvement in ORR, PFS, and all OS outcomes than single-HER2-targeted agent+a taxane. Ranking analysis based on their P-scores suggested that trastuzumab+pertuzumab+a taxane was the best combination treatment for all the efficacy outcomes.. These findings demonstrate that combining two HER2-targeted agents (trastuzumab+pertuzumab) with a taxane is much more beneficial for the treatment of HER2

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Female; Humans; Molecular Targeted Therapy; Network Meta-Analysis; Receptor, ErbB-2; Survival Rate; Taxoids; Trastuzumab; Treatment Outcome

In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC).. Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints.. The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators.. The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Molecular Targeted Therapy; Network Meta-Analysis; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Capecitabine is frequently used alone or combined with other chemotherapy agents for the treatment of metastatic breast cancer in relapsed patients.. The objective of this meta-analysis is to evaluate the effectiveness and safety of capecitabine monotherapy versus combination in the treatment of metastatic breast cancer patients pretreated with anthracycline and taxane.. Eligible randomized controlled trials examining the efficacy and safety of capecitabine alone compared to capecitabine combination were systematically searched. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grades 3-4 drug-related adverse events were the outcomes assessed.. A total of 6,714 patients of 9 trials were involved in the pooled analysis. Our findings demonstrated that capecitabine combination is significantly superior to capecitabine monotherapy in improving PFS (hazard ratio [HR] 1.32, 95% CI 1.13-1.54, p < 0.0001) and ORR (risk ratio [RR] 0.67, 95% CI 0.54-0.83, p < 0.001), but it was insignificant in OS (HR 1.09, 95% CI 0.98-1.22, p = 0.12). On the other hand, the incidence of non-hematological adverse events such as hand-foot syndrome and diarrhea was lower in capecitabine combination compared to capecitabine monotherapy.. Capecitabine-based combination chemotherapy showed superiority over capecitabine monotherapy in terms of PFS and ORR, with no significant difference in OS. Non-hematological adverse effects such as hand-foot syndrome were fewer with a combination regimen. However, hematological adverse events were fewer with capecitabine monotherapy regimen.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Diarrhea; Female; Hand-Foot Syndrome; Humans; Middle Aged; Progression-Free Survival; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Treatment Outcome

Chemotherapy-induced alopecia (CIA) remains a distressing adverse event of cancer treatment but may be prevented by scalp cooling. The effectiveness of scalp cooling, however, is dependent on the chemotherapy regimen with successful hair preservation (i.e., < 50% hair loss) in 41-59% of women on taxane-based therapies in comparison to 16-36% on anthracycline-based therapies. Despite the potential utility, use of scalp cooling has shown a more equivocal impact on quality of life (QoL). In this review, we aim to evaluate the use of scalp cooling for CIA and quantitative QoL measures.. A systematic review of PubMed, Embase, Web of Science, and Cochrane databases for clinical studies on scalp cooling to prevent CIA published before October 29, 2018 was performed. Clinical studies with 5 or more patients that reported on a quantitative QoL measure were included and graded according to a modified five-point scale from the Oxford Centre for Evidence-Based Medicine.. Studies meeting inclusion criteria included 4 randomized clinical trials (RCT), 8 cohort studies, and 1 cross-sectional study with 1282 unique patients. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30: 46%) and Breast Cancer Module (QLQ-BR23: 46%) represented the most commonly used QoL assessments. Overall, 4 (31%) of the 13 studies concluded that scalp cooling was associated with significant improvements in QoL measures; 8 (62%) determined that there was either non-significant or no improvements; and 1 (7.7%) provided a mixed conclusion. Although 2 (50%) RCT demonstrated that scalp cooling can effectively prevent CIA depending on the chemotherapy regimen, these studies did not show that successful hair preservation was associated with improved QoL measures.. This review demonstrates that scalp cooling is not consistently associated with significant QoL improvements as assessed by EORTC QLQ-C30 and -BR23. Representing a critical limitation, more than one-third of the studies did not subcategorize QoL outcomes for successfully or unsuccessfully scalp-cooled patients but rather reported on QoL measures for all scalp-cooled patients in general. Failure to prevent hair loss in patients undergoing an expensive and potentially uncomfortable treatment likely contributes to decreased well-being, impacting the overall distribution of QoL measures in scalp cooling patients compared to controls. Future studies should incorporate validated QoL instruments specific to hair disease and classify QoL outcomes for scalp-cooled patients based on the degree of hair preservation.

Topics: Alopecia; Breast Neoplasms; Bridged-Ring Compounds; Cryotherapy; Female; Humans; Induction Chemotherapy; Quality of Life; Scalp; Taxoids

Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN.. Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

Topics: Black or African American; Breast Neoplasms; Bridged-Ring Compounds; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Genotype; Humans; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; Taxoids; White People

Taxanes are chemotherapeutic drugs employed in the clinic to treat a variety of malignancies. Despite their overall efficacy, cancer cells often display resistance to taxanes. Therefore, new strategies to increase the effectiveness of taxane-based chemotherapeutics are urgently needed. Multiple molecular players are linked to taxane resistance; these include efflux pumps, DNA repair mechanisms, and hypoxia-related pathways. In addition, emerging evidence indicates that both non-coding RNAs and epigenetic effectors might also be implicated in taxane resistance. Here we focus on the causes of taxane resistance, with the aim to envisage an integrated model of the 'taxane resistance phenome'. This model could help the development of novel therapeutic strategies to treat taxane-resistant neoplasms.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Hypoxia; Drug Resistance, Neoplasm; Female; Humans; RNA, Untranslated; Taxoids

Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor developed for the treatment of HER2-positive advanced solid tumours. Based on positive results in a phase II trial, the drug recently received conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy. This article summarizes the milestones in the development of pyrotinib leading to this first global approval for the treatment of HER2-positive advanced breast cancer.

Topics: Acrylamides; Aminoquinolines; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Humans; Protein Kinase Inhibitors; Receptor, ErbB-2; Taxoids

Capecitabine monotherapy is usually used for advanced breast cancer (ABC) resistant to anthracycline and taxane, but there are still many other options too. Our meta-analysis assessed whether capecitabine monotherapy was superior or noninferior to the other regimens in ABC pretreated with anthracycline and taxane.. PubMed databases and abstracts from the proceedings of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched for randomized controlled trials that compared capecitabine monotherapy with other regimens for ABC progression after anthracycline- and taxane-treatment. Hazard ratios (HRs) were used for progression-free survival (PFS) and overall survival (OS). Risk ratios (RRs) were used for overall response rate (ORR) and Grade 3-4 drug-related adverse events. All statistical analyses were conducted with RevMan 5.3 software, and statistical significance was defined as P < 0.05.. In total, 4671 patients from eight trials were included. Target therapy as treatment group was involved in four trials, and the other four trials were merely chemotherapy in treatment group. Our study indicated that capecitabine monotherapy was not superior but also noninferior to the other regimens in ORR (RR = 1.32-95% confidence interval [CI] 0.98-1.77, P = 0.07), PFS (HR = 1.03, 95% CI 0.85-1.25, P = 0.76), and OS (HR = 0.96, 95% CI 0.88-1.05, P = 0.40). Subgroup analysis showed that both the other chemotherapy regimens and target drugs failed to improve efficacy compared with capecitabine monotherapy, and target drugs could shorten PFS (HR = 1.22, 95% CI 1.06-1.39, P = 0.004). Incidences of Grade 3-4 hematology toxicity in other regimens group significantly increased compared with capecitabine monotherapy.. Our meta-analysis demonstrated that capecitabine monotherapy could be the first choice for ABC pretreated with anthracycline and taxane due to its efficacy and low toxicity.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Incidence; Neoplasm Grading; Progression-Free Survival; Taxoids; Treatment Outcome

Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS).. Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method).. A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529).. Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Staging; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Survival Rate; Tamoxifen; Taxoids; Time Factors

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A healthy 56-year-old postmenopausal woman discovered a palpable mass at the one o'clock position of the left breast. After an initial biopsy confirmed breast cancer, she underwent mastectomy and axillary node dissection for a left-sided breast cancer that measured 3.5 cm. There was extensive lymphovascular invasion. Pathology review indicated a poorly differentiated, grade 3 invasive ductal carcinoma and ductal carcinoma in situ (largest focus, 3.5 cm). The margins were negative. Two of the 11 axillary lymph nodes contained metastatic carcinoma. Immunohistochemical studies previously obtained on the core biopsy indicated that the tumor was positive for estrogen receptor expression (50%), negative for progesterone receptor expression, and had a Ki-67 score of 60%. There was no amplification of the human epidermal growth factor receptor 2/ neu gene. Staging scans were negative for metastatic disease. Our multidisciplinary tumor board recommended adjuvant chemotherapy, postmastectomy radiation therapy, and endocrine therapy. A 52-year-old postmenopausal woman presented with a palpable mass of the right breast. An initial core biopsy confirmed carcinoma in the breast. She underwent quadrantectomy and axillary node dissection. The final pathology report disclosed a moderately differentiated invasive ductal carcinoma (diameter, 2.5 cm). The margins were negative. None of the three sentinel lymph nodes contained metastatic carcinoma. Immunohistochemical studies showed that the tumor was positive for estrogen receptor expression (90%) and for progesterone receptor expression (40%) and had a Ki-67 score of 20%. There was no amplification of the human epidermal growth factor receptor 2/ neu gene. Staging scans were negative for metastatic disease. A genomic assay was obtained and suggested an intermediate to high risk of recurrence. Her past medical history was notable for hypertension and moderately overweight status (body mass index, 39 kg/m

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chemotherapy, Adjuvant; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Invasiveness; Radiotherapy, Adjuvant; Taxoids

The aim of this review was to systematically evaluate the safety and efficacy of the addition of pertuzumab to trastuzumab emtansine (T-DM1) ± taxane in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer (LABC) or metastatic breast cancer (MBC).. Several databases were searched for relevant clinical trials. The study characteristics, details of adverse events (AEs) and details of treatment efficacy were extracted for analysis.. Six studies with 996 patients were included. Common AEs of T-DM1 + pertuzumab ± taxane included fatigue, diarrhea, nausea, epistaxis, peripheral neuropathy, increased aspartate transaminase (AST), increased alanine transaminase (ALT) and thrombocytopenia. Major grade ≥3 AEs of T-DM1 + pertuzumab ± taxane included thrombocytopenia, neutropenia, fatigue, increased ALT, anemia and peripheral neuropathy. The addition of pertuzumab to T-DM1 ± taxane led to higher risks of diarrhea (especially grade ≥3 diarrhea), rash and vomiting, and decreased risks of thrombocytopenia and grade ≥3 increased AST. The relative risks of the addition of pertuzumab to T-DM1 ± taxane for objective response (1.068, 95% CI 0.945-1.207) and clinical benefit (1.038, 95% CI 0.974-1.106) were not statistically significant.. Common AEs should be carefully monitored in HER2-positive LABC or MBC patients treated with T-DM1 + pertuzumab ± taxane. The addition of pertuzumab to T-DM1 ± taxane showed noninferior, but not superior, objective response rate and clinical benefit rate. However, more studies are needed to further verify these findings.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Maytansine; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Trastuzumab

Patients with bilateral breast cancer (BBC) are usually excluded from participating in clinical trials and little is known about the response and outcome of BBC to neoadjuvant chemotherapy compared to unilateral BC (UBC).. We prospectively captured the information on patients with BBC in our database treated within four neoadjuvant chemotherapy trials and collected retrospectively the rate of pathological complete response (pCR) defined as ypT0 ypN0, ypT0/is ypN0, ypT0 ypNX, clinical and histologic parameters. Synchronous carcinoma in the contralateral breast was considered as the non-indicator lesion. Patients with UBC only treated within the same neoadjuvant trials performed the control group.. From the 6727 patients treated within 4 German neoadjuvant trials 119 (1.8%) patients have been identified with the diagnosis of BBC. The pCR rate (ypT0 ypN0) was 12.6% in the non-indicator lesion group versus 10.9% the indicator lesion group versus 20.9% for patients with unilateral disease (p = 0.003). There were more advanced tumor stages and positive axillary lymph nodes in the indicator lesion than in the nonindicator lesion or in UBC. In 52.5% the molecular subtype was identical between indicator and non-indicator lesion with more triple negative and HER2 positive BC in the group of UBC. The disease free survival rate (DFS) was 25.8% for patients with UBC versus 39.6% for patients with BBC.. The selection for the indicator lesion was based on tumor size, nodal status and inclusion criteria. Patients with BBC patients had a lower pCR rate and a lower DFS.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Female; Germany; Humans; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasms, Multiple Primary; Prospective Studies; Retrospective Studies; Taxoids; Tumor Burden; Young Adult

In HER2-positive early breast cancer, neoadjuvant treatment with a combination of sequential chemotherapy and HER2-targeted therapy is currently the standard of care. This is followed by breast surgery, radiotherapy (if indicated), completion of 12 months of HER2-directed therapy, and - depending on the tumor biology - endocrine adjuvant therapy, and ultimately follow up. 10-year survival rates in the HER2-positive subgroup of breast cancer do reach now more than 75% with the introduction of first adjvuant and later neoadjuvant HER2-targeted therapies over the last 15 years. The neoadjvuant setting helps to downstage locally advanced tumors, to provide early information of tumor response, to assess the efficacy of new therapies in vivo, to reduce treatment duration, and to introduce new targeted therapies into the clinical routine. It also allows enrolling fewer patients into clinical trials in order to reach adequate effects in clinical outcome. The neoadjuvant approach and our interest in this setting are based on pCR (pathological complete response) and its translation into better long-term outcome. In recent trials, we have reached more than 60% pCR with a subsequent improvement of DFS and hopefully OS. Therefore, chemotherapy schedules and new HER2-targeted agents such as lapatinib, pertuzumab, and T-DM1 have been introduced into the neoadjuvant setting. To balance over- and undertreatment, current trials include personalized concepts and assess new biomarkers and tumorbiological factors. We have learned for example to differentiate between HR (hormone receptor)-positive and -negative tumors in the HER2-positive population. Depending on pCR or non-pCR after neoadjuvant treatment, the adjuvant therapy may be adjusted. This concept of post-neo-adjuvant trials is now entering the field of strategies in the neoadjuvant setting for HER2-positive non-metastatic primary breast cancer. The 2017 standard of care in the neoadjuvant setting according to national and international guidelines combines a taxane-containing chemotherapy with a dual blockade of trastuzumab and pertuzumab. This review will point out current trials and their strategies to continue improving outcome and reduce morbidity as well as mortality in HER2-positive early breast cancer.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Lapatinib; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Quinazolines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane.

Topics: Albumins; Animals; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Nanoparticles; Paclitaxel; Taxoids

Along with anthracyclines, taxanes are the most active cytotoxics in breast cancer (BC). Balancing efficacy against toxicity in older patients with reduced physiological reserves and significant comorbidities is both important and difficult. This is especially so given the under-representation of elderly patients in major trials and a consequent lack of evidence for drug, dose and schedule. However, BC is frequent in elderly women, who are a growing proportion of the population. Careful consideration of their care is therefore imperative. Treatment that can cure or extend the duration and quality of life should not be restricted by age, but needs to be tailored to the circumstances of elderly patients. In adjuvant use, taxane toxicity in older women is greater than in their younger counterparts, limiting its sequential combination with anthracyclines for high-risk disease unless patients are in very good health. More frequently taxanes are used alone (weekly paclitaxel, three-weekly docetaxel) or combined with cytotoxics other than anthracyclines (e.g. docetaxel plus cyclophosphamide) to reduce cardiac risk, especially in HER-2-positive patients who may develop additional trastuzumab-related cardiac events. In elderly patients with metastases, weekly paclitaxel and three-weekly docetaxel are among the cornerstones of treatment, with generally acceptable toxicity. Three-weekly docetaxel at the approved dose of 100mg/m(2) is not appropriate for the elderly. Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication but has been little studied in older BC patients. A head-to-head comparison with weekly paclitaxel favoured the solvent-free formulation for pathologic response, but those studied were a general adult population. Compared with early stage disease, choice of taxane and regimen in the metastatic setting relies even more on availability and preferences with regard to schedule, toxicity profile and cost, especially for recently developed formulations.

Topics: Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Medication Therapy Management; Neoplasm Staging; Quality of Life; Receptor, ErbB-2; Risk Adjustment; Taxoids

Chemotherapy is one of the most frequently employed and reliable treatment options for the management of a variety of cancers. Taxanes (paclitaxel, docetaxel and cabazitaxel) are frequently prescribed to treat breast cancer, hormone refractory prostate cancer, non-small cell lung cancer and ovarian cancer. Most of the commercial products of taxanes are available as injectables, which are not patient compliant and are associated with frequent side effects like ototoxicity, baldness and neurotoxicity. Most of these concerns are ascribable to the presence of toxic solvents in these commercial formulations, which are used to solubilize these drug(s). However, there have been several attempts to develop toxic solvent free taxane formulations, especially employing novel drug delivery systems (NDDS). These systems have been reported to result in the advancement of anticancer activity, therapeutic index, stability, biocompatibility, tissue or organ targeting, encapsulation capacity, tissue permeability, oral bioavailability, reduced toxicity and reduced incidences of abnormal reactions, sustained and controlled release in comparison to the conventional solvent-based formulations. The review is an attempt to analyze the potential of NDDS-mediated taxane delivery for safer and effective cancer chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Colloids; Drug Carriers; Drug Delivery Systems; Female; Humans; Lung Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Taxoids

Treatment with pertuzumab-trastuzumab-taxane combinations has become the international standard of care for patients with HER2-positive metastatic breast cancer. In this paper we discuss the practicalities of treating patients with this combination with a particular focus on treatment in the Australian setting.. An expert panel was convened to discuss practical aspects for use of pertuzumab in the Australian clinical setting. The findings of this panel are reported in this article.. The combination of pertuzumab-trastuzumab-docetaxel has established efficacy in patients with HER2-positive metastatic breast cancer, prolonging progression-free and overall survival compared to trastuzumab-taxane combinations. In Australia, combinations of pertuzumab and trastuzumab with docetaxel or paclitaxel are reimbursed. Management of treatment related side-effects such as diarrhea, febrile neutropenia and neuropathy typically include dose reduction or switching taxane. Specific patients with poorer tolerance of chemotherapy such as the elderly or those from Asian backgrounds may require particular management strategies.. The advent of targeted therapies for women with metastatic HER2-positive breast cancer has markedly improved survival. Combinations of pertuzumab-trastuzumab and a taxane are the standard of care in patients with good performance status. Given prolongation of survival and the importance of quality of life endpoints, the treatment paradigm for patients with metastatic HER2-positive breast cancer is changing rapidly. Careful management of toxicities is required, and dose reduction or switching taxane may be necessary. Further research is required on the efficacy of pertuzumab combinations in patients with brain metastases, and on those who relapse quickly following adjuvant therapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Australia; Breast Neoplasms; Bridged-Ring Compounds; Disease Management; Disease Progression; Docetaxel; Female; Humans; Neoplasm Recurrence, Local; Paclitaxel; Receptor, ErbB-2; Taxoids; Trastuzumab

Breast cancer in young women represents a public health problem with specific age-related issues to be faced by both patients and their treating physicians.. This manuscript reviews the recent data on the medical management of young women with early-stage HER2-negative breast cancer.. For women candidates to receive (neo)adjuvant chemotherapy, anthracycline- and taxane-based regimens are standard of care. In high-risk patients, dose-dense regimens should be preferred; in women with triple-negative breast cancer and BRCA mutations, the addition of platinum compounds may also be considered. Several adjuvant endocrine therapy options have become available for the treatment of premenopausal women with early-stage luminal breast cancer. Specifically, young patients at low risk of relapse may be safely spared chemotherapy: endocrine therapy alone with tamoxifen for 5 years is the most appropriate treatment. In women at higher risk of relapse, ovarian function suppression is therapeutic: in this scenario, luteinizing hormone-releasing hormone agonists (LHRHa) should be considered in addition to tamoxifen or aromatase inhibitors. To women concerned about the possible risk of chemotherapy-induced premature ovarian failure, the use of temporary ovarian suppression with LHRHa should be proposed as a valid strategy to potentially preserve ovarian function and fertility.

Topics: Anthracyclines; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Gonadotropin-Releasing Hormone; Humans; Neoplasm Recurrence, Local; Receptor, ErbB-2; Tamoxifen; Taxoids

Systematic analysis of cancer gene-expression patterns using high-throughput transcriptional profiling technologies has led to the discovery and publication of hundreds of gene-expression signatures. However, few public signature values have been cross-validated over multiple studies for the prediction of cancer prognosis and chemosensitivity in the neoadjuvant setting.. To analyze the prognostic and predictive values of publicly available signatures, we have implemented a systematic method for high-throughput and efficient validation of a large number of datasets and gene-expression signatures. Using this method, we performed a meta-analysis including 351 publicly available signatures, 37,000 random signatures, and 31 breast cancer datasets. Survival analyses and pathologic responses were used to assess prediction of prognosis, chemoresponsiveness, and chemo-drug sensitivity.. Among 31 breast cancer datasets and 351 public signatures, we identified 22 validation datasets, two robust prognostic signatures (BRmet50 and PMID18271932Sig33) in breast cancer and one signature (PMID20813035Sig137) specific for prognosis prediction in patients with ER-negative tumors. The 22 validation datasets demonstrated enhanced ability to distinguish cancer gene profiles from random gene profiles. Both prognostic signatures are composed of genes associated with TP53 mutations and were able to stratify the good and poor prognostic groups successfully in 82%and 68% of the 22 validation datasets, respectively. We then assessed the abilities of the two signatures to predict treatment responses of breast cancer patients treated with commonly used chemotherapeutic regimens. Both BRmet50 and PMID18271932Sig33 retrospectively identified those patients with an insensitive response to neoadjuvant chemotherapy (mean positive predictive values 85%-88%). Among those patients predicted to be treatment sensitive, distant relapse-free survival (DRFS) was improved (negative predictive values 87%-88%). BRmet50 was further shown to prospectively predict taxane-anthracycline sensitivity in patients with HER2-negative (HER2-) breast cancer.. We have developed and applied a high-throughput screening method for public cancer signature validation. Using this method, we identified appropriate datasets for cross-validation and two robust signatures that differentiate TP53 mutation status and have prognostic and predictive value for breast cancer patients.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Databases, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Neoadjuvant Therapy; Neoplasm Proteins; Prognosis; Receptors, Estrogen; Taxoids; Tumor Suppressor Protein p53

Breast cancer is a heterogeneous disease, characterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxanes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experience severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clinical parameters, such as toxicity or outcome.. The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015.. We studied the literature in order to find any possible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population.. Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experimental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxicity and with resistant or responsive outcome, before the administration of taxanes.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Biomarkers; Breast Neoplasms; Bridged-Ring Compounds; Cytochrome P-450 CYP1B1; Evidence-Based Medicine; Female; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Taxoids

The molecular subtypes of breast cancer have individual patterns of behaviour, prognosis and sensitivity to treatment, with subsequent implications for the choice of, or indeed role for adjuvant therapy. The luminal A and B subtypes make up the majority of breast cancers, but despite sharing expression of the oestrogen receptor (ER), they are molecularly distinct. It follows then that they would have different sensitivities to chemotherapy. Clinically, luminal A disease has a better prognosis than luminal B, and may not derive significant benefit from adjuvant chemotherapy. However no prospective trials have specifically investigated the benefit of adjuvant chemotherapy in each subtype, nor do we know if certain agents are more or less effective. This paper will briefly summarise the role of molecular profiles in assessing the need for chemotherapy and predicting its effectiveness, followed by an assessment of the relative value of newer anthracycline- or taxane-containing regimes in the luminal-like subtypes, providing a review of retrospective analyses.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Female; Fluorouracil; Humans; Methotrexate; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Taxoids

Different adjuvant chemotherapy regimens are available for early-stage breast cancer. Because conventional meta-analysis does not allow comparing all regimens, we performed a network meta-analysis to identify the most effective adjuvant chemotherapy regimen.. To find the most effective adjuvant therapy regimen for early-stage breast cancer.. We searched MEDLINE, Embase, and the Cochrane Library for articles published before June 2015; the American Society of Clinical Oncology annual meeting abstracts from January 1983 through December 2014; and the American Association for Cancer Research annual meeting abstracts from January 1916 through December 2014. Additionally, we manually searched bibliographies for related references.. We included randomized clinical trials of adjuvant treatments for early-stage breast cancer that compared 2 or more of the following: no adjuvant chemotherapy; sequential anthracycline-cyclophosphamide and taxane (AC-T); concurrent anthracycline-cyclophosphamide and taxane (ACT); anthracycline-cyclophosphamide without taxane (AC); docetaxel and cyclophosphamide (TC); cyclophosphamide, methotrexate, and fluorouracil (CMF); and platinum-containing regimens.. We followed the PRISMA guidelines. Two investigators independently selected the articles and extracted information. Disagreements were resolved by discussion with another author. Quality was assessed by Cochrane risk-of-bias method. Data were pooled using random-effects models.. We used network meta-analysis to test the most effective adjuvant therapy regimen in terms of overall survival (OS) by comparing regimens listed in the National Comprehensive Cancer Network guidelines and platinum-containing regimens.. We identified 24 trials. The TC and platinum-containing regimens had OS benefit similar to that of sequential AC-T (TC hazard ratio [HR], 0.93; 95% CI, 0.62-1.40; and platinum HR, 0.93; 95% CI, 0.66-1.31). Patients treated with CMF or AC had significantly worse OS than those treated with sequential AC-T (CMF HR, 1.56; 95% CI, 1.32-1.85; and AC HR, 1.22; 95% CI, 1.10-1.37). Platinum-containing regimens tended to be more toxic than sequential AC-T. The toxicity of TC was similar to or less than that of sequential AC-T. Meta-regression analysis showed that hormone receptor status did not impact the HRs for OS for any regimen.. Sequential AC-T is likely to be the most effective adjuvant therapy regimen for early-stage breast cancer regardless of hormone receptor status.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cisplatin; Cyclophosphamide; Docetaxel; Female; Fluorouracil; Humans; Platinum Compounds; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Predictive markers for response to chemotherapy are required in breast cancer. The Tau protein is a microtubule-associated protein variably expressed in breast cancer. The objective of our study was to describe drug resistance induced by the tau protein, and its predictive and prognostic value in breast cancer.. Medline and PubMed databases were searched in April 2015 for terms "tau protein", "breast cancer", "chemotherapy sensitivity", "biomarker" and "taxane resistance".. In vitro, tau protein competes with taxane for controlling microtubule dynamic and loss of tau expression may render microtubules more vulnerable to the effects of taxanes. High tau protein expression was associated with better prognosis, even after adjustment for grade, hormone receptor and human epidermal growth factor receptor-2 expression, nodal status. The predictive value of the tau protein for sensitivity to taxane is discordant despite there being a trend for an association between low tau expression and increased response rate.. Tau protein expression is insufficient for identifying a subset of patients with carcinomas that may benefit more from chemotherapy.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Prognosis; tau Proteins; Taxoids

To compare the efficacy and safety between anthracycline & taxane and anthracycline in the treatment of breast cancer.. Computer-assisted literature search was performed with PubMed, MEDLINE, EMBASE and Cochrane Controlled Trials Register (CCTR) to identify pertinent literatures. Software RevMan 5.0 was used for statistical analysis. The measurement of interest outcomes included severe neurotoxicity, death without breast cancer recurrences, leukemia, venous thrombus and severe cardiotoxicity.. A total of 10 randomized controlled trial studies (RCTs) containing 18,198 cases were selected in this meta-analysis. Of which, 9,902 cases were treated with anthracycline & taxane and 8,296 cases treated with anthracycline alone as control. Anthracycline & taxane showed lower risks of incident leukemia (RR = 0.40; 95% CI: 0.18, 0.90), venous thrombus (RR = 0.49; 95% CI: 0.29, 0.84) and severe cardiotoxicity (RR = 0.41, 95%CI: 0.26, 0.66), but higher risks of incident severe neurotoxicity (RR = 5.97; 95% CI: 1.72, 20.65) and non-recurrent death (RR = 1.79; 95% CI: 1.06, 3.04), compared to anthracycline alone.. Clinically important differences exist for general safety in favour of the anthracycline & taxane rather than anthracycline alone. However, as a result of tumor recurrent rate, anthracycline might be superior to anthracycline & taxane. A longer duration of follow-up and a larger number of cases are required to better assess the efficacy and safety profile of the treatment of breast cancer.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Taxoids

Sequential anthracycline/taxane regimens are routinely used as neoadjuvant therapy (NAT) for locally advanced breast cancer. Unfortunately, the majority of patients do not achieve a pathological complete response (pCR). Efforts to improve pCR rates include the addition of novel targeted agents. The purpose of this article is to review recent developments in this area and to demonstrate the clinical and research advantages of a neoadjuvant platform for the evaluation of novel targeted therapy.. Dual human epidermal growth factor 2 (HER2)-targeting concurrent with chemotherapy has demonstrated superiority over chemotherapy with trastuzumab alone. Bevacizumab appears to have a modest effect on pCR rates and its role in neoadjuvant treatment remains uncertain. Despite promising preclinical signals, mTOR inhibition in combination with chemotherapy has yet to yield a benefit in the neoadjuvant setting and trials are ongoing. In contrast, mTOR inhibition in combination with endocrine therapy has demonstrated potential as NAT.. Dual HER2-targeting considerably improves pCR rates. Thus, far incorporation of non-HER2 targeted agents has been less successful. NAT provides an opportunity to evaluate novel agents, and thereby assist the development of a rationale adjuvant strategy, and facilitates the collection of samples for correlative research into breast cancer biology and predictive biomarkers/pathways.

Topics: Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Genes, erbB-2; Humans; Taxoids; TOR Serine-Threonine Kinases

Although neoadjuvant therapy (NAT) has become a popular approach in the systemic management of breast cancer, several important clinical questions remain unanswered. In this article, we review the literature pertaining to these questions and discuss the management strategies based on our findings.. Currently, the optimal duration of NAT is unclear. At this time, there is no compelling data to support the extension of traditional neoadjuvant chemotherapy regimens. In patients with triple-negative breast cancer, pathologic complete response may be prognostic and the appropriate use of neoadjuvant chemotherapy is crucial to achieve improved survival. In human epidermal growth factor receptor 2 (HER2)-positive disease, it is reasonable to consider dual blockade with trastuzumab and pertuzumab in combination with a taxane in the neoadjuvant setting. Finally, there is currently no evidence to support the use of further adjuvant chemotherapy in those patients with residual disease after NAT.. There remain many unanswered questions with the use of neoadjuvant chemotherapy in breast cancer, and further randomized clinical trials are needed. The results of these trials will permit the clinicians to develop 'personalized' treatment approaches, thus giving women the best chance of survival.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Receptor, ErbB-2; Taxoids; Trastuzumab

Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system.. To assess the evidence on the efficacy and safety of therapy with trastuzumab (overall) and in relation to the type of co-administered regimen and the line of treatment, i.e. first-line or beyond progression, in women with HER2-positive metastatic breast cancer.. We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL (2013, Issue 1), MEDLINE, EMBASE, BIOSIS, the WHO International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (up to 17 January 2013).. RCTs comparing the efficacy and safety of trastuzumab alone or in combination with chemotherapy, hormonal therapy or targeted agents in women with HER2-positive metastatic breast cancer.. We collected data from published trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included type of regimen (taxane-containing, anthracycline-containing, aromatase inhibitor-containing or other) and treatment line (first-line, beyond progression).. The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths.. Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab.Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.

Topics: Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Lapatinib; Quinazolines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids; Trastuzumab

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing.. Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1.. T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Disease-Free Survival; Docetaxel; Female; Fluorouracil; Humans; Immunoconjugates; Lapatinib; Maytansine; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

Chromosomal instability, which is a characteristic of many human cancers, contributes to intratumour heterogeneity and has been functionally implicated in resistance to taxane therapy in tumour models. However, defining the status of tumour chromosomal instability in a given tumour to test this hypothesis remains challenging. Measurements of numerical and structural chromosomal heterogeneity demonstrate that histological grade correlates with chromosomal instability in oestrogen receptor (ER)-positive breast cancer. Using data on adjuvant taxane therapy in women with breast cancer, we propose that patients with low-grade ER-positive tumours, which are thought to be chromosomally stable, might derive unexpected benefit from taxane therapy. We discuss the implications of the relationships between tumour grade, chromosomal instability and intratumour heterogeneity, the development of high-throughput methods to define tumour chromosomal instability and the potential use of chromosomal instability to tailor therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chromosomal Instability; Female; Humans; Neoplasm Grading; Taxoids

Metastatic breast cancer is currently incurable and the goals of therapy focus on prolonging survival and maintaining quality of life by controlling symptoms and minimizing toxicity. Treatments for metastatic breast cancer include chemotherapeutic agents from various classes, such as taxanes, vinca alkaloids, anthracyclines and antimetabolites. This review provides an overview of chemotherapeutic agents for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes, focusing on a clinical evaluation of eribulin, the most recently approved agent for the treatment of metastatic breast cancer. Eribulin is a synthetic derivative of halichondrin B, a tumour growth inhibitor found in marine sponges, which prevents microtubule growth and sequesters the tubulin molecules into unusual aggregates, initiating apoptosis. Studies of eribulin have shown that the drug is effective in the treatment of previously treated metastatic breast cancer, and has an acceptable toxicity profile. Importantly, in the phase III EMBRACE study, eribulin treatment resulted in a survival advantage, a difficult endpoint to achieve with a single chemotherapeutic agent. An additional phase III study showed that eribulin has similar efficacy to capecitabine in women treated with no more than three prior therapies. Furthermore, pre-specified exploratory analyses suggest that particular patient subgroups may have greater therapeutic benefit with eribulin and may warrant further study to explore the potential mechanisms.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Female; Furans; Humans; Ketones; Taxoids

Hormone-receptor (HR)-positive breast cancer is associated with a poor response to adjuvant chemotherapy. Thus, it is important to identify HR-positive patients who can benefit from chemotherapy and the Ki-67 index may help to predict chemotherapy efficacy in such populations. However, controversies exist regarding the prognostic and predictive role of Ki-67 and its exact cut-off value in HR-positive patients. Therefore, we conducted this study.. The meta-analysis included 4512 patients in five trials. Due to different data formats provided by studies, we classified the trials into two groups to facilitate analysis. Group 1 included the PACS01, USON 01062, and IBCSG VIII and IX trials, while Group 2 included the BCIRG001, USON 01062, and IBCSG VIII and IX trials.. In Group 1, Ki-67 high patients had a worse prognosis in disease-free survival (DFS) than Ki-67 low counterparts (risk ratio [RR] = 1.62, 95% confidence index [CI] = 1.36-1.94, P < 0.001). In Group 2, Ki-67 high patients had a better prognosis in DFS (RR = 0.53, 95% CI = 0.45-0.61, P < 0.001) and overall survival (OS) (RR = 0.32, 95% CI = 0.25-0.42, P < 0.001). In Ki-67 high patients administered anthracycline/taxane-based chemotherapy, the experimental group (FAC → T, AC → TX) achieved a better DFS than the control group (FAC, AC → T, respectively) (RR = 0.60, 95% CI = 0.39-0.90, P = 0.014). With a cut-off point ≥19%, Ki-67 high patients achieved a worse DFS (RR = 1.49, 95% CI = 1.28-1.72, P < 0.001).. This study had limitations due to its retrospective nature and the lack of standardized Ki-67 measurement methods. Nevertheless, our findings indicate that Ki-67 high patients have a worse prognosis and may be more sensitive to anthracycline/taxane-based regimens. The ideal Ki-67 cut-off point for predicting chemosensitivity may be a certain value among a range of values ≥19% in HR-positive patients.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Ki-67 Antigen; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Taxoids

Despite remarkable improvements in breast cancer survival in the last decades, a proportion of patients still relapse after treatment for early disease. Different prognostic parameters may permit to roughly quantify the residual risk of relapse after (neo)adjuvant therapy. They include: tumor stage and classical molecular features at baseline, newly proposed prognosticators (such as tumor-infiltrating lymphocytes and integrated genomic tools) and the evaluation of tumor response after primary systemic therapy. However, the performance of these factors is still suboptimal and should be improved. Further research aimed to discover new possible prognostic factors in patients who received optimal systemic therapy is needed. Moreover, to exploit at the best the potential of each of these parameters, they should be integrated into algorithms to guide treatment decisions and to select those patients who may deserve the inclusion in clinical trials.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents, Hormonal; Biopsy, Needle; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Genomics; Humans; Immunohistochemistry; Lymphocytes, Tumor-Infiltrating; Mastectomy; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

The first-generation taxanes, conventional paclitaxel and docetaxel, are established treatment options for adjuvant and metastatic breast cancer (MBC). However, these agents have limitations, including primary/secondary resistance and harsh toxicities. The introduction of paclitaxel albumin represents a significant advance in taxane therapy as the first of a new generation of taxanes. This agent utilizes albumin pathways to achieve enhanced and targeted drug delivery to the tumour. The lack of solvent also means that it is well tolerated, despite the lack of premedications. Paclitaxel albumin is licensed in the United States and Europe as ≥2nd-line therapy in MBC (260mg/m(2) once every three weeks), but emerging evidence suggests it has activity in various settings as weekly therapy and in combination with other agents. Additional strategies to optimize taxane-based therapy are also being evaluated, including the possibility of tailoring treatment according to patient/disease characteristics, identifying predictive biomarkers and evaluating other novel taxanes.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Female; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Taxoids; Treatment Outcome

Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use.. We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview.. Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance.. Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Humans; Taxoids

The purpose of this study was to evaluate the use of taxane chemotherapy during pregnancy and compare maternal and neonatal outcomes with those in women who did not receive taxanes during pregnancy, and review current existing data.. This is a retrospective cohort study in which women were identified from the Cancer and Pregnancy Registry at Robert Wood Johnson Medical Center. A retrospective chart analysis and an independent t-test were carried out comparing patient outcomes. A literature search in Ovid, Medline and PubMed was then carried out using the terms 'breast or ovarian cancer', 'pregnancy', 'paclitaxel', 'docetaxel', 'taxanes' and 'chemotherapy'.. Twelve of 129 women with breast cancer were exposed to taxanes during pregnancy. Three of nine women with ovarian cancer received taxane-based treatment during pregnancy. Birth weight, gestational age at delivery, rate of growth restriction, congenital anomalies and incidence of maternal and neonatal neutropenia were not statistically different between the two groups.. Taxane-based chemotherapy does not appear to increase the risk of fetal or maternal complications when compared with conventional chemotherapy in the small cohort of women in our Registry.

Topics: Antineoplastic Agents; Birth Weight; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Docetaxel; Female; Gestational Age; Humans; Ovarian Neoplasms; Paclitaxel; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Retrospective Studies; Taxoids

Neoadjuvant chemotherapy provides a means both of improving subsequent surgical intervention and of testing novel therapies or combinations. Historically, triple-negative breast cancer (TNBC) has responded well in the neoadjuvant setting, with rates of pathological complete response (pCR) commonly higher than for other breast tumour types. However, more than half of TNBC patients do not achieve a pCR and have a very poor prognosis. The lack of drug-targetable receptors on TNBC tumours has made improving the available interventions in TNBC an area of important medical need. The routine use of neoadjuvant anthracycline/taxane combinations in TNBC is currently being supplemented by ongoing investigations of their use with other types of agent. In particular, the substantial proportion of TNBC tumours associated with BRCA1 mutations is driving clinical research into the use of DNA-damaging agents such as platinums, as well as of potentiators of DNA damage such as the investigational agent iniparib and inhibitors of poly-ADP ribose polymerase such as olaparib. Tyrosine kinase receptor inhibitors and microtubule-targeting inhibitors of cell cycling are also under active investigation. The use of neoadjuvant treatment with pCR as a surrogate of overall survival will allow the rapid evaluation and comparison of these and other much-needed new treatments for TNBC.

Topics: Anthracyclines; Antineoplastic Agents; Benzamides; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle; Chemotherapy, Adjuvant; Female; Humans; Neoadjuvant Therapy; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Treatment Outcome

Conventional chemotherapy is the mainstay of adjuvant systemic treatment for most patients with early triple-negative breast cancer (TNBC). At present, comparisons between adjuvant chemotherapy regimens are retrospective in nature, and so the optimal drugs or drug combinations have not been established for patients with early TNBC. In retrospective subgroup analyses, taxanes are more effective than 5-fluorouracil in combination with cyclophosphamide and doxorubicin. Classical CMF (cyclophosphamide, methotrexate and 5-fluorouracil) has shown efficacy, whereas few data on the role of anthracyclines are available. An unplanned subgroup analysis of one randomised study suggests that capecitabine adds efficacy to a taxane-anthracycline regimen, but this observation requires confirmation. High-dose adjuvant chemotherapy is considered experimental. Ongoing trials are comparing standard adjuvant regimens with regimens that integrate an anti-angiogenic agent, a platin or maintenance capecitabine. Inhibitors of DNA repair or specific tyrosine kinases have not yet been addressed in the adjuvant setting. In the absence of data from prospective trials that focus on adjuvant therapy of early TNBC, several regimens, such as a taxane and an anthracycline-containing regimen or classical CMF may be considered reasonable choices.

Topics: Angiogenesis Inhibitors; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Chemotherapy, Adjuvant; Cisplatin; Deoxycytidine; Female; Fluorouracil; Humans; Methotrexate; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Treatment Outcome

This paper presents a summary of the evidence review group (ERG) report into the use of bevacizumab (Avastin®, Roche) in combination with a taxane for the treatment of untreated metastatic breast cancer (mBC). The main clinical effectiveness data were derived from a single, open-label randomised controlled trial (RCT) (E2100) that evaluated the addition of bevacizumab to weekly (q.w.) paclitaxel in patients with human epidermal growth factor receptor 2-negative mBC who had not previously received chemotherapy for advanced disease. This trial reported statistically significant increases in median progression-free survival (PFS) for the addition of bevacizumab (5.8-11.3 months). Median overall survival was not significantly different between the two groups; whether this is a true null finding or due to crossover between treatment arms cannot be established, as relevant data were not collected. The manufacturer reported that the addition of bevacizumab to paclitaxel q.w. therapy was associated with a significant improvement in quality of life, as measured by FACT-B (functional assessment of cancer therapy for breast cancer) scores. However, the ERG noted that these results were based on extreme imputed values, the removal of which led to non-significant differences in quality of life. The manufacturer conducted an indirect comparison. However, owing to methodological limitations and concerns about the validity and exchangeability of the included trials, the ERG did not consider the findings to be reliable. One additional relevant RCT [AVADO (Avastin and Docetaxel); BO17708] evaluating the addition of bevacizumab to docetaxel was excluded from the manufacturer's submission. This was summarised by the ERG. In terms of response rate and PFS, AVADO reported a markedly smaller benefit of adding bevacizumab to docetaxel than that reported for adding bevacizumab to q.w. paclitaxel in E2100. AVADO also reported no statistically significant effect of combination therapy versus docetaxel in terms of overall survival. The manufacturer developed a de novo economic model that considered patients with the same baseline characteristics as women in the E2100 trial. The model assessed BEV + PAC - bevacizumab 10 mg/kg every 2 weeks in combination with paclitaxel 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; PAC q.w. - paclitaxel (monotherapy) 90 mg/m2 weekly for 3 weeks followed by 1 week of rest; DOC - docetaxel (monotherapy) 75 mg/m2 on day 1 every 21 days (consid

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease-Free Survival; Docetaxel; Drug Therapy, Combination; Female; Gemcitabine; Humans; Neoplasm Metastasis; Paclitaxel; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids

Breast cancer consists of a heterogeneous group of diseases, with a number of tumor-specific and patient-specific factors, which influence response to therapy and survival. Ixabepilone is a member of a novel class of antineoplastic agents, the epothilones, that has demonstrated activity in a number of human solid tumor types and is the first agent in this class to be approved by the Food and Drug Administration (FDA) for the treatment of metastatic or locally advanced breast cancer, that is resistant/refractory to anthracyclines, taxanes, and/or capecitabine. Both retrospective and prospective studies have been conducted to evaluate the efficacy of ixabepilone in various populations. The role of ixabepilone in poor prognosis subgroups of the metastatic breast cancer population is reviewed in this article.

Topics: Adult; Aged; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Drug Approval; Drug Delivery Systems; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome; United States; United States Food and Drug Administration

Breast cancer is the second most common cause of cancer death in women among the United States. Fortunately, it continues to be an active area of research. Today, it is well recognized that breast cancer can often be a systemic disease, with micrometastatic involvement at diagnosis in many patients. Over the past decade, adjuvant systemic therapy has been used to eradicate micrometastatic disease, and it has been shown to decrease the rates of recurrence and improve the survival of patients with early-stage, resected breast cancer. Some of the success of modern adjuvant systemic therapy has come from the advent of new chemotherapy and endocrine agents but also from the development of targeted therapies, which have improved the efficacy of conventional, cytotoxic therapy. There has also been increasing awareness that the dosing and schedule of administration of systemic therapies are equally important factors in achieving better outcomes in patients with early-stage breast cancer. Growing research into the biology and genomics of breast cancer has fueled the development of more accurate risk stratification tools and helped individualize the decision to recommend adjuvant systemic therapy. Herein, we present a review of salient developments over the past decade that have helped shape the adjuvant systemic therapy of today.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Endocrine System; Female; Humans; Taxoids

To review data relating to anthracyclines in the adjuvant treatment of early breast cancer.. This is a report from a seminar in which the future of anthracyclines in the adjuvant treatment of breast cancer was considered. In particular, the question of whether anthracyclines should now be discarded and replaced by taxanes was addressed.. Accumulating data from large randomized trials indicate that genetic markers may have a role in predicting sensitivity to cytotoxic drugs. However, no reliable, validated test is available for predicting sensitivity to anthracyclines in particular. Topoisomerase IIalpha amplification and/or deletion, especially in conjunction with human epidermal growth factor receptor-2 amplification, has been proposed to fulfill this role but more data are needed. Currently, only one published trial has shown that a taxane-based regimen may be superior to an anthracycline-based regimen, but several trials indicate that combinations including both anthracyclines and taxanes may be better still. Further studies aimed at optimizing anthracyclines and taxanes in combination, and integrating biologic agents, seem to be the way forward. There is no validated test that can determine whether anthracyclines can be of greater benefit than other agents for individual patients.. Anthracyclines have been extensively tested in clinical trials spanning several decades; currently, there are insufficient data to recommend replacing them in the adjuvant treatment of breast cancer.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Receptor, ErbB-2; Taxoids; Treatment Outcome

One of the major recent clinical advances in cancer treatment is the use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib. Bevacizumab, the monoclonal anti-VEGF antibody, has been approved for the first line treatment of metastatic breast cancer (MBC) when combined with taxane. However, the clinical benefits are modest; despite a doubling of response rates and significant prolongation of progression free survival times, no increase in overall survival is attained. This review summarizes some of the possibilities to account for this discrepant result. These include rapid development of acquired drug resistance due to the redundancy of proangiogenic growth factors, acceleration of tumor growth after antiangiogenic drug treatments are stopped, and increases in tumor cell malignant aggressiveness driven by mechanisms such as increased tumor hypoxia. Some possible strategies to improve the benefits of antiangiogenic drug therapy are discussed such as prolonging the treatment beyond tumor progression, combination with other therapeutic modalities, e.g. long term ('maintenance') low-dose metronomic chemotherapy or additional targeted/biologic drugs, e.g. trastuzumab.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Metastasis; Taxoids; Vascular Endothelial Growth Factor A

About 30% of the randomized clinical trials are stopped early because of appearance of clear clinical benefit. Though interim analyses protect patients in case of significant imbalance between two treatment arms, conclusions drawn from truncated studies can be premature and should be viewed with caution. We report the lesson learnt from the Herceptin adjuvant (HERA) trial.

Topics: Adjuvants, Immunologic; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bias; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Randomized Controlled Trials as Topic; Taxoids; Trastuzumab

High-risk situations in early breast cancer concern patients with less than 3 involved lymph nodes but additional risk factors as well as patients with more than 3 involved lymph nodes. For the first group, new risk assessment methods to better identify the need for chemotherapy with or without a taxane or with a taxane instead of an anthracycline are needed. For the second group, further improvement of anthracycline- or taxane-containing chemotherapy regimens is warranted. Current approaches include the sequential or simultaneous use of these groups of agents, the combination with antimetabolites, antibodies or small molecules, the neoadjuvant use of chemotherapy as well as dose-dense and dose-escalated chemotherapy regimens.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy; Humans; Practice Patterns, Physicians'; Risk Factors; Taxoids

Taxanes and anthracyclines are two of the most potent and broadly effective classes of chemotherapeutic agents. However, resistance to these agents is common and significantly limits their potential. As such, there is a great need to understand the mechanisms underlying de novo and acquired resistance to these agents. Beyond the resistance barrier lies even greater potential to significantly alter the natural course of human cancer. This review discusses what we currently understand about the mechanisms of resistance to taxanes and anthracyclines. Preclinical models suggest a role for ATP-binding cassette transporters, tubulin isoforms, microtubule-associated proteins, tubulin gene mutations, and mitotic checkpoint signaling proteins in resistance to taxanes. Preclinical models also suggest that drug transport proteins, antioxidant defenses, apoptotic signaling, and topoisomerase modulation may mediate anthracycline resistance. Many of these hypotheses remain untested in appropriately designed clinical studies, but limited clinical evidence will be reviewed. Epothilones represent a novel class of non-taxane microtubule stabilizing agents with distinct drug-resistance profiles. Potential mechanisms behind these differences and their potential role in the treatment of both taxane- and anthracycline-refractory patients are discussed.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Microtubules; Mitosis; Taxoids

Results of clinical trials over the past 15 years demonstrate that the taxanes are among the most effective new class of cytotoxic drugs to treat breast cancer and other solid tumors. Moreover, the efficacy of the taxanes added further credence to the relevance of the microtubule as a tumor target. In spite of the significant benefits observed in early and advanced breast cancer, a number of factors contribute to disease relapse and, perhaps more discouragingly, disease refractoriness. After exhausting cytotoxic chemotherapy, hormonal therapy, and other molecular-based-therapies, patients whose tumors exhibit taxane resistance had virtually no additional options. This paper, a product of the ongoing advances in the treatment of breast cancer, reviews two important areas: first, molecular concepts and relevance of the microtubule in breast cancer and second, clinical implications of ixabepilone, a novel, nontaxane tubulin-stabilizing agent in patients with taxane-resistant breast cancer.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Female; Humans; Microtubules; Taxoids; Tubulin Modulators

Many chemotherapeutic and biologic agents used for advanced breast cancer exhibit activity alone or in combination, but the small number of randomized trials, coupled with the significant heterogeneity of patient and tumor characteristics, have precluded the development of standardized, evidence-based approaches to therapy for advanced disease. This expert faculty roundtable discussion focused on chemotherapy regimens used in pretreated patients. Given the increasing data on taxanes in this setting, a specific need was identified that led to the theme of standard and novel taxanes in this discussion. Numerous factors can predict response and long-term outcome: tumor characteristics like hormone and HER2 receptor status and grade and clinical characteristics like age, functional status, disease-free interval, previous adjuvant therapy, and sites or burden of metastatic disease. The choice of therapeutic agents or combinations, therefore, relies not only on randomized or phase II trial results but also on patient context in relation to these variables. After anthracycline and taxane therapy, agents such as capecitabine, vinorelbine, gemcitabine, and platinum agents and combinations thereof can be active. Taxanes themselves also possess activity, with a dependency on a specific agent and schedule. Albumin-bound paclitaxel has demonstrated superiority to certain taxane agents and schedules and has demonstrated activity after taxane exposure. This discussion highlights basic paradigms by which standard taxanes and albumin-bound paclitaxel can be evaluated as possible therapeutic or investigative options, along with nontaxane agents, emerging biologic agents, and combinations.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemistry, Pharmaceutical; Female; Humans; Neoplasm Staging; Taxoids

Over the past decade the taxanes have proved to be fundamental in the treatment of breast cancer. Initially found to have efficacy in metastatic breast cancer, the taxanes are now vital components in the treatment of early-stage disease, in which their addition to adjuvant treatment of early breast cancer has been shown to improve overall survival. In addition, the taxanes have demonstrated a role in first-line therapy for metastatic disease, with some of the highest efficacy of any class of chemotherapy. Targeted therapies in combination with the taxanes have further improved survival for both early and metastatic disease. New formulations of taxanes may both improve antitumor activity and reduce toxicity.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Humans; Neoadjuvant Therapy; Taxoids

We report five women who presented with scleroderma due to taxanes, mimicking systemic sclerosis. All five patients had received taxane chemotherapy for the treatment of metastatic breast cancer. Marked oedema began first, followed by skin sclerosis occurring mainly at the distal ends of the extremities 6-12 months after the administration of taxane in all patients. Skin biopsies showed full-layer dermal fibrosis with thickened collagen bundles, and perivascular monocytic cell infiltration. These cases resemble systemic sclerosis in terms of their clinical course and histological findings. However, clinical findings including Raynaud's phenomenon and pulmonary fibrosis as well as immunological abnormalities associated with systemic sclerosis were not detected in any of the patients. Although the mechanisms have not been clarified, it should be noted that taxane is causally involved in the formation of scleroderma-like skin conditions.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Lymphatic Metastasis; Middle Aged; Scleroderma, Localized; Taxoids

We examined if inclusion of a taxane and more prolonged preoperative chemotherapy improves pathologic complete response (pCR) rate in estrogen receptor (ER)-positive breast cancer compared with three to four courses of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC).. Pooled analysis of results from seven consecutive neo-adjuvant chemotherapy trials including 1079 patients was carried out. These studies were conducted at MD Anderson Cancer Center from 1974 to 2001. Four hundred and twenty-six (39.5%) patients received taxane-based neo-adjuvant therapy. pCR rates and survival times were analyzed as a function of chemotherapy regimen and ER status. Multivariate logistic and Cox regression analysis were carried out to identify variables associated with pCR and survival.. Patients with ER-negative cancer had higher overall pCR rate than patients with ER-positive tumors (20.1% versus 4.9%, P < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with and without a taxane (P < 0.001). In ER-positive patients, the pCR rates were 8.8% and 2.0% with and without a taxane (P < 0.001). In multivariate analysis, clinical tumor size (P < 0.001), ER-negative status (P < 0.001) and inclusion of a taxane (P = 0.01) were independently associated with pCR. For patients with pCR, survival was similar regardless of ER status or the type of regimen that induced pCR.. pCR rates increased for patients with both ER-positive and ER-negative tumors as regimens started to include a taxane and became longer. This indicates that a subset of patients with ER-positive breast cancer benefits from more aggressive chemotherapy, similarly to patients with ER-negative tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prognosis; Receptors, Estrogen; Survival Analysis; Taxoids; Tumor Burden

A 9-week regimen of trastuzumab (Herceptin) given concurrently with a taxane will be funded for HER2-positive early breast cancer patients in New Zealand. The use of trastuzumab in this population has been investigated in sequential (after chemotherapy) or concurrent (with taxane chemotherapy) settings. Five RCTs have been reported--HERA, NSABP B31, NCCTG N9831, BCIRG 006, and FinHer. Uncertainty persists about optimal regimen duration, dose and sequencing, how to minimise cardiotoxicity, and long-term clinical outcomes. The evidence for the 9-week concurrent regimen was sufficient to justify funding. This regimen has shown results comparable to longer duration treatments; allows more patients to be treated; is relatively cost-effective; and DHBs have indicated they can provide sufficient ancillary support services. Longer duration regimens remain unfunded because of uncertainty surrounding long term clinical benefits and risks; the high cost; effects on DHB services; and their consequential unfavourable relative cost effectiveness. New data--from the sequential treatment arm of trial N9831, showing benefits that were small and statistically non-significant, and the HERA 23-month follow-up, suggesting a waning in efficacy with time--have since cast further doubt on the extent and durability of the sequential 12-month regimen's efficacy. DHBs and PHARMAC remain open to funding longer duration regimens if cost effectiveness improves significantly and budget/resource implications become acceptable. PHARMAC has committed to international efforts (the SOLD trial) to resolve questions of optimal treatment duration.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Industry; Female; Financial Management; Follow-Up Studies; Genes, erbB-2; Humans; Middle Aged; New Zealand; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Taxoids; Time Factors; Trastuzumab

The management of early breast cancer has evolved rapidly in recent years. Consequently, the range of first-line treatment options for metastatic breast cancer (MBC) is becoming increasingly complicated and therapy depends on a complex interaction of tumor, patient, and physician variables. Arguably one of the most important factors determining choice of first-line chemotherapy is prior adjuvant therapy. We have reviewed data from large, randomized clinical trials to identify the most effective regimens and help clinicians to select first-line treatment based on previous adjuvant therapy. In this review we provide recommendations on the most appropriate first-line therapy according to the type of previous adjuvant therapy. With such a wide array of treatment options available, none is likely to become the gold-standard first-line treatment for MBC. Furthermore, as increasing emphasis is placed on the quality as well as the duration of survival after development of MBC, treatment decisions should take into account tumor characteristics, toxicity, convenience, potential impact on quality of life, and patient preference, in addition to robust efficacy data.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Genes, erbB-2; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Neoadjuvant chemotherapy for breast cancer has achieved a higher response rate with the combination of anthracycline and taxane. Molecular targeted agents, such as trastuzumab, are expected to enhance the effectiveness of treatment. The main objectives of neoadjuvant chemotherapy are to reduce tumor size, increase breast conserving rate, identify treatment response, adjust the following treatment strategy, and develop a new treatment using biological specimens. Recently, there has been an increasing demand to provide a tailored treatment in neoadjuvant chemotherapy with establishment of genetic testing for biological markers and adjustment of therapeutic strategy following identification of the early treatment response. We reviewed recent advances in neoadjuvant chemotherapy for breast cancer.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Neoadjuvant Therapy; Prednisolone; Taxoids; Trastuzumab; Vincristine

In recent decades, the use of adjuvant systemic therapies for early breast cancer has increased extensively and has most likely contributed to the decline in breast cancer mortality observed in the U.S. and in some European countries. The last few years have witnessed accelerated progress in the treatment of early breast cancer, with the introduction of taxanes and aromatase inhibitors and, most impressively, trastuzumab to the adjuvant portfolio. When compared with anthracycline-based regimens, the addition of taxanes to treatments for patients with node-positive breast cancer has shown benefits in disease-free survival and, in some trials, in overall survival; however, these drugs are not yet universally accepted as standard treatment. Significant improvements in endocrine therapy in both pre- and postmenopausal patients with endocrine-responsive disease have been made. In the postmenopausal setting, aromatase inhibitors have shown superiority over tamoxifen in a direct comparison upfront or when given in sequence after 2-5 years of tamoxifen, but the optimal modality of administration remains unclear. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogues combined with tamoxifen has generated similar results to cyclophosphamide, methotrexate, 5-fluorouracil (CMF)-based regimens. Recently, trastuzumab has had a dramatic impact on the evolution of human epidermal growth factor receptor 2 (HER-2)-positive early breast cancer treated with standard adjuvant modalities; specifically, relapses, including distant relapses, have been halved. In this review, we summarize these main achievements, discuss the currently available adjuvant treatment options for breast cancer patients, and emphasize the need for more efficient translational research to improve individual treatment tailoring.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Estrogen Replacement Therapy; Female; Humans; Menopause; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Trastuzumab; Treatment Outcome

Adjuvant chemotherapy for breast cancer patients has been derived from the results of various clinical studies and metaanalysis. Currently, an anthracycline-containing regimen is a standard chemotherapy for node-negative breast cancer patients with any risk of recurrence. Node-positive breast cancer patients employ AC followed by taxane. The concept of dose-dense therapy or adjuvant trastuzumab for HER 2-positive breast cancer patients will be introduced in the near future. We have to catch the procedures of standard treatments and treat our patients with the latest knowledge. Therefore, we can refer to any guidelines based on evidence-based medicine.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cisplatin; Cyclophosphamide; Epirubicin; Evidence-Based Medicine; Female; Fluorouracil; Guidelines as Topic; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Meta-Analysis as Topic; Methotrexate; Receptor, ErbB-2; Taxoids; Trastuzumab

Vinorelbine, a novel vinca alkaloid derivative developed in France, has been widely used for the treatment of breast cancer and non-small cell lung cancer since the 1990s in many foreign countries. In Japan, it has been available for the treatment of non-small cell lung cancer since 1999, and the additional indication of breast cancer was approved in May 2005. Japanese phase I clinical trials started in 1988. A total of six trials have been conducted in patients with advanced or recurrent breast cancer, and have provided evidence of efficacy in all groups of patients, including those receiving vinorelbine as first-line monotherapy and those previously treated with both anthracyclines and taxanes. This report reviews the data from these studies and also presents the results of combination therapy evaluated outside Japan. In addition,we explain why it took 17 years for vinorelbine to be approved despite the fact that as early as the beginning of development, it was scientifically proven to be very useful in patients with breast cancer, and that the new drug application was submitted in 1993. The relationship between healthcare professionals, patients and the regulatory agency is also discussed to point out related issues.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Approval; Female; Fluorouracil; Humans; Japan; Lung Neoplasms; Male; Paclitaxel; Taxoids; Vinblastine; Vinorelbine

Breast cancer is one of the most common malignancies among Japanese women. Approximately 40,000 new patients are diagnosed annually. In the USA, however,the mortality from breast cancer has recently been declining. A nationwide screening promotion using mammography, and recent advances in the treatment for early breast cancer have been the main reasons. It was widely accepted that for breast cancer as a systemic disease, appropriate systemic treatment of either chemotherapy and endocrine therapy improved the survival. We describe here the contributions of new agents to the improvement in survival for breast cancer patients and introduced the concept of dose density.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Menopause; Perioperative Care; Tamoxifen; Taxoids; Trastuzumab

Capecitabine is an important drug in the therapeutic armamentarium for metastatic breast cancer. A comprehensive worldwide clinical trial program involving >10,000 patients with locally advanced and metastatic breast cancer has provided evidence for the current treatment strategies. On the basis of data demonstrating consistent activity across several trials in patients with heavily pretreated breast cancer, capecitabine was approved in the U.S. in 1998 for the treatment of patients with metastatic disease resistant to paclitaxel and anthracycline-containing therapy, with later European Union approval for single-agent capecitabine in the metastatic setting. Capecitabine plus docetaxel (XT) was approved by the U.S. Food and Drug Administration for the treatment of metastatic breast cancer in 2001 on the basis of the large phase III trial comparing XT with docetaxel alone, which showed a survival advantage for combination therapy compared with single-agent therapy. This was shortly followed by European approval for the combination in metastatic breast cancer. The clinical utility of capecitabine in the management of breast cancer is supported by its convenient oral dosing schedule and favorable safety profile, as well as its excellent clinical activity in primary and metastatic breast cancer. Recently, clinical trials have studied single-agent capecitabine as first-line treatment and evaluated other capecitabine-containing combinations with cytotoxic and novel targeted agents.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Taxoids

The recent development of chemotherapeutic agents for breast cancer will be reviewed. The paradigm shift from CMF to anthracycline containg regimens +/- taxanes in an adjuvant setting may be considered to decide the sequence of recommended chemotherapy for metastatic breast cancer. Recurrent breast cancer patients who never have undergone anthracycline-containing regimens should be treated with anthracycline regimens. Patients who have already received only an anthracycline-containing regimen in adjuvant therapy will be treated with taxane with or without capecitabine. For patients already having received both anthracycline and taxanes, capecitabine monotherapy will be indicated as a first-line treatment. Physicians will choose the best treatment option among chemotherapeutic agents for patients with distant metastasis.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Taxoids

Topics: Anastrozole; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Nitriles; Progestins; Tamoxifen; Taxoids; Trastuzumab; Triazoles

Management of metastatic breast cancer (MBC) is difficult and overall response rates (ORR) resulting from anthracycline and taxane-based regimens remain modest. The antimetabolite drug gemcitabine has been shown to have high activity when used as first-line treatment of MBC, particularly when incorporated into combined therapy regimens. Gemcitabine-containing regimens have also been used successfully as salvage therapy in women with anthracycline or taxane-pretreated MBC. Phase II clinical studies have demonstrated high ORR with gemcitabine-docetaxel (ORR: 36-65.5%) and gemcitabine-paclitaxel (ORR: 40-68%) combination regimens. A highly favourable risk-benefit ratio has also been reported for gemcitabine-containing triplets such as gemcitabine-paclitaxel-epirubicin (ORR: 92%) and gemcitabine-paclitaxel-doxorubicin (ORR: 80.4%). Gemcitabine-containing regimens have a favourable toxicity profile with few serious toxic events reported. An important step forward in the evaluation of novel chemotherapeutic regimes for MBC is establishing a correlation between disease markers and response to therapy. Preliminary data suggest that there is a close relationship between HER2 extracellular domain levels (>30 ng/ml) and treatment outcome. HER2-positive patients had a lower ORR to gemcitabine-paclitaxel chemotherapy than women who were HER2-negative. Further studies to establish a link between other breast cancer markers and predicted response to treatment are warranted.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Remission Induction; Taxoids; Treatment Outcome

Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Administration Schedule; Drug Synergism; Female; Gemcitabine; Humans; Neoplasm Metastasis; Paclitaxel; Receptor, ErbB-2; Remission Induction; Taxoids; Trastuzumab

A number of novel microtubule-targeting agents are currently under investigation. These agents can potentially evade the mechanisms underlying the development of the multidrug resistance (MDR) phenotype commonly associated with recurrent breast cancer. Epothilones are among the most advanced of the new agents in clinical development. Structurally unrelated to taxanes, epothilones may be poor substrates for MDR, and the expression of MDR proteins is not altered in epothilone-resistant in vitro models. Cross resistance between epothilones and taxanes is not observed in vitro or in vivo. Ixabepilone (BMS-247550) is a semisynthetic analog of epothilone B that has shown antitumor activity both in vitro and in vivo, including taxane-resistant human tumor xenograft models. Ixabepilone is currently being studied in phase III trials in patients with metastatic breast cancer as monotherapy and in combination with capecitabine. Activity has also been observed in other solid tumors. Patupilone (EPO906, epothilone B) and epothilone D (KOS-862) are in early phase I/II clinical studies in patients with a variety of solid tumors. The development of these novel agents may evade MDR and may improve the outcome of patients with breast cancer.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Humans; Taxoids

As anthracycline-based regimens have become a standard treatment and are frequently used in the adjuvant therapy of breast cancer, the number of anthracycline-resistant cancers has begun to increase. Taxanes have also become more commonly used in the first-line metastatic and adjuvant setting, producing a need for new treatment options that are not cross-resistant with anthracyclines or taxanes and that have a relative non-overlapping toxicity profile with these agents. The combination of gemcitabine/cisplatin has been shown to have synergistic cytotoxic activity in vitro in breast cancer cell lines. In addition, several phase II trials have suggested that this combination is feasible and active in patients who have received prior anthracycline and/or taxane therapy.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Taxoids

EBCTCG meta-analysis revealed a significant reduction in mortality in patients receiving chemotherapy irrespective of nodal status and ER status. Compared with CMF, 5-year RFS and OS favored the anthracycline-containing regimens, 57% vs 54% (p = 0.006) and 72% vs 69% (p = 0.02), respectively. No survival benefit was obtained for CMF durations greater than 6 months. Delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and may be preferable for patients at high risk of distant metastasis. No difference in disease-free survival for the 3 dose levels of doxorubicin (60, 75, and 90 mg/m2) was found. Higher doses (100 mg/m2) of epirubicin led to a high survival rate in women with poor-prognosis disease. Dose-dense therapy seems promising but still needs further investigation. Incorporation of taxanes into adjuvant chemotherapy for early breast cancer is also controversial.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Mastectomy, Segmental; Meta-Analysis as Topic; Methotrexate; Receptors, Estrogen; Survival Rate; Tamoxifen; Taxoids

Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling > or =30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Docetaxel; Female; Humans; Paclitaxel; Taxoids; Treatment Outcome

The use of neoadjuvant chemotherapy in the treatment of breast cancer has been evolving during the past two decades. Fisher's group accomplished the scientific rationale in mouse models in the 1970s. The Milan group was the first to use neoadjuvant therapy in locally advanced breast cancer and also determined that adjuvant sequential doxorubicin with cyclophosphamide/methotrexate/fluorouracil (CMF) offered improved survival when compared to alternating CMF with doxorubicin. Other groups (M. D. Anderson and NSABP) have evaluated similar doxorubicin-based neoadjuvant therapies in locally advanced breast cancer (LABC) and in early disease. These studies have shown an increase in breast-conserving therapy (BCT) and an increase in pathologic complete response (pCR) when neoadjuvant therapy was used. Due to anthracycline resistance, taxanes were added to the doxorubicin-based neoadjuvant chemotherapy regimen with an increase in BCT and pCR than when an anthracycline regimen was used alone. Overall survival has yet to be determined when comparing an anthracycline-based regimen to the same regimen with the addition of a sequential taxane. Therefore, a combined treatment of an anthracycline/cyclophosphamide/taxane regimen is the recommended neoadjuvant chemotherapy for patients with breast cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Humans; Mice; Models, Animal; Taxoids

Neodjuvant chemotherapy has been primitively used in locally advanced breast cancer. More recently, indications have been extended to operable lesions. Several randomized trials have compared preoperative chemotherapy with postoperative surgery. None of these studies with anthracyclines have shown benefit in terms of progression free survival and/or overall survival. The rate of breast-conservative surgery seems slightly increased. However, in the NSABP 18 study, there was also a marginally significant increase in local recurrence when patients were converted from mastectomy lumpectomy to as originally planned. The introduction of taxanes in neoadjuvant chemotherapy protocol leads to a better clinical response and a complete histological responses increase when docetaxel is used. In only one study using docetaxel after anthracyclin treatment, a survival benefit is reported but it is a small study; a longer follow up and the updated results of the NSABP B27 trial are needed to confirm the impact of taxotere in the outcome of breast cancer. The integration of trastuzumab with taxane based chemotherapy has already shown high rate of histological complete responses. At least, neoadjuvant chemotherapy has the advantage to study biologic predictive factors of chemotherapy response. This article will review data on standard therapeutic and new agents in neoadjuvant treatment.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Female; Humans; Neoadjuvant Therapy; Randomized Controlled Trials as Topic; Taxoids; Trastuzumab

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Docetaxel; Humans; Neoadjuvant Therapy; Paclitaxel; Taxoids

Adjuvant chemotherapy has gained increasing prominence in the treatment of nonmetastatic breast cancer, producing gradual improvement in the survival of these patients. The taxanes offer great hope for adding to the progress in adjuvant treatment, but data have been conflicting. Early results of multi-center trials testing the sequential addition of paclitaxel to anthracycline-based adjuvant chemotherapy have perhaps been prematurely reported, but have already made a major impact on patterns of care for node-positive and even some node-negative patients. The early dramatic improvements in CALG 9344 are fading with time, however, and have not been confirmed by a second similar trial, NSABP B-28. Moreover, it cannot be stated with certainty whether the modest improvements observed by sequential addition of paclitaxel reflect the ability of this drug to kill anthracycline-resistant cancer cells or the increased total duration and amount of treatment. By contrast, the early results of the BCIRG 001 trial suggest that combining docetaxel with doxorubicin may significantly increase survival, but these early results should be viewed with caution and do not necessarily mean that docetaxel is superior to paclitaxel. The role of neoadjuvant chemotherapy for breast cancer has also expanded over the past 2 decades, from its initial use for inoperable locally advanced breast cancer (LABC) to its current use for patients with large operable tumors to make BCT feasible. The neoadjuvant approach also has an important role in clinical trials, where it will allow more rapid comparison of treatment regimens than can be accomplished in the adjuvant setting and provides an opportunity to analyze biologic markers as predictors of response. The value of this approach, however, will ultimately depend on a clear demonstration, not yet available, that a change in therapy that increases primary tumor response will also lead to improved long-term survival. The roles of docetaxel and paclitaxel in the neoadjuvant setting has been actively investigated over the past 5 to 10 years, and exciting results are beginning to emerge. Clearly, docetaxel has potent antitumor activity against breast cancer. Several preliminary results suggest that addition of docetaxel to an anthracycline-based regimen, particularly when added sequentially, as in NASBP B-27 and the Aberdeen trial, results in higher clinical and pathologic response rates. Whether this will translate into increased long-term survi

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Docetaxel; Female; Humans; Neoadjuvant Therapy; Paclitaxel; Taxoids

The association of doxorubicin (DOX) and paclitaxel (PTX) is very active in breast cancer. Unfortunately, PTX may potentiate the cardiotoxic effects of anthracyclines: it causes nonlinear disposition of DOX and its metabolites, leading to persistant of elevated plasma concentrations of the anthracyclines. However, this pharmacokinetic interference is not sufficient to explain the enhanced cardiotoxicity of the combination. Recent data suggest that PTX stimulates the conversion of DOX to cardiotoxic metabolites (namely doxorubicinol) inside cardiomyocytes. Docetaxel (DTX) does not have a major influence on DOX plasma concentration because it does not interfere with its elimination. Clinical data suggest that DTX may not enhance anthracycline cardiotoxicity, but patients seldom received a total anthracycline dose compatible with increased risk. Furthermore, there are experimental data indicating that DTX can also stimulate the metabolism of DOX to toxic species in human heart.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Heart Diseases; Humans; Paclitaxel; Risk; Taxoids

It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer.. To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer.. The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library.. Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer.. Data were collected from published trials. Studies were assessed for eligiblity and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present.. Twenty eligible trials were identified of which 17 had published at least some results, and 12 had published time-to-event data. The quality of randomisation was generally not described. An estimated 2659 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.90 (95% CI=0.84-0.97, p=0.009) and no significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.12). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.87, 95%CI 0.81-0.93, p<0.0001) and overall response (overall OR 1.29, 95%CI 1.13-1.47, p<0.0001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials.. When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Female; Humans; Paclitaxel; Randomized Controlled Trials as Topic; Tamoxifen; Taxoids

Anthracyclines have been incorporated into adjuvant chemotherapy regimens for breast cancer since the 1980s. A metaanalysis confirmed that regimens containing anthracyclines result in better disease-free and overall survival than standard CMF (cyclophosphamide/methotrexate/5-fluorouracil), with a proportional reduction of 11% in risk of death at 10 years with the addition of these agents. Dose escalation of doxorubicin results in outcome improvement up to a threshold dose beyond which no further improvement is seen. Epirubicin, with its better toxicity profile, can be escalated to higher doses than doxorubicin, with better outcomes associated with higher dose levels. Tumors expressing HER2/neu may respond better to anthracycline-containing regimens than to standard CMF, but this remains controversial. Newer regimens combining anthracyclines with taxanes may offer a slight additional advantage in terms of disease-free and overall survival in some patient populations. The scheduling of treatment is important, with recent results of dose-dense scheduling showing a greater survival benefit than conventional scheduling. Ongoing clinical trials should further define the best choice of anthracycline and the optimal dose and schedule of treatment.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Female; Genes, erbB-2; Humans; Taxoids

In patients with advanced breast cancer, treatment with paclitaxel and doxorubicin has been shown to produce impressive overall response rates (up to 94%) and to prolong overall survival significantly over a combination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide (Cytoxan, Neosar) in one prospective phase III clinical study. These results have been challenged, however, by other data demonstrating no survival advantage for taxane-based therapies. In addition, the combination of paclitaxel and doxorubicin has repeatedly been shown to be complicated by the development of treatment-related congestive heart failure, when cumulative doxorubicin doses exceed 300-360 mg/m2. Consequently, attempts have been made to increase the complete remission rate and overall survival resulting from first-line treatment of metastatic breast cancer without compromising patient safety. Gemcitabine (Gemzar)--a relatively effective, well-tolerated and partially non-cross-resistant antitumor compound with limited toxicity--represents an attractive alternative to paclitaxel/anthracycline combinations. Initial studies of combination therapy with gemcitabine and paclitaxel have produced an average response rate of 52%, with time to progression ranging between 7.0 and 14.5 months. Three-drug regimens containing gemcitabine, an anthracycline, and paclitaxel have been tested in phase II studies and have produced impressive response rates of 82.9% with gemcitabine, doxorubicin, and paclitaxel and 92% with gemcitabine, epirubicin (Ellence), and paclitaxel (GET). The Central European Cooperative Oncology Group has evaluated the GET regimen vs a regimen containing 5-FU, epirubicin, and cyclophosphamide (FEC) in a randomized, prospective phase III study. Interim toxicity analysis showed that the GET regimen was well tolerated but produced more grade 4 neutropenia (64% vs 42%, P = .084) and significantly more grade 4 thrombocytopenia (12% vs 0%; P < .001) than FEC. Anaphylactic/allergic reactions, peripheral polyneuropathy, nausea, and cardiotoxicity constituted rare events and did not exceed grade 1 or 2 in severity. Although final data from this phase III trial are not yet available, preliminary analysis suggests the GET regimen represents an attractive option for patients with advanced breast cancer.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease-Free Survival; Female; Follow-Up Studies; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Severity of Illness Index; Taxoids

This article summarizes the European experience with docetaxel in the adjuvant treatment of breast cancer patients. Four categories of trials evaluating the role of docetaxel are discussed: (1) 2-arm trial in which an anthracycline-based regimen administered for 6-8 cycles is compared to 3-4 cycles of the same regimen followed by full doses of 3-4 cycles of docetaxel; (2) 2-arm trial in which anthracycline-based polychemotherapy is compared to an anthracycline/docetaxel-based regimen; (3) 4-arm trial in which 2 different concepts are under evaluation: the role of docetaxel and the comparison between different anthracycline/docetaxel-based regimens, in which the 2 drugs are administered either in combination or sequentially; (4) translational research prospective trials aiming to identify a specific subgroup of patients deriving the largest benefit from the use of docetaxel. While it is expected that these trials will show the superiority of the docetaxel-based treatment, it is also anticipated that the benefit related to the use of docetaxel will not be of the same magnitude in all patients. For this reason, it will be extremely important to identify subgroups of patients deriving the highest benefit from the use of docetaxel. In the past few years, substantial progress has been made in the area of molecular biology, and several molecular markers that could predict the efficacy of docetaxel have been identified. The p53 gene mutations seem to be the most promising predictive markers because preclinical data suggest that taxane-induced apoptosis is p53 independent. Other molecular markers of potential interest are the microtubule-associated parameters, which might confer different degrees of sensitivity to a docetaxel-based therapy, depending on the pattern of expression.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Dose-Response Relationship, Drug; Doxorubicin; Europe; Female; Genes, p53; Humans; Multicenter Studies as Topic; Paclitaxel; Randomized Controlled Trials as Topic; Taxoids

The use of systemic adjuvant therapy in women with early-stage breast cancer has been demonstrated to have a profound impact on survival. The role of paclitaxel and docetaxel in the adjuvant setting has attracted a great deal of attention. Both of these agents are highly active in patients with advanced breast cancer. In addition, they can be utilized in combination with anthracyclines, which have been shown to provide a slightly better outcome in patients with early-stage breast cancer compared to non-anthracycline-containing regimens. Randomized trials have demonstrated a potential role for paclitaxel in adjuvant chemotherapy. In the Cancer and Leukemia Group B 9344 trial, which explored the use of doxorubicin and cyclophosphamide with or without paclitaxel, the initial analysis demonstrated a 22% reduction in the relative risk of relapse and a 26% reduction in the relative risk of death in the paclitaxel group. However, a clear role for the use of paclitaxel in adjuvant therapy remains to be defined. The Breast Cancer International Research Group trial 001 compared the combination of docetaxel/doxorubicin/cyclophosphamide to 5-fluorouracil/doxorubicin/cyclophosphamide. This trial demonstrated a promising reduction in the relative risk of recurrence of 32% for the docetaxel/doxorubicin/cyclophosphamide group. Ongoing trials will help to further define the role of taxanes in the adjuvant setting for patients with operable breast cancer.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Multicenter Studies as Topic; Paclitaxel; Randomized Controlled Trials as Topic; Risk Factors; Taxoids; Trastuzumab; United States

The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20-30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Resistance, Neoplasm; Europe; Female; Humans; Neoplasm Metastasis; Patient Care Planning; Salvage Therapy; Taxoids

The clinical utility of capecitabine as a single agent in metastatic breast cancer has been demonstrated with significant responses seen in women already treated with anthracyclines and taxanes. A phase II study in older women with metastatic breast cancer demonstrated capecitabine to be an effective front-line therapeutic agent. Clinical trials of capecitabine in combination with the taxanes, paclitaxel and docetaxel, have been based on the observed upregulation of thymidine phosphorylase (TP) in preclinical studies. This taxane-mediated upregulation is synergistic, time dependent, and persists for up to 10 days. Studies of taxanes administered every 3 weeks with capecitabine have shown favorable antitumor responses and the combination of a taxane with capecitabine was favored over a taxane alone. The day-to-day administration of taxanes and capecitabine led to toxicity concerns, which have hindered their daily use. The administration of taxanes on a weekly schedule has demonstrated a more favorable toxicity profile (i.e., less myelosuppression), and initial studies in combination with capecitabine have demonstrated their utility in various solid tumors. Schedule optimization based on the upregulation of TP may result in a greater therapeutic index, thus allowing for the determination of the most advantageous way of combining these agents.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Docetaxel; Drug Administration Schedule; Drug Synergism; Fluorouracil; Humans; Paclitaxel; Survival Analysis; Taxoids; Thymidine Phosphorylase; Treatment Outcome; Up-Regulation

Gemcitabine (2',2'-difluorodeoxycytidine) is a pyrimidine antimetabolite with broad activity in a variety of solid tumors including breast cancer. Pemetrexed (Alimta) is a novel, multitargeted antifolate that inhibits 3 folate-dependent enzymes, and is also broadly active in a wide variety of solid tumors. In breast cancer, pemetrexed has activity in patients previously treated with anthracyclines and taxanes, and pemetrexed demonstrates preclinical and clinical cytotoxic synergy with gemcitabine. This drug combination is being evaluated in a phase II study for the treatment of metastatic breast cancer patients who have previously received a taxane and an anthracycline.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase II as Topic; Deoxycytidine; Drug Synergism; Female; Gemcitabine; Glutamates; Guanine; Humans; Pemetrexed; Taxoids; Treatment Failure; Treatment Outcome

The combination of gemcitabine and cisplatin has proven effective as first-line chemotherapy for patients with breast cancer, inducing a response rate of 80% in one phase II study. Five additional studies in intensively pretreated breast cancer patients demonstrated a median response rate of 43% (range, 26%-50%). The toxicity profile was moderate, with thrombocytopenia and neutropenia as the main side effects. The gemcitabine/ cisplatin combination, therefore, offers a tolerable and effective treatment option, particularly for patients whose disease progressed after treatment with anthracyclines and/or taxanes.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Clinical Trials, Phase II as Topic; Deoxycytidine; Female; Gemcitabine; Humans; Neoplasm Metastasis; Taxoids; Trastuzumab; Treatment Failure; Treatment Outcome

More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Neoplasm Metastasis; Platinum Compounds; Practice Guidelines as Topic; Taxoids; Trastuzumab; Vinca Alkaloids

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m(2), while paclitaxel was significantly inferior to doxorubicin 75 mg/m(2) over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Taxoids

The proven benefits of adjuvant chemotherapy on disease-free and overall survival in breast cancer can be explained by concepts of cell kill. Interventions which result in greater log kill can be expected to produce improved clinical results. The application of log-kill concepts to human breast cancer growth, which appears to follow Gompertzian kinetics, suggests not only that the use of non-cross-resistant drugs is important, but that dose-dense schedules may have an advantage over conventional schedules of drug administration. Sequential therapy may allow dose-dense administration of cytotoxic agents and encourage the integration of new biological agents into combination regimens, particularly with the taxanes. Ongoing trials in these concepts are reviewed.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Taxoids; Treatment Outcome

Doxorubicin/paclitaxel (Taxol) combinations are very active in advanced breast cancer, with objective response rates up to 90%, but have shown a high incidence of cardiotoxicity. A phase I/II trial replacing doxorubicin with epirubicin (Ellence), a less cardiotoxic analog, produced an objective response rate of 84%, but with a low rate of cardiotoxicity. A careful cardiac monitoring in more than 100 patients treated with this combination has demonstrated that the risk of congestive heart failure is below 10% up to a cumulative epirubicin dose of 990 mg/m2. To examine the possibility that the pharmacokinetic and pharmacodynamic interactions that occur when anthracycline and paclitaxel are administered together might result in subadditive antitumor activity, a phase III study is comparing concomitant vs sequential administration of epirubicin and paclitaxel in patients with advanced breast cancer. A phase I/II study of epirubicin plus docetaxel as first-line chemotherapy for advanced breast cancer patients evaluated the maximum tolerated doses and for subsequent studies recommended epirubicin at 75 mg/m2 plus docetaxel at 80 mg/m2. In the adjuvant setting, an ongoing phase III trial is comparing epirubicin plus paclitaxel vs FEC (fluorouracil, epirubicin, and cyclophosphamide [Cytoxan, Neosar]) in node-positive patients. Preliminary data confirm the cardiac safety of these treatments.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Drug Therapy, Combination; Epirubicin; Female; Humans; Italy; Meta-Analysis as Topic; Paclitaxel; Taxoids

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Estramustine; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

The 1990s have seen the emergence of several classes of new efficacious drugs which have become established as treatment for breast cancer. Thus, aromatase inhibitors, taxanes and herceptin have all emerged as potentially valuable therapeutic agents for treatment of advanced breast cancer. Bisphosphonates have found a place in preventing skeletal complications in breast cancer patients with bone metastasis. Tamoxifen has a new role in chemoprevention in patients at high risk of breast cancer. This paper summarises these results.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cholesterol; Clinical Trials as Topic; Diphosphonates; Estrogens; Female; Guidelines as Topic; Humans; Neoplasm Metastasis; Postmenopause; Receptors, Estrogen; Tamoxifen; Taxoids; Trastuzumab

HER2 is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinases and is involved in the growth, invasion, metastasis, and prognosis of breast cancer. The rationale for prospective trials evaluating the role of anti-HER2 monoclonal antibody therapy for patients with high-risk HER2-positive resected breast cancer is based on several factors. These include 1) the relative and absolute poor prognosis of patients with node-positive, HER2-positive breast cancer; 2) the emerging data of potential importance concerning anthracyclines as a component of adjuvant therapy for patients with HER2-positive breast cancer; 3) the role of taxanes in the management of patients with HER2-positive metastatic breast cancer; and 4) the feasibility and efficacy of molecularly targeted anti-HER2 monoclonal antibody treatment alone or in combination with chemotherapy for patients with advanced breast cancer.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Lymphatic Metastasis; Prognosis; Receptor, ErbB-2; Risk Factors; Taxoids

Substantial progress has been made in the multidisciplinary management of primary breast cancer during the last 30 years. Adjuvant chemotherapy has been shown to significantly reduce the annual risk of cancer recurrence and mortality, and these effects persist even 15 years after diagnosis. Combination chemotherapy is superior to single-agent therapy and anthracycline-containing regimens. Those that combine an anthracycline with 5-fluorouracil and cyclophosphamide are more effective than regimens without an anthracycline. Six cycles of a single regimen appear to provide optimal benefit. Dose reductions below the standard range are associated with inferior results. Dose increases that require growth factor or hematopoietic stem cell support are under investigation; at this time, the existing results provide no compelling reason to use this strategy outside a clinical trial. Regimens using fixed crossover designs with two non-cross-resistant regimens are being evaluated. The addition of a taxane to anthracycline-containing regimens is currently under intense scrutiny, and preliminary analysis of the first three clinical trials has shown encouraging, albeit not compelling, results. For patients with estrogen receptor-positive breast cancer, the sequential administration of chemotherapy and 5 years of tamoxifen therapy provides additive benefits. No compelling evidence exists to combine ovarian ablation with chemotherapy. Most side effects and toxic effects are self-limited, although premature menopause requires monitoring and preventive interventions to preserve bone mineral density. The small risk of acute leukemia is of concern, and additional research to develop safer regimens is clearly indicated. The overall effect of optimal local/regional treatment combined with an anthracycline-containing adjuvant chemotherapy and a taxane (and, for patients with estrogen receptor-positive tumors, 5 years of tamoxifen therapy) is a greater than 50% reduction in annual risks of recurrence of and death from breast cancer. For most patients at intermediate or high risk of cancer recurrence, the benefits of adjuvant chemotherapy exceed by far its unwanted effects.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Synergism; Hormones; Humans; Taxoids; Time Factors; Treatment Outcome

Breast cancer is relatively sensitive to chemotherapy. However, although response rate to chemotherapy is reported to be from 50 to 70% in metastatic breast cancer, it is incurable. Current standard chemotherapeutic regimens do not provide a large survival benefit according to the evidence obtained from clinical studies. Before developing a treatment program, we should therefore realize that the aims of chemotherapy for metastatic breast cancer are improvement of quality of life through relief of symptoms, and prolonging survival.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Evidence-Based Medicine; Female; Humans; Meta-Analysis as Topic; Neoplasm Metastasis; Quality of Life; Taxoids

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Paclitaxel; Premedication; Taxoids; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Docetaxel; Doxorubicin; Female; Fluorouracil; Humans; Methotrexate; Paclitaxel; Practice Guidelines as Topic; Prognosis; Taxoids

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Taxoids

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early-or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin-cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Female; Genes, erbB-2; Humans; Infusions, Intravenous; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome

Although it has been shown that adequate local therapy of primary breast cancer decreases the risk of distant failure and death due to the disease, treatment results with local therapy alone are clearly inadequate with c. 30-40% of patients developing a disease recurrence within the first ten years after primary diagnosis. In the past 10-15 years there has been significant progress in the field of systemic adjuvant therapy of breast cancer. It is now reliably established that the concept is valid; that is, that early treatment with either cytotoxic chemotherapy or endocrine therapy does result in improved survival compared with treatment deferred until relapse. Despite considerable progress, several controversial issues remain. These include the optimal timing and sequencing of treatment, optimal drug doses, and the role of new drugs such as taxanes and new endocrine agents. The identification of more powerful prognostic and/or predictive tests might have substantial clinical implications but major breakthroughs in this field of research are still to come. A relatively new and important issue in clinical decision-making regarding the use of different adjuvant therapies is long-term toxicity such as leukemia with some types of chemotherapy and endometrial cancer (and possibly other malignancies) with long-term tamoxifen. Further progress in the field of adjuvant therapy of breast cancer continues to rely on well-designed, prospective, controlled clinical trials and overviews of such studies.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Castration; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Humans; Leukemia; Prognosis; Tamoxifen; Taxoids

The promising activity of taxanes in advanced breast cancer patients has prompted the investigators to explore their role in the adjuvant setting. Methodological issues, still unsolved pharmacokinetic and pharmacodynamic problems, and potential severe toxicities could jeopardize these attractive regimens and should be taken into account in the design and interpretation of adjuvant trials. In order to minimize the methodological drawbacks, the potential role of taxanes in the adjuvant setting should be assessed in clinical trials powered to detect an absolute survival increase of near 7% at 10 years. The use of paclitaxel in combination with anthracyclines is complicated by pharmacokinetic interactions which may be responsible for unexpected side effects and/or subadditive cytotoxicity. Moreover, possible interactions between taxanes and tamoxifen are still unclear, and therefore more data are necessary before recommending the combined use of the two drugs in the adjuvant setting. Nowadays, the majority of breast cancer patients receive conservative surgery followed by radiotherapy; when adjuvant taxanes are used, radiotherapy should be delayed because of their radiosensitization effect, with potential detrimental effects. Finally, the majority of side effects of taxane-containing regimens are short-lasting and reversible, but other potential toxicities, such as the cardiotoxicity and long-term possible sequelae of the use of high-dose steroids, need long-term evaluation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Tamoxifen; Taxoids

The taxanes paclitaxel and docetaxel are the prototype drugs of a new class of anticancer drugs that exploits a completely new mechanism of action. Their testing in metastatic breast cancer has been extensive. The results indicating very high response rate with either taxane have given rise to an unprecedented effort in the scientific community to define their optimal application in all stages of the disease. In metastatic breast cancer, initial data suggest that paclitaxel may increase the survival obtained with standard combinations such as CMFP, and similarly promising studies of docetaxel are almost complete. Significant therapeutic benefit has also been observed by the addition of sequential paclitaxel after adjuvant doxorubicin plus cyclophosphamide in operable breast cancer. Overall, more than 20 randomized studies with paclitaxel or docetaxel, either as single agents or in combination, are ongoing or planned in women with high-risk operable breast cancer. This massive effort is mainly based on empirical study designs. However, some preclinical characteristics of the taxanes, such as their increased antitumor effect in tumors overexpressing HER2/neu, the preclinical and clinical evidence of potential synergism with monoclonal antibodies directed against the HER2 receptor, and preclinical evidence of antiangiogenic properties should be pursued to test whether the use of taxanes in breast cancer could be tailored to individual tumor characteristics rather than following the usual pattern of indiscriminate application.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Genes, erbB-2; Humans; Neoadjuvant Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Patient Selection; Taxoids

The introduction of new drugs may offer significant hope for improvement in the treatment of breast cancer. They include new cytotoxic agents such as Taxanes, Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory metastatic breast cancer and new bisphosphonates for those who have metastases to bone. Therefore, some reports evaluating such new drugs were reviewed. Japanese studies revealed response rate of Taxanes in the treatment of metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72 (44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%) with 5 CR were observed in phase II study of Fadrozol but results from the phase II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan. However, any european reports did not show a difference in response rate in patients with tamoxifen refractory breast cancer between newer aromatase inhibitor and megasterol, and a good choice of hormones in the treatment of metastatic breast cancer appears to be difficult.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclophosphamide; Diphosphonates; Drug Resistance, Multiple; Female; Humans; Ibandronic Acid; Imidazoles; Letrozole; Nitriles; Tamoxifen; Taxoids; Triazoles; Zoledronic Acid

Metastatic disease in women who have undergone appropriate local therapy remains the leading ultimate cause of death in breast cancer. Therapy for overt metastatic disease is unlikely to offer curative potential for any but a small proportion of patients. Therapy for micrometastatic disease is offered in the hope that patients with a smaller tumor burden will be more amenable to cure. This report will examine the extent to which this hope has been fulfilled and discuss the future of adjuvant therapy. The initial adjuvant therapy trials used chemotherapy to treat women with lymph node-positive breast cancer. These trials clearly demonstrated a disease-free and overall survival benefit for women receiving combination chemotherapy in the adjuvant setting. These benefits were subsequently extended to women with lymph node-negative disease, and (in the form of adjuvant hormonal therapy) to women with steroid receptor-positive breast cancer. Current adjuvant therapy clearly improves disease-free and overall survival in patients with micrometastatic disease. It is less clear whether these improvements translate to a "cure" in the sense of total elimination of micrometastatic disease. Numerous questions remain to be answered regarding the dose intensity of chemotherapy, the appropriate sequencing of chemotherapy agents, and the use of novel chemotherapy agents, such as the taxanes. These and other questions are the subject of ongoing clinical trials.

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Forecasting; Humans; Lymphatic Metastasis; Neoplasm Staging; Survival Rate; Taxoids

The systemic management of patients with hormone-refractory breast cancer metastatic to sites beyond regional axillary lymph nodes is classically characterized by the thoughtful, step-wise administration of cytotoxic chemotherapeutic agents. At various junctures in the continuum of care, a patient/physician analysis of the potential risks and benefits of chemotherapy may lead to the decision to proceed with subsequent systemic therapy, to consider an investigational strategy, or to opt for supportive care alone. The emergence of new active agents such as the taxanes has provided a valuable alternative option for such patients. While other cytotoxic agents in development may ultimately prove useful in the management of stage IV breast cancer, including some with novel antineoplastic mechanisms, there is evidence for optimism that the ability to perturb autocrine and paracrine growth factor pathways (eg, with monoclonal antibodies) may afford a viable alternative systemic approach, perhaps with a greater therapeutic index than "conventional" agents. Throughout the process of drug development, an increasing focus on the impact of new systemic regimens on quality of life, and costs associated with the palliative care of metastatic breast cancer should optimize the care of women with this disease.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Continuity of Patient Care; Costs and Cost Analysis; Decision Making; Drug Design; Female; Growth Inhibitors; Humans; Lymphatic Metastasis; Neoplasm Staging; Palliative Care; Quality of Life; Risk Assessment; Taxoids

The taxanes paclitaxel and docetaxel are undergoing extensive evaluation in women with breast cancer in the United States and in Europe. Their dose-limiting toxicity is neutropenia. Paclitaxel also causes peripheral neuropathy, while docetaxel can cause unpredictable and severe skin toxicity, as well as edema and effusions due to a capillary leak syndrome. Due to threshold pharmacodynamics and nonlinear pharmacokinetics, tolerability of paclitaxel is schedule dependent. Single-agent paclitaxel was very active in multiple phase II trials in patients with different numbers and types of prior chemotherapy and disease extent (20% to 60% complete plus partial responses). Effective doses ranged from 135 to 250 mg/m2. Activity was observed with all infusion schedules (1, 3, and 24 hours) and in women with anthracycline-resistant tumors (25% to 38%). The use of a 96-hour infusion schedule was very active in anthracycline-refractory patients (48%) and in women who failed short infusion taxanes. The drug is undergoing extensive evaluation in combination with doxorubicin, cyclophosphamide, cisplatin, and antimetabolites. Very promising efficacy was observed for paclitaxel by 3-hour infusion plus bolus doxorubicin (approximately 40% complete responses and 50% partial responses). The combination also caused a high incidence of clinically reversible congestive heart failure(14% to 18%). Docetaxel also has very good efficacy in breast cancer, with approximately 70% major responses in untreated patients and more than 50% in anthracycline-resistant tumors. There is no evidence that efficacy and tolerability are schedule dependent as is the case for paclitaxel. At recommended doses (100 or 75 mg/m2 by 1-hour infusion every 3 weeks), docetaxel causes a fluid retention syndrome that may affect quality of life. Its common onset after multiple cycles may limit the use of docetaxel for palliation in metastatic breast cancer. These results clearly indicate that the taxanes will become a standard component of initial chemotherapy for women with breast cancer. The definition of their actual role still requires an answer to the unresolved questions of their optimal dose and combination with other anticancer agents. Most importantly, the drugs should be prospectively evaluated in a randomized study using comparable doses and schedules to assess which of the two has the better therapeutic index in breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase II as Topic; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Humans; Paclitaxel; Prospective Studies; Randomized Controlled Trials as Topic; Remission Induction; Taxoids

Based on the results of randomized clinical trials as multi-center studies in patients with advanced recurrent breast cancer, we discussed the future direction of chemotherapy for breast cancer and node 4 conclusions: 1) Concerning the combination of endocrine therapy and chemotherapy, ACT therapy with ADM, CPA, and tamoxifen seemed to be appropriate as the standard therapy. 2) Concerning the chemotherapy period, continuous administration seemed to be more standard than intermittent administration in terms of the QOL of patients. 3) There are limits in chemotherapy that increases the dose intensity by combination with G-CSF or bone marrow transplantation to overcome drug resistance and achieve a cure. However, the effectiveness of this method can be expected in selected patients in the future. 4) There are new promising drugs for chemotherapy such as taxanes. These drugs are expected to contribute to the development of treatment methods. From these aspects, we discussed the future direction of chemotherapy in clinical treatment and studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cyclophosphamide; Doxorubicin; Drug Therapy; Female; Humans; Randomized Controlled Trials as Topic; Tamoxifen; Taxoids

This study investigated whether there are pharmacogenomic markers predictive of chemotherapy induced peripheral neuropathy (CIPN) as a result of taxane-based chemotherapy.. Patients were enrolled from August 2020 to November 2020 in a prospective, case-control trial evaluating pharmacogenetic predictors of CIPN. All women were treated with at least 3 cycles of taxane-based chemotherapy for histologically confirmed gynecologic malignancies. Buccal saliva samples were used to test for 32 drug metabolism variations. All testing was performed by ⍺LPHA-GENOMIX laboratories. Fisher's Exact test was used to assess for event differences of categorical variables.. Of 102 enrolled patients, 58%, 28%, and 14% had ovarian, endometrial, or cervical cancers, respectively. The median age was 67, 72% were Caucasian and 25% were African American. 16% of patients were treated with 3-4 cycles, 57% received 5-7 cycles, and 27% received 8 or more cycles of chemotherapy that included paclitaxel. Grade 2 CIPN was experienced by 51 patients. There was no difference in age, race, disease site, or number of chemotherapy cycles (p > 0.05) between those who did or did not develop CIPN. CYP2D6 genotype (p = 0.009) and CYP3A5 genotype (p = 0.023) had different frequencies among those with and without CIPN. Patients classified as having poor or intermediate function of CYP2D6 had increased risk of CIPN (OR 1.63, 95% CI 1.04-2.57, p = 0.026). There was no difference in CYP2D6 phenotype by race (p = 0.29). No patients with normal function of CYP3A5 developed CIPN. There were no Caucasians with normal function of CYP3A5, but 28% of African Americans had normal CYP3A5 function (p < 0.001).. Pharmacogenomics appear associated with the development of CIPN and may be able to help personalize treatment decision making.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Case-Control Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Genital Neoplasms, Female; Humans; Peripheral Nervous System Diseases; Pharmacogenetics; Prospective Studies; Taxoids

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of taxane treatment and can significantly affect patient quality of life. Currently, there are no effective treatments to alleviate symptoms of CIPN; thus, starting with prevention steps in high-risk patients is considered advantageous. However, for these prevention steps to be applicable to all patients, their side effects or accompanying discomforts should be minimal, and the intervention cost-effective. Compression therapy can be considered a prevention intervention, and using surgical gloves is feasible and cost-effective (approximately $0.6 per pair). Although previous studies on compression therapy using surgical gloves have reported decreased incidence of PN, these studies were non-randomized, limited to nab-paclitaxel treatment, and involved the use of small gloves, which may have caused discomfort. Therefore, this study aimed to assess the preventive effects of compression therapy using normal-sized surgical gloves on CIPN in patients treated with paclitaxel.. This clinical trial is designed to evaluate the preventive effects of compression therapy using surgical gloves on CIPN in women with stage II-III breast cancer who received paclitaxel chemotherapy for at least 12 weeks. This multicenter, randomized-controlled, open-label study will be conducted in six academic hospitals. Patients with medication or a medical history related to neuropathy or hand disease will be excluded. The primary outcome will be the preventive effect of compression therapy using surgical gloves, measured based on changes in the neurotoxicity component of the Functional Assessment of Cancer Therapy-Taxane questionnaire. Furthermore, we will assess the National Cancer Institute's Common Terminology Criteria for Adverse Events grade of CIPN after 6 months. Notably, the estimated sample size, based on a p-value < 0.025 and statistical power of 0.9, will consist of 104 patients (52 per group), accounting for a 10% sample loss.. This intervention can be easily implemented in clinical practice and may serve as a preventive strategy for CIPNs with strong patient adherence. If successful, this intervention could improve the quality of life and treatment adherence in patients receiving chemotherapy that can induce PN, extending beyond paclitaxel treatment alone.. ClinicalTrials.gov, NCT05771974; Registered on March 16, 2023.

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Gloves, Surgical; Humans; Paclitaxel; Peripheral Nervous System Diseases; Quality of Life; Taxoids

To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel).. Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score).. Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea.. Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID.. Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Docetaxel; Female; Humans; Paclitaxel; Quality of Life; Receptor, ErbB-2; Taxoids; Trastuzumab

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Genome-Wide Association Study; Humans; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; Quality of Life; Taxoids

The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC.. In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative.. A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%).. Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Furans; Humans; Ketones; Neoadjuvant Therapy; Prospective Studies; Receptor, ErbB-2; Taxoids; Treatment Outcome

Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques.. POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed.. This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy.. ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979.

Topics: Anthracyclines; Antineoplastic Agents; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Dose Fractionation, Radiation; Female; Humans; Lymphatic Irradiation; Lymphatic Metastasis; Mastectomy; Postoperative Care; Prospective Studies; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Conformal; Taxoids; Tomography, X-Ray Computed

The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.. MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.. Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]).. With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.. European Commission Sixth Framework Programme.

Topics: Adolescent; Adult; Age Factors; Aged; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Transcriptome; Treatment Outcome; Young Adult

Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect.. A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival.. From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1-22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%-59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5-11.6).. The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.

Topics: Ado-Trastuzumab Emtansine; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Maximum Tolerated Dose; Middle Aged; Piperazines; Pyridines; Taxoids; Trastuzumab

Chemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy.. Female patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis.. Thirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events.. A combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.

Topics: Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chloroquine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Staging; Taxoids

The purpose of this study was to provide a rationale for "chemotherapy-periodized" exercise by characterizing cyclical variations in fatigue and exercise response across a chemotherapy cycle and comparing exercise adherence during chemotherapy between a prescription that is periodized according to chemotherapy cycle length and a standard linearly progressed prescription.. Women with breast cancer who were prescribed taxane-based chemotherapy were randomly assigned to a supervised aerobic and resistance exercise program after a chemotherapy-periodized exercise prescription (n = 12) or to usual care during chemotherapy (n = 15). Fatigue and steady state exercise responses were assessed in both groups before the first taxane treatment and across the third treatment (i.e., 0-3 d prior and 3-5 d after the third treatment, and 0-3 d before the fourth treatment) to assess cyclical variations. Adherence to the chemotherapy-periodized exercise prescription was compared with adherence to a standard linear prescription from a prior study in a similar population (n = 51).. Fatigue increased from baseline (marginal mean ± standard error: 3.2 ± 0.4) to before the third treatment (4.1 ± 0.4, P = 0.025), then peaked at 3 to 5 d after the third treatment (5.1 ± 0.4, P = 0.001), before recovering before the fourth treatment (4.3 ± 0.5, P = 0.021). The peak in fatigue at 3 to 5 d post-third treatment corresponded to a decrease in steady state exercise oxygen consumption (V˙O2) (P = 0.013). Compared with a standard linear exercise prescription during chemotherapy, a chemotherapy-periodized exercise prescription resulted in higher attendance during the week after chemotherapy (57% ± 30% vs 77% ± 28%, P = 0.04) and overall attendance (63% + 25% vs 78% ± 23%, P = 0.05).. Fatigue and exercise V˙O2 vary across a chemotherapy cycle. A chemotherapy-periodized exercise prescription that accommodates cyclical variations in fatigue may increase adherence to supervised exercise.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Exercise Therapy; Fatigue; Female; Humans; Middle Aged; Patient Compliance; Resistance Training; Taxoids; Time Factors

A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit.. To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone.. In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019.. The adjuvant chemotherapy regimen was selected by the treating physician.. Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]).. Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%).. The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.. ClinicalTrials.gov identifier: NCT00310180.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Female; Fluorouracil; Humans; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Taxoids; Treatment Outcome; Young Adult

Randomized controlled trials (RCT) of scalp cooling (SC) to prevent chemotherapy induced alopecia (CIA) did not evaluate its effect on hair regrowth (HR) and was conducted in a predominantly taxane (T) treated population. We conducted an RCT of SC in a setting of anthracycline (A) and taxane chemotherapy (CT) and assessed its effect on CIA and HR.. Non-metastatic breast cancer women undergoing (neo) adjuvant CT were randomized to receive SC using the Paxman scalp cooling system during every cycle of CT, or no SC. The primary end point (PEP) was successful hair preservation (HP) assessed clinically and by review of photographs after CT. HR was assessed at 6 and 12 weeks.. 51 patients were randomized to SC (34) or control arm (17) in a 2:1 ratio. Twenty-five (49%) patients received A followed by T and the two arms were balanced with respect to this factor. HP rate was significantly higher in SC arm compared to control arm (56.3% vs 0%, P = 0.000004). HR was higher in SC arm compared to control at 6 weeks (89% vs 12%; P < 0.001) and 12 weeks (100% vs 59%, P = 0.0003). Loss of hair at PEP evaluation, which was a quality of life measure, was significantly lower in SC versus control arm (45% vs 82%, P = 0.016). There were no grade 3-4 cold related adverse effects.. Women with breast cancer receiving A or T chemotherapy receiving SC were significantly more likely to have less than 50% hair loss after CT, superior hair regrowth and improvement in patient reported outcomes, with acceptable tolerance. It merits wider usage.

Topics: Adult; Alopecia; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cryotherapy; Female; Humans; Middle Aged; Patient Reported Outcome Measures; Quality of Life; Scalp; Taxoids; Treatment Outcome; Young Adult

Taxane-induced peripheral neuropathy (TIPN) is a main toxicity of taxanes with no effective treatment. This study aimed to compare the efficacy and safety of pregabalin (150 mg daily) and duloxetine (60 mg daily) for managing TIPN in breast cancer patients.. This randomized, double-blind, Phase II clinical trial was carried out at a chemotherapy center affiliated to Mazandaran University of Medical Sciences. Patients with breast cancer who received paclitaxel or docetaxel and had a grade 1 or more neuropathy (based on the National Cancer Institute Common Terminology Criteria for Adverse Events version (NCI-CTCAE v4.03), and who had score 4 or higher neuropathic pain severity [based on the visual analog scale (VAS)] were enrolled. Response to treatment was assessed based on improvements in the VAS, NCI-CTCAE, and Patient Neurotoxicity Questionnaire (PNQ) scores during a 6-week trial.. Both interventions were effective in decreasing TIPN compared to baseline. At Week 6, the VAS scores were improved in 37/40 (92.5%) and 16/42 (38.1%) of the patients in the pregabalin and duloxetine groups, respectively (p < 0.001). Improvement in NCI-CTCAE sensory neuropathy was also more significant with pregabalin (37/40; 92.5%) in comparison to duloxetine (13/42; 31%) (p < 0.001). Pregabalin was also more beneficial than duloxetine in improving the PNQ scores by 36/40 (90%) and 13/42 (31%), respectively (p < 0.001). Both interventions were tolerated well with mild adverse events.. Both pregabalin and duloxetine were well tolerated and efficacious in relieving neuropathic pain, however a 60 mg dose of duloxetine is inferior to a 150 mg dose of pregabalin.

Topics: Adult; Analgesics; Breast Neoplasms; Bridged-Ring Compounds; Double-Blind Method; Duloxetine Hydrochloride; Female; Humans; Middle Aged; Neuralgia; Pregabalin; Surveys and Questionnaires; Taxoids; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Exercise Therapy; Female; Follow-Up Studies; Humans; Middle Aged; Neuralgia; Neurological Rehabilitation; Outcome Assessment, Health Care; Peripheral Nervous System Diseases; Single-Blind Method; Taxoids

Women with residual invasive breast cancer at the primary site or axillary lymph nodes following neoadjuvant chemotherapy have a high risk of recurrence. Eribulin improves survival in patients with metastatic breast cancer who progress after anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of postoperative eribulin in breast cancer patients who did not achieve a pCR following standard neoadjuvant chemotherapy.. Women with localized breast cancer who had residual invasive cancer following ≥ 4 cycles of standard anthracycline and/or taxane-containing neoadjuvant chemotherapy received adjuvant eribulin treatment. HER2-positive patients also received trastuzumab for 1 year. Adjuvant hormonal therapy and locoregional radiotherapy were administered as per institutional guidelines. Primary endpoint was the 2-year DFS rate. Three patient cohorts were analyzed: TNBC (Cohort A), HR+/HER2- (Cohort B), and HER2+ (Cohort C).. One hundred twenty-six patients (Cohort A-53, Cohort B-42, and Cohort C-31) were enrolled. Neoadjuvant chemotherapy included a taxane and an anthracycline in 70%. Eribulin was well tolerated; 84% of patients received the planned 6 cycles. After a median follow-up of 28 months, the 24-month DFS rates were 56% (95% CI 42, 69), 83% (95% CI 67, 91), and 73% (95% CI 53, 86) for Cohorts A, B, and C, respectively. The most common grade 3/4 treatment-related adverse events were neutropenia (26%), leukopenia (13%), and neuropathy (7%).. Administration of adjuvant eribulin after neoadjuvant chemotherapy was feasible and well tolerated. The 24-month DFS rate did not reach the study target levels in any of the cohorts and was similar to DFS previously described in these cohorts following neoadjuvant chemotherapy alone.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cohort Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Furans; Humans; Ketones; Middle Aged; Neoadjuvant Therapy; Non-Randomized Controlled Trials as Topic; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Taxoids; Trastuzumab

Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer.. We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer RESULTS: Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + ( OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P < .0001). However, according to time-dependent Cox model that was used to reduce guarantee-time bias, CIA was not a statistically significant prognostic factor in both ER-positive and ER-negative patients.. Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings.

Topics: Adult; Amenorrhea; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Incidence; Lymphatic Metastasis; Mastectomy; Middle Aged; Paclitaxel; Premenopause; Prognosis; Prospective Studies; Receptors, Estrogen; Retrospective Studies; Taxoids; Young Adult

Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, there is no biological rationale that justifies this current standard of care. We compared a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting.. In a randomized, open-label, single-center phase II trial, women with inoperable, locally advanced, HER2-negative breast cancer were stratified by hormone receptor status and randomized to three cycles of docetaxel (T) followed by three cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus three cycles of FAC followed by three cycles of docetaxel. Surgery, radiotherapy, and adjuvant hormonal therapy were administered as per local guidelines. The primary endpoint was pathological complete response (pCR), and secondary endpoints included toxicity, event-free survival (EFS), and overall survival (OS).. Treatment sequence did not improve pCR, which was 7% with T-FAC and 3% with FAC-T. However, after a median follow-up of 79 months, the 5-year EFS rate was 75.7% (95% confidence interval [CI], 65.4%-87.7%) with T-FAC and 48.2% (95% CI, 37.0%-62.7%) with FAC-T (hazard ratio [HR], 0.46; 95% CI, 0.26-0.81; log-rank p = .0054), and the 5-year OS rate was 89.7% (95% CI, 82.2%-97.8%) with T-FAC and 64.7% (95% CI, 53.6%-78.1%) with FAC-T (HR, 0.41; 95% CI, 0.22-0.78; p = .0052). There were no unexpected toxicities.. We showed for the first time an improvement in EFS and OS with taxane-first compared with anthracycline-first sequencing chemotherapy in HER2-negative, locally advanced breast cancer. Confirmation of these results may have implications for clinical practice. This trial was registered with Clinicatrials.gov identifier NCT01270373.. The NeoSAMBA trial showed a benefit for taxane-first sequencing chemotherapy consistent with the systematic review of the literature as well as the larger Neo-tAnGo study. Many recent and current ongoing clinical trials have already followed this treatment strategy. As a taxane-before-anthracycline sequence carries neither an incremental cost nor an increased toxicity, and given the available literature on this issue, reinforced that taxane-first regimen can be easily incorporated into daily clinical practice while awaiting confirmation of these findings from larger trials.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Female; Humans; Taxoids

Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial.. To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents.. Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.. Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.. Pathologic complete response and 3-year EFS and DRFS.. Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.. The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.. ClinicalTrials.gov Identifier: NCT01042379.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Progression-Free Survival; Proportional Hazards Models; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.. We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data.. From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1).. The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.. Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients.. We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day -1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided.. In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001).. The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Gangliosides; Humans; N-Acetylneuraminic Acid; Neuroprotective Agents; Peripheral Nervous System Diseases; Taxoids

We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC).. A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS.. There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea.. Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Drug Administration Schedule; Female; Humans; Irinotecan; Middle Aged; Progression-Free Survival; Quality of Life; Taxoids; Treatment Outcome

Aim To compare the effect of neoadjuvant chemotherapy based on taxane and/or anthracycline to the extent of an objective response in female patients with unresectable breast cancer with evaluation of the toxic profile of applied chemotherapy. Methods One hundred patients with histologically verified breast cancer, treated with neoadjuvant chemotherapy were divided into two groups: a study group A (50 patients), who had received 4 to 6 cycles of taxane-based chemotherapy, and control group B (50 patients), who had received 4 to 6 cycles of anthracyclines-based chemotherapy. Pathohistological response was evaluated after tumour excision and axillary resection at the end of chemotherapy and it was defined as pathologic complete (pCR), partial (pPR), or no response (pNR). Toxic effects were evaluated and quantified by the Common Terminology Criteria for Adverse Events v4.0. Results After neoadjuvant chemotherapy, 8% of patients in the group A achieved pCR, 54% achieved pPR, while 38% of patients had no tumour response to applied chemotherapy. In the group B pCR was achieved in 6%, pPR in 42% of patients, while 51% of patients were pNR to the administered chemotherapy. Significant reduction of tumour mass was achieved in the group of patients treated with taxanes: 20.00 (7.75-30.25) vs. 13.50 (6.00-25.00) mm (p=0.024). Toxicity of chemotherapy in group A and group B was within the limits of grade 2. Conclusion The addition of taxane to anthracycline-based neoadjuvant chemotherapy in patients with breast cancer resulted in a significant reduction in tumour mass compared to the group of patients treated with anthracyclines, but without increasing the overall side effects.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoadjuvant Therapy; Taxoids; Treatment Outcome

Eribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors.. Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin.. The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia.. Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.

Topics: Adult; Aged; Aged, 80 and over; Antimitotic Agents; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Treatment Outcome; Young Adult

Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.. In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).. Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).. Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.. NCT01572038.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Receptor, ErbB-2; Survival Rate; Taxoids; Trastuzumab; Young Adult

In high-risk early breast cancer, adjuvant taxane-Gemcitabine combinations result in a recurrence-free survival similar to single-agent taxanes. However, haematologic toxicities and need for dose reductions are more frequent in combinations. Which option ultimately provides a better quality of life (QoL) is unknown. We compared the QoL curves before, during, and up to one year after three cycles of Fluorouracil-epirubicin-cyclophosphamide followed by three cycles of Docetaxel-Gemcitabine or Docetaxel.. Overall, 3691 women with recent R0-resection of a primary epithelial breast cancer participated in the nationwide SUCCESS A clinical trial. The centres sent QoL questionnaires of the European Organisation for Research and Treatment of Cancer before and up to 15 months after randomisation to Docetaxel-Gemcitabine versus Docetaxel. Multilevel analysis by chemotherapy arm estimated the QoL time curves, questionnaire return, and dropout.. The combination caused one-point higher global QoL (95% confidence ±1; p = 0.05) and 1.1 lower odds of adherence to the outcome (95% confidence 1.0-1.1; p = 0.23) than the monotherapy. In both groups, a 10-point decrease during therapy preceded a 16-point increase after chemotherapy (p < 0.001). The secondary QoL outcomes showed transient superiority of the combination at the end of chemotherapy. Discontinuation from chemotherapy and its reasons were equal in both groups.. While patients perceive a one-point QoL difference as meaningless, a six-point increase is clinically relevant for them. That is, both regimens cause the same relevant long-term QoL improvement. With the similar recurrence-free survival, the lower toxicity, and the shorter chemotherapy duration in mind, taxanes without Gemcitabine are the preference. This challenges previous recommendations supporting combinations.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Deoxycytidine; Female; Gemcitabine; Humans; Middle Aged; Patient Compliance; Quality of Life; Survival Analysis; Taxoids; Treatment Outcome; Young Adult

To evaluate and compare the efficacy and safety of the taxane plus anthracycline (TA) regimen vs. the taxane plus anthracycline plus cyclophosphamide (TAC) regimen as adjuvant chemotherapy in Chinese patients with node-positive breast cancer (BCa).. Patients with BCa (n = 640) were recruited between January 2010 and June 2012. All patients were randomized to receive six cycles of adjuvant therapy with the TA or TAC regimen. The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS), quality of life (QoL), and chemotherapy-related toxicity. Finally, 630 patients were evaluable, with a median follow-up of 70 months.. There were no differences in the 70-month median DFS and OS between the two groups (DFS: TA 79.7% vs. TAC 75.6%, P = 0.371; OS: TA vs. TAC, 85.1% vs. 87.6%, P = 0.271). The TA group had lower frequencies grade III/IV vomiting (TA vs. TAC, 11.7% vs. 18.1%, P = 0.025) and nausea (13.0% vs. 19.4%, P = 0.031). The health-related QoL score was higher in the TA group (74.1 ± 5.3 vs. 67.9 ± 4.4, P = 0.001 vs. TAC).. In the adjuvant setting, compared with the TAC regimen, the TA regimen exhibits no significant difference with respect to DFS and OS in Chinese patients with node-positive BCa. On the other hand, TA is associated with less severe adverse events, lower economic burden, and better QoL.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; China; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Middle Aged; Quality of Life; Taxoids; Treatment Outcome

The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting.. In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed.. Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers).. In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing.. Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Maytansine; Membrane Proteins; Mutation; Prognosis; PTEN Phosphohydrolase; Receptor, ErbB-2; Receptor, ErbB-3; RNA, Messenger; Survival Analysis; Taxoids; Trastuzumab

To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial.. Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis.. The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness.. First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Combinations; Female; Fluorouracil; Health Status; Humans; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Patient Reported Outcome Measures; Quality of Life; Surveys and Questionnaires; Taxoids; Tegafur

Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms.. Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness.. Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076).. Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients.. Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov .

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Exercise Therapy; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Organoplatinum Compounds; Peripheral Nervous System Diseases; Taxoids; Vinca Alkaloids

The current experimental study aimed to evaluate the effectiveness of reflexology on the management of symptoms and functions of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients.. This study was conducted as a randomized controlled trial in 60 patients (30 experimental and 30 control patients) who had chemotherapy-induced Grade II-IV peripheral neuropathy complaints from July 2013 to November 2015. Data were collected using the patient identification form, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-CIPN-20) form, and BPI (used for related chemotherapy-induced peripheral neuropathy symptoms).. The majority of the patients were being treated for gastrointestinal or breast cancer and were primarily receiving Eloxatine- or taxane-based treatment. It was found that reflexology applications did not lead to differences in either group in terms of peripheral neuropathy severity and incidence (p > 0.05) and only led to improvement in sensory functions in the experimental group (p < 0.05).. It was determined that reflexology is not an effective method in the management of patients' activity levels, walking ability etc. and motor, autonomic functions related CIPN, but reflexology is effective method in the management of patients' sensory functions related CIPN. Key Words: Peripheral neuropathy, reflexology, chemotherapy, EORTC QLQ-CIPN-20, BPI.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Pilot Projects; Quality of Life; Reflexotherapy; Surveys and Questionnaires; Taxoids

The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy.. The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon's two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively.. The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60-91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13-46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases.. Eighty percent of HR-negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2-targeted therapy during the taxane phase only of sequential taxane-anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2-targeted therapies combined with chemotherapy in the neoadjuvant setting.

Topics: Adult; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug-Related Side Effects and Adverse Reactions; Epirubicin; Female; Fluorouracil; Humans; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Receptor, ErbB-2; Taxoids; Trastuzumab

Capecitabine is an approved standard therapy for anthracycline- and taxane-pretreated locally advanced or metastatic breast cancer (BC). Vinflunine has demonstrated single-agent activity in phase II studies in this setting and activity and tolerability when combined with capecitabine. We compared the combination of vinflunine plus capecitabine (VC) with single-agent capecitabine.. Patients with locally recurrent/metastatic BC previously treated or resistant to an anthracycline and resistant to taxane therapy were randomly assigned to either vinflunine (280 mg/m2, day 1) plus oral capecitabine [825 mg/m2 twice daily (b.i.d.), days 1-14] every 3 weeks (q3w) or single-agent oral capecitabine (1250 mg/m2 b.i.d., days 1-14) q3w. The primary end point was progression-free survival (PFS) assessed by an independent review committee. The study had 90% power to detect a 30% improvement in PFS.. Overall, 770 patients were randomised. PFS was significantly longer with VC than with capecitabine alone [hazard ratio, 0.84, 95% confidence interval (CI), 0.71-0.99; log-rank P = 0.043; median 5.6 versus 4.3 months, respectively]. Median overall survival was 13.9 versus 11.7 months with VC versus capecitabine alone, respectively (hazard ratio, 0.98; 95% CI, 0.83-1.15; log-rank P = 0.77). No difference in quality of life was observed between the two treatment arms. The most common adverse events (NCI CTCAE version 3.0) in the combination arm were haematological and gastrointestinal. Grade 4 neutropenia was more frequent with VC (12% versus 1% with capecitabine alone); febrile neutropenia occurred in 2% versus 0.5%, respectively. Hand-foot syndrome was less frequent with VC (grade 3: 4% versus 19% for capecitabine alone). Peripheral neuropathy was uncommon in both arms (grade 3: 1% versus 0.3%).. Vinflunine combined with capecitabine demonstrated a modest improvement in PFS and an acceptable safety profile compared with capecitabine alone in patients with anthracycline- and taxane-pretreated locally recurrent/metastatic BC.. NCT01095003.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Chemotherapy-Induced Febrile Neutropenia; Drug Resistance, Neoplasm; Female; Hand-Foot Syndrome; Humans; Middle Aged; Neoplasm Recurrence, Local; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Progression-Free Survival; Quality of Life; Survival Analysis; Taxoids; Vinblastine

Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC.. Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan-Meier method.. Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months.. The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Kaplan-Meier Estimate; Maximum Tolerated Dose; Maytansine; Middle Aged; Neoplasm Staging; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Retreatment; Taxoids; Thiazoles; Trastuzumab; Treatment Outcome

Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy.. HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety.. A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001).. This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.. EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cardiotoxicity; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Mastectomy; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Receptor, ErbB-2; Taxoids; Time Factors; Trastuzumab

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Docetaxel; Doxorubicin; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Mastectomy; Middle Aged; Prospective Studies; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial.. EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m. Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months [95% CI 26·3-34·1] vs 25·9 months [95% CI 22·7-28·3]; hazard ratio 0·75 [95% CI 0·64-0·88]). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months [IQR 19·5-26·1]). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 [49%] of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 [48%] of 490) than with capecitabine plus lapatinib control treatment (291 [60%] of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 [21%] of 488 patients) followed by palmar-plantar erythrodysaesthesia syndrome (87 [18%]), and vomiting (24 [5%]). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 [14%] of 490), increased aspartate aminotransferase levels (22 [5%]), and anaemia (19 [4%]). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group [coronary artery disease and multiorgan failure] and three in the trastuzumab emtansine group [metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia]).. This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population.. F Hoffmann-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Anemia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Capecitabine; Diarrhea; Disease-Free Survival; Female; Hand-Foot Syndrome; Humans; Lapatinib; Male; Maytansine; Middle Aged; Quinazolines; Receptor, ErbB-2; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab; Vomiting; Young Adult

In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.. Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.. Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4-27·5] vs 15·8 months [13·5-18·7]; hazard ratio 0·68 [95% CI 0·54-0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).. In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.. F Hoffman-La Roche/Genentech.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Chemotherapy-Induced Febrile Neutropenia; Diarrhea; Early Termination of Clinical Trials; Female; Hemorrhage; Humans; Lapatinib; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Neutropenia; Practice Patterns, Physicians'; Quinazolines; Receptor, ErbB-2; Retreatment; Survival Rate; Taxoids; Thrombocytopenia; Trastuzumab

Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status.. Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%).. The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Topics: Administration, Oral; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Diarrhea; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Hand-Foot Syndrome; Humans; Hypertension; Kaplan-Meier Estimate; Middle Aged; Niacinamide; Phenylurea Compounds; Placebos; Receptor, ErbB-2; Sorafenib; Taxoids; Treatment Outcome

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship.. Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C. An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C

Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Maytansine; Middle Aged; Receptor, ErbB-2; Taxoids; Trastuzumab

Hormone receptor-positive (HR+) tumors have heterogeneous biology and present a challenge for determining optimal treatment. In the Neoadjuvant Breast Registry Symphony Trial (NBRST) patients were classified according to MammaPrint/BluePrint subtyping to provide insight into the response to neoadjuvant endocrine therapy (NET) or neoadjuvant chemotherapy (NCT).. The purpose of this predefined substudy was to compare MammaPrint/BluePrint with conventional 'clinical' immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) subtyping in 'clinical luminal' [HR+/human epidermal growth factor receptor 2-negative (HER2-)] breast cancer patients to predict treatment sensitivity.. NBRST IHC/FISH HR+/HER2- breast cancer patients (n = 474) were classified into four molecular subgroups by MammaPrint/BluePrint subtyping: Luminal A, Luminal B, HER2, and Basal type. Pathological complete response (pCR) rates were compared with conventional IHC/FISH subtype.. The overall pCR rate for 'clinical luminal' patients to NCT was 11 %; however, 87 of these 474 patients were reclassified as Basal type by BluePrint, with a high pCR rate of 32 %. The MammaPrint index was highly associated with the likelihood of pCR (p < 0.001). Fifty-three patients with BluePrint Luminal tumors received NET with an aromatase inhibitor and 36 (68 %) had a clinical response.. With BluePrint subtyping, 18 % of clinical 'luminal' patients are classified in a different subgroup, compared with conventional assessment, and these patients have a significantly higher response rate to NCT compared with BluePrint Luminal patients. MammaPrint/BluePrint subtyping can help allocate effective treatment to appropriate patients. In addition, accurate identification of subtype biology is important in the interpretation of neoadjuvant treatment response since lack of pCR in luminal patients does not portend the worse prognosis associated with residual disease in Basal and HER2 subtypes.

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Decision-Making; Cyclophosphamide; Docetaxel; Doxorubicin; Female; Gene Expression Profiling; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Letrozole; Mastectomy, Segmental; Middle Aged; Molecular Typing; Neoadjuvant Therapy; Nitriles; Prospective Studies; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Registries; Tamoxifen; Taxoids; Treatment Outcome; Triazoles; Young Adult

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Tolerance; Female; Humans; Maytansine; Middle Aged; Quality of Life; Random Allocation; Receptor, ErbB-2; Taxoids; Trastuzumab

Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial.. To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects.. Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized.. Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device.. The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale.. At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events.. Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects.. clinicaltrials.gov Identifier: NCT01986140.

Topics: Adult; Aged; Alopecia; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Early Termination of Clinical Trials; Female; Humans; Hypothermia, Induced; Middle Aged; Primary Prevention; Quality of Life; Scalp; Taxoids

The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial.. A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted.. In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained.. According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Cost-Benefit Analysis; Disease Progression; Docetaxel; Female; Health Resources; Humans; Kaplan-Meier Estimate; Netherlands; Paclitaxel; Quality-Adjusted Life Years; Receptor, ErbB-2; Taxoids

To evaluate the safest timing of pegfilgrastim administration in dose-dense anthracycline- and taxane-based chemotherapy, three different cohorts of patients enrolled in the Gruppo Italiano Mammella (GIM) 2 study and treated at the coordinating center received pegfilgrastim 24 h (cohort A) or 72 h (cohort B) or 96 h (cohort C) after chemotherapy.. A total of 41 patients were included. The safety of pegfilgrastim administration in terms of occurrence of early and late leukocytosis and the behavior of white blood cells (WBC) counts in the three cohorts across all chemotherapy cycles were evaluated. Anthracycline and taxane cycles were analyzed separately.. The occurrence of early leukocytosis was a more common event in patients in cohort A in both anthracycline and taxane cycles (75 and 66.7%) as compared to cohort B (50 and 60%) and cohort C (66.7 and 33.3%). More patients in cohort C developed late leukocytosis in both anthracycline and taxane cycles (50 and 100%) as compared to cohort A (0 and 66.7%) and cohort B (35.7 and 86.7%). Patients in cohort A experienced the highest median value of WBC count 24 h after pegfilgrastim administration in both anthracycline and taxane cycles (61.2 × 10(3)/μl and 67.8 × 10(3)/μl). Patients in cohort C experienced the highest median value of WBC count at day 13 in both anthracycline and taxane cycles (19.4 × 10(3)/μl and 24.2 × 10(3)/μl).. For the prevention of leukocytosis, the safest timing of pegfilgrastim administration based on WBC count in dose-dense anthracycline- and taxane-based regimens seems to be 72 h after chemotherapy.. This study is registered with https://clinicaltrials.gov/ct2/show/NCT00433420.

Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Drug Administration Schedule; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Italy; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Risk Factors; Taxoids; Time Factors

To investigate the effect of electro-acupuncture (EA) as a non-pharmacological intervention to prevent or reduce chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients undergoing chemotherapy of taxane. Women with stage I-III breast cancer scheduled to receive taxane therapy were randomized to receive a standardized protocol of 12 true or sham EA (SEA) weekly treatments concurrent with taxane treatment. Subjects completed the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Taxane neurotoxicity subscale (FACT-NTX), and other assessments at baseline and weeks 6, 12, and 16. A total of 180 subjects were screened, 63 enrolled and 48 completed week 16 assessments. Mean age was 50 with 25 % white, 25 % black, and 43 % Hispanic; 52 % had no prior chemotherapy. At week 12, both groups reported an increase in mean BPI-SF worst pain score, but no mean differences were found between groups (SEA 2.8 vs. EA 2.6, P = .86). By week 16, the SEA group returned to baseline, while the EA group continued to worsen (SEA 1.7 vs. EA 3.4, P = .03). The increase in BPI-SF worst pain score was 1.62 points higher in the EA group than in the SEA group at week 16 (P = .04). In a randomized, sham-controlled trial of EA for prevention of taxane-induced CIPN, there were no differences in pain or neuropathy between groups at week 12. Of concern, subjects on EA had a slower recovery than SEA subjects. Future studies should focus on EA for treatment as opposed to prevention of CIPN.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Double-Blind Method; Electroacupuncture; Female; Humans; Middle Aged; Peripheral Nervous System Diseases; Pilot Projects; Taxoids; Treatment Outcome

Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes.. Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype.. Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) <14 %) and 22 as luminal B (Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype.. It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Female; Humans; Kaplan-Meier Estimate; Ki-67 Antigen; Middle Aged; Neoadjuvant Therapy; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Taxoids; Treatment Outcome

Metastatic breast cancer (MBC) remains an incurable disease despite major therapeutic advances. Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) has been established to have anti-proliferative effects against breast cancer cells in preclinical experiments, and is indicated for treatment of cancer in China. We performed a phase II trial combining PA-MSHA with capecitabine in patients with heavily pretreated MBC.. Eligibility criteria included human epidermal growth factor receptor 2-negative MBC, prior therapy with anthracyclines and taxanes, at least one prior chemotherapy regimen for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. PA-MSHA 1 mg was administered subcutaneously every other day and capecitabine 1000 mg/m2 orally twice a day for 2 weeks on, 1 week off. The primary end point was progression-free survival.. A total of 97 patients were enrolled. Median progression-free survival (PFS) was 4.0 months [95 % confidence interval (CI) 3.0-4.9], which was not significantly different from that in historical controls. However, median PFS was significantly longer (8.2 months; 95 % CI 6.7-9.7) in 24 patients with moderate immune-related adverse events (irAEs) such as fever or skin induration at the injection site than in those with no or mild irAEs (3.1 months, 95 % CI 2.5-3.6; p = 0.003). Overall survival was also improved in these patients (25.4 vs. 16.4 months; p = 0.044). PA-MSHA has a good safety profile, with only 6 patients (6.2 %) discontinuing treatment. PA-MSHA did not increase capecitabine-related toxicities such as hand-foot syndrome, nausea, and vomiting.. Adding PA-MSHA to capecitabine has a good safety profile in patients with heavily pre-treated MBC, although benefit from this regimen might occur only in patients with moderate PA-MSHA-related adverse events.. ClinicalTrials.gov NCT01380808.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Female; Hemagglutinins; Humans; Mannose; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Pseudomonas aeruginosa; Receptor, ErbB-2; Safety; Salvage Therapy; Taxoids; Young Adult

The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown.. The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors.. From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03).. As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Drug Eruptions; Female; Follow-Up Studies; Humans; International Cooperation; Kaplan-Meier Estimate; Lapatinib; Middle Aged; Neoplasm Staging; Patient Selection; Quality of Life; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Anthracycline and taxane are classes of drugs that are frequently used in the adjuvant and palliative settings of metastatic breast cancer (MBC); however, treatment failure occurs in most cases. Limited data demonstrated favorable response in MBC after previous taxane-based treatment. The aim of this study was to evaluate the efficacy and safety of pegylated liposomal doxorubicin (Lipo-Dox®) used as part of a combination salvage therapy for patients with MBC whose tumors progressed during or after taxane-based treatment.. Patients with MBC who failed to respond to previous taxane-based treatments were recruited. Treatment with pegylated liposomal doxorubicin (40 mg/m(2)), cyclophosphamide (500 mg/m(2)), and 5-fluorouracil (500 mg/m(2)) was administered every 3 weeks. Tumor response to treatment was determined by using the Response Evaluation Criteria in Solid Tumor criteria version 1.0, and left ventricular ejection fraction was measured before and after treatment using echocardiography. Each patient was followed for 30 days after the last dose of study medication or until resolution/stabilization of any drug-related adverse event.. Forty-five patients were recruited. As of December 2012, the median follow-up duration was 29.8 months, the overall response rate was 41.9 %, the median progression-free survival was 8.2 months, and the median overall survival was 36.6 months for all treated patients. Grade 3/4 neutropenia, leucopenia, and neutropenic fever were observed in 14 %, 9 %, and 1 % of the cycles, respectively. Other non-hematologic adverse effects were mild to moderate and were manageable. No decrease in left ventricular ejection function was noted.. This regimen of combined of pegylated liposomal doxorubicin, cyclophosphamide, and 5-fluorouracil exhibited a promising overall response rate, progression-free survival rate, and overall survival rate, with a safe cardiac toxicity profile and manageable adverse effects. This regimen could be considered as a treatment option for patients with MBC whose tumors progressed during or after taxane-based treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Polyethylene Glycols; Retreatment; Salvage Therapy; Survival Analysis; Taxoids; Treatment Outcome

New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.. In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101.. Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock).. This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients.. Nektar Therapeutics.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Middle Aged; Neoplasm Staging; Physicians; Polyethylene Glycols; Taxoids

Observational studies suggest that physical activity after a breast cancer diagnosis is associated with improved cancer outcomes; however, no randomized data are available. Here, we report an exploratory follow-up of cancer outcomes from the Supervised Trial of Aerobic versus Resistance Training (START).. The START was a Canadian multicenter trial that randomized 242 breast cancer patients between 2003 and 2005 to usual care (n = 82), supervised aerobic (n = 78), or resistance (n = 82) exercise during chemotherapy. The primary end point for this exploratory analysis was disease-free survival (DFS). Secondary end points were overall survival, distant DFS, and recurrence-free interval. The two exercise arms were combined for analysis (n = 160), and selected subgroups were explored.. After a median follow-up of 89 months, there were 25/160 (15.6%) DFS events in the exercise groups and 18/82 (22.0%) in the control group. Eight-year DFS was 82.7% for the exercise groups compared with 75.6% for the control group (HR, 0.68; 95% confidence interval (CI), 0.37-1.24; log-rank, P = 0.21). Slightly stronger effects were observed for overall survival (HR, 0.60; 95% CI, 0.27-1.33; log-rank, P = 0.21), distant DFS (HR, 0.62; 95% CI, 0.32-1.19; log-rank, P = 0.15), and recurrence-free interval (HR, 0.58; 95% CI, 0.30-1.11; Gray test, P = 0.095). Subgroup analyses suggested potentially stronger exercise effects on DFS for women who were overweight/obese (HR, 0.59; 95% CI, 0.27-1.27), had stage II/III cancer (HR, 0.61; 95% CI, 0.31-1.20), estrogen receptor-positive tumors (HR, 0.58; 95% CI, 0.26-1.29), human epidermal growth factor receptor 2-positive tumors (HR, 0.21; 95% CI, 0.04-1.02), received taxane-based chemotherapies (HR, 0.46; 95% CI, 0.19-1.15), and ≥85% of their planned chemotherapy (HR, 0.50; 95% CI, 0.25-1.01).. This exploratory follow-up of the START provides the first randomized data to suggest that adding exercise to standard chemotherapy may improve breast cancer outcomes. A definitive phase III trial is warranted.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Exercise Therapy; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Staging; Obesity; Receptors, Estrogen; Resistance Training; Survival Rate; Taxoids; Treatment Outcome

To evaluate diffusion changes in the breast tumor-stromal boundary and adjacent tissue in response to neoadjuvant chemotherapy using high resolution diffusion-weighted imaging (HR-DWI).. Seven patients with invasive breast cancer were imaged with HR-DWI before and early during treatment. The mean apparent diffusion coefficient (ADC) was plotted in 1-mm increments around the tumor boundary. Early change in ADC was measured for tumor, tumor boundary, and stromal regions, and the relationship to treatment response was evaluated using Spearman's correlation.. Statistically significant correlations between treatment response and early changes in ADC were found for: (i) whole tumor (ρ = 0.93, 95% confidence interval [CI] = (0.58, 0.99), P = 0.003); (ii) tumor rim (ρ = 0.75, 95% CI = (-0.007, 0.96), P = 0.05); and (iii) boundary transition region (ρ = 0.86, 95% CI = (0.29, 0.98), P = 0.01). Early change in ADC of distal stroma had a marginally statistically significant positive correlation to treatment response (ρ = 0.71, 95% CI = (-0.084, 0.95), P = 0.07).. Proximity-dependent evaluation of HR-DWI data in the breast tumor-stromal boundary and adjacent tissue may provide information about response to therapy.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Diffusion Magnetic Resonance Imaging; Doxorubicin; Female; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Neoplasm Invasiveness; Pilot Projects; Reproducibility of Results; Sensitivity and Specificity; Taxoids; Treatment Outcome

The TACT trial (CRUK/01/001) compared adjuvant sequential FEC-docetaxel (FEC-D) chemotherapy with standard anthracycline-based chemotherapy of similar duration in women with early breast cancer. Results at a median of 5 years suggested no improvement in disease-free survival with FEC-D. Given differing toxicity profiles of the regimens, the impact on quality of life (QL) was explored.. Patients from 44 centres completed standardised QL questionnaires before chemotherapy, after cycles 4 and 8, at 9, 12, 18 and 24 months and at 6 years follow-up. Patient diaries assessed frequency, associated distress and impact on daily activity of 15 treatment related side effects.. 830 patients (415 FEC-D; 415 controls) contributed assessments during 0-24 months; 362 of whom participated again at 6 years. During chemotherapy, FEC-D impaired global health/QL and depression rates and significantly more QL domains than standard regimens. Novel diary card ratings highlighted significantly more distress and interference with daily activities due to FEC-D side effects compared with standard treatment. In both groups, most QL parameters returned to baseline levels by 2 years and were unchanged at 6 years.. Within expected negative effects of chemotherapy on wide ranging QL domains FEC-D patients reported greater toxicity, disruption and distress during treatment with no improvement in disease outcome at 5 years than patients receiving standard anthracycline-based chemotherapy. Findings should inform future patients of relative costs and benefits of adjuvant chemotherapy.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Epirubicin; Female; Fluorouracil; Humans; Methotrexate; Middle Aged; Quality of Life; Surveys and Questionnaires; Tamoxifen; Taxoids; Therapeutics; United Kingdom

Gross cystic disease fluid protein 15 (GCDFP-15), which is regulated by the androgen receptor (AR), is a diagnostic marker for mammary differentiation in histopathology. We determined the expression of GCDFP-15 in breast cancer subtypes, its potential prognostic and predictive value, as well as its relationship to AR expression.. 602 pre-therapeutic breast cancer core biopsies from the phase III randomized neoadjuvant GeparTrio trial (NCT00544765) were investigated for GCDFP-15 expression by immunohistochemistry. Expression data were correlated with disease-free (DFS) and overall survival (OS) time as well as pathological complete response (pCR) to neoadjuvant chemotherapy.. 239 tumors (39.7%) were GCDFP-15 positive. GCDFP-15 expression was positively linked to hormone receptor (HR) and HER2 positive tumor type, while most triple negative carcinomas were negative (p < 0.0001). GCDFP-15 was also strongly correlated to AR expression (p 0.001), and to the so-called molecular apocrine subtype (HR-/AR+, p < 0.0001). Higher rates of GCDFP-15 positivity were seen in tumors of lower grade (<0.0001) and negative nodal status (p = 0.008). GCDFP-15 positive tumors tended to have a more favourable prognosis than GCDFP-15 negative tumors (DFS (p = 0.052) and OS (p = 0.044)), which was not independent from other factors in multivariate analysis. GCDFP-15 expression was not linked to pCR. Histological apocrine differentiation was frequent in molecular apocrine carcinomas (60.7%), and was associated with GCDFP-15 within this group (p = 0.039).. GCDFP-15 expression is higher in tumors with favorable prognostic features. GCDFP-15 expression is further a frequent feature of AR positive tumors and the molecular apocrine subtype. It might have reduced sensitivity as a diagnostic marker for mammary differentiation in triple negative tumors as compared to HR or HER2 positive tumor types.

Topics: Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Carrier Proteins; Female; Glycoproteins; Humans; Membrane Transport Proteins; Neoadjuvant Therapy; Prognosis; Receptor, ErbB-2; Receptors, Androgen; Survival Analysis; Taxoids; Treatment Outcome

We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea.. This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m(2) gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m(2) capecitabine orally twice daily on days 1-14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen.. Of 41 patients, the ORR was 39.0% (CR 0%; PR 39.0%), and DCR was 78.0% using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8%, respectively. Median PFS was 10.0 months [95% confidence interval (CI) 7.8-12.1], and median OS was 25.1 months (95% CI 18.2-32.1). Prominent toxicities were neutropenia and hand-foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95% CI 0.034-0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95% CI 0.017-0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination.. This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Fluorouracil; Gemcitabine; Hand-Foot Syndrome; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Republic of Korea; Severity of Illness Index; Taxoids; Treatment Outcome

The international phase IIIb study, ATHENA assessed the combination of bevacizumab/taxane-based chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (mBC) in real-life setting. Among the 365 patients included in France, median overall survival (OS) is 28.4 months (CI95% 24.8-33.0), with a median time from treatment start to end of study of 36,5 months (25,1-45,4). Exploratory analyses in three sub-groups show that the median OS in long responder patients (not progressing for at least one year; n = 116) is not reached. In responder patients (n = 308), median OS is 33.0 months (CI95% 28.6-37.4) and 12.4 months (CI95% 11.2-17.4) in non-responders (n = 41). In patients with mBC expressing hormone receptors (HR+), treated with first-line hormone therapy before inclusion (n = 87) median OS in is 23.2 months (CI95% 19.6-28.6), and 35.3 months (CI95% 32.2-not reached); P = 0.004 in patients treated first with chemotherapy + bevacizumab (n = 179). The safety analysis in the various sub-groups of grade 3-5 adverse events of particular interest to bevacizumab of this study was comparable to the safety data of randomized phase III studies.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; France; Humans; Middle Aged; Receptor, ErbB-2; Survival Analysis; Taxoids; Time Factors; Vascular Endothelial Growth Factor A

Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or treatment of physician's choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m(2) b.i.d. on days 1-14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio [HR] 0.85; 95% CI 0.77, 0.95; P = 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82; P = 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids

Pemetrexed-carboplatin and gemcitabine‑vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m², D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m² D1, D8 i.v. q21; vinorelbine 30 mg/m² D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Gemcitabine; Glutamates; Guanine; Humans; Middle Aged; Neoplasm Staging; Pemetrexed; Taxoids; Vinblastine; Vinorelbine

This study was designed to determine (1) rates of clinically meaningful tumor reduction in breast tumor size following neoadjuvant chemotherapy (NAC), (2) which receptor subtypes and MRI phenotypes are associated with clinically meaningful tumor reduction, and (3) whether MRI phenotype impacts concordance between pathologic and MRI size.. We analyzed data from the I-SPY TRIAL, a multicenter, prospective NAC trial. Reduction in tumor size from >4 to ≤4 cm was considered clinically meaningful, as crossing this threshold was considered a reasonable cutoff for potential breast conservation therapy (BCT). MRI phenotypes were scored between one (well-defined) and five (diffuse) on pre-NAC MRIs.. Of 174 patients with tumors >4 cm, 141 (81%) had clinically meaningful tumor reduction. Response to therapy varied by MRI phenotype (p = 0.003), with well-defined phenotypes more likely than diffuse phenotypes to have clinically meaningful tumor shrinkage (91 vs. 72%, p = 0.037). Her2+ and triple-negative (Tneg) tumors had the highest rate of clinically meaningful tumor reduction (p = 0.005). The concordance between tumor diameter on MRI and surgical pathology was highest for Her2+ and Tneg tumors, especially among tumors with solid imaging phenotypes (p = 0.004).. NAC allows most patients with large breast tumors to have clinically meaningful tumor reduction, meaning response that would impact ability to undergo BCT. However, response varies by imaging and tumor subtypes. Concordance between tumor size on MRI and surgical pathology was higher in well-defined tumors, especially those with a Tneg subtype, and lower in HR+ diffuse tumors.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Trastuzumab

We conducted a prospective observational study for premenopausal women receiving adjuvant adriamycin and cyclophosphamide-containing regimens to define the pattern of chemotherapy-induced amenorrhea (CIA), the menopause-specific quality of life (MENQOL), and the hormone profiles.. From October 2003 to July 2007, 387 patients with breast cancer who underwent curative surgery were prospectively included. Patient self-assessment by MENQOL questionnaires and blood samples for hormone assays were taken before chemotherapy, and 1, 6, and 12 months after chemotherapy was completed.. Patients were categorized into three groups according to their duration and reversibility of amenorrhea, with 312 eligible patients split into long-term CIA (n = 180, 57.7 %), temporary CIA (n = 113, 36.2 %), and menstrual irregularity (n = 19, 6.1 %) groups. Risk factors for long-term CIA were identified as age ≥40 years (p < 0.001), the addition of taxane (p = 0.01), and tamoxifen use (p = 0.03). MENQOL was worst immediately after the completion of adjuvant chemotherapy, and this was not fully recovered even 12 months after chemotherapy had finished. Age ≥40 years and tamoxifen exposure were inversely associated with MENQOL. In long-term CIA patients, the level of follicle-stimulating hormone increased after chemotherapy; this level, however, was reduced in patients who received tamoxifen, but remained high and stable in those who did not (p < 0.001 at 6 months; p < 0.001 at 12 months).. This study showed that most premenopausal breast cancer patients who received adjuvant chemotherapy experienced clinically significant CIA, followed by impaired MENQOL. Our findings may be relevant in the decision-making processes for premenopausal women with breast cancer.

Topics: Adult; Age Factors; Amenorrhea; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cohort Studies; Cyclophosphamide; Doxorubicin; Female; Humans; Middle Aged; Premenopause; Prospective Studies; Quality of Life; Risk Factors; Surveys and Questionnaires; Tamoxifen; Taxoids; Time Factors

This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Carbonic Anhydrases; Chemotherapy, Adjuvant; Estrogen Receptor alpha; Female; Humans; Membrane Proteins; Middle Aged; Neoadjuvant Therapy; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Receptors, Estrogen; RNA; tau Proteins; Taxoids; Transcriptome; Treatment Outcome

We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT.. The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher.. Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11).. Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Lymphocytes; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Receptor, ErbB-2; Taxoids

To evaluate the efficacy and tolerability of combined treatment with irinotecan (I) and capecitabine (X), we conducted a phase II study of the IX combination in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC). Patients received 80 mg/m(2) I on days 1 and 8 and 1,000 mg/m(2) X twice daily on days 1-14 of 21-day cycles until disease progression. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Thirty-six patients were enrolled between September 2006 and April 2008. The median follow-up was 47.6 months. The ORR was 58.3 % (95 % CI, 42.2-72.9), with 3 complete responses and 18 partial responses. The median PFS was 7.6 months (95 % CI, 5.0-10.2), and the median OS was 20.0 months (95 % CI, 11.6-28.4). Neutropenia was the most common adverse event (grade 3, 30.6 %; grade 4, 27.8 %) with febrile neutropenia in 2 patients (5.6 %). Three patients (8.3 %) had grade 3 diarrhea, 3 patients (8.3 %) had grade 3 asthenia, and 1 patient (2.8 %) had grade 3 hand-foot syndrome. The IX combination was effective and tolerable for anthracycline- and taxane-pretreated patients with MBC. A phase III trial of this combination is ongoing.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Camptothecin; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Irinotecan; Middle Aged; Taxoids; Treatment Outcome

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor. TSU-68 demonstrated a strong anti-tumor effect against established human breast cancer xenografts in nude mice without apparent toxicity. We conducted a phase II study to evaluate the efficacy and safety of TSU-68 monotherapy in patients with metastatic breast cancer progressing despite prior treatment with an anthracycline-containing regimen and taxane.. TSU-68 was administered daily at a dose of 400 mg twice a day after meals in 20 patients. The primary endpoint was objective overall response rate according to the Response Evaluation Criteria in Solid Tumors guideline version 1.0. Secondary endpoints included clinical benefit rate (complete response, partial response and stable disease lasting for at least 24 weeks), exploratory assessments of change in mRNA levels of biological markers associated with angiogenesis in tumor tissue at the end of Cycle 1, and safety of TSU-68.. Twenty patients were enrolled into the study from October 2002 through April 2003. TSU-68 monotherapy produced objective overall response in none of the patients; however, clinical benefit was seen in 5 % of the patients. The mRNA levels of CD31, Flt-1 and Flk-1/KDR showed a decreasing trend in all 4 patients who provided additional written informed consent for collection of tumor tissue. However, no significant difference was observed in the change in mRNA level due to the small sample size. The most common adverse drug reaction (ADR) was tumor pain (60 %); hematological ADRs rarely occurred, and they were mild in severity. Only one patient experienced grade 2 rash and no patient experienced hypertension. No patients experienced a grade 4 ADR and no episode of death related to the study treatment occurred in the 20 patients.. TSU-68 monotherapy produced clinical benefit in only 5 % of the patients and did not produce objective overall response; however, the treatment was well tolerated. Further evaluation of the efficacy of TSU-68 will be worthwhile because the mRNA levels of CD31, Flt-1 and Flk-1/KDR decreased in 4 patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Drug Administration Schedule; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Middle Aged; Neovascularization, Pathologic; Oxindoles; Propionates; Protein Kinase Inhibitors; Pyrroles; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor A

Oral administration of cyclophosphamide (CTX) and capecitabine may have a greater potential for treatment of metastatic breast cancer (MBC) due to anti-angiogenesis resulting from the metronomic dosage and upregulation of thymidine phosphorylase by CTX. The purpose of this phase II study was to evaluate the efficacy and safety profile of an all-oral combination of metronomic CTX plus capecitabine for women with anthracycline- and taxane-pretreated MBC.. In this prospective single-center, open-label, phase II trial, patients with measurable disease received oral metronomic CTX 65 mg/m(2) daily on days 1-14 plus capecitabine 1,000 mg/m(2) twice daily on days 1-14. The treatment was repeated every 3 weeks, and continued until disease progression, unacceptable toxicity or withdrawal of informed consent. The primary endpoint of the study was time to progression (TTP).. A total of 68 patients were enrolled and received 537 cycles of chemotherapy with a median of 8 cycles (range: 1-30 cycles) per patient. Sixty-six patients were evaluated for efficacy with all patients for toxicity. With a median follow-up time of 26 months, the median time to progression was 5.2 months (95% CI, 4.2-6.2 months), and the median overall survival was 16.9 months. The overall response rate was 30.3% (95% CI, 20-43%). Clinical benefit rate was 53.0% (95% CI, 38-62%). The doublet was well tolerable, with anorexia (7.5%), the only grade 3/4 adverse events occurring in more than 5% of patients. Grade 3 hand-foot syndrome was 4.4%.. The all-oral combination of metronomic CTX plus capecitabine is an effective and convenient and well-tolerated regimen for MBC. (ClinicalTrials.gov number, NCT00589901).

Topics: Administration, Oral; Adult; Aged; Anorexia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Hand-Foot Syndrome; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Prospective Studies; Taxoids; Treatment Outcome

We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy.. In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554.. Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group.. This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy.. GlaxoSmithKline, Roche, and Sanofi-Aventis.

Topics: Aged; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Lapatinib; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab; Young Adult

Three randomised trials have demonstrated that combining bevacizumab with first-line chemotherapy significantly improves progression-free survival versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). However, data from Chinese populations are limited and possible differences between ethnic and geographic populations are unknown. This study was conducted to determine whether there are differences in safety and efficacy in patients with HER2-negative LR/mRC between Chinese and Western populations after they receive first-line bevacizumab combined with taxane-based therapy.. In the single-arm, open-label, Avastin Therapy for Advanced Breast Cancer (ATHENA) study (NCT00448591), patients with HER2-negative LR/mBC received first-line bevacizumab (investigator's choice of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) combined with taxane-based therapy. The primary endpoint was safety profile and the secondary is time to progression (TTP). A subpopulation analysis was conducted to assess safety and efficacy in Chinese patients.. Of 2264 patients treated in ATHENA, 202 were enrolled in China. Bevacizumab was combined with docetaxel in 90% of Chinese patients and paclitaxel in 10%. The most common grade 3/4 adverse events were diarrhoea (in 5.0% of patients) and hypertension (in 2.5% of patients). Grade 3/4 proteinuria occurred in 0.5%. After median follow-up of 17.6 months and events in 56% of patients, median TTP was 9.0 months (95%CI, 8.4-11.1). Overall survival data were immature.. We found no evidence of increased bevacizumab-related toxicity or reduced efficacy in Chinese LR/mBC patients receiving first-line bevacizumab-taxane therapy compared with predominantly Western populations. The safety profile was generally similar to previously reported LR/mBC trials. Subtle differences may be attributable to different lifestyle and cardiovascular risk factors in Chinese patients compared with the overall population. It appears reasonable to extrapolate findings from bevacizumab-based randomised trials to Chinese populations.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Receptor, ErbB-2; Taxoids; Young Adult

To determine whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) -targeted delivery of the potent antimicrotubule agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-positive metastatic breast cancer (MBC) who have previously received all standard HER2-directed therapies.. In this single-arm phase II study, T-DM1 3.6 mg/kg was administered intravenously every 3 weeks to patients with HER2-positive MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety.. Among 110 pretreated patients (median, seven prior agents for MBC; median follow-up, 17.4 months), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clinical benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 months (95% CI, 4.2 to 8.4 months), and median duration of response was 7.2 months (95% CI, 4.6 months to not estimable). In patients with confirmed HER2-positive tumors (n = 80 by retrospective central testing), the response rate was 41.3% (95% CI, 30.4% to 52.8%), and median PFS was 7.3 months (95% CI, 4.6 to 12.3 months). Most adverse events were grades 1 to 2; the most frequent grade ≥ 3 events were thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%).. T-DM1 is well tolerated and has single-agent activity in patients with HER2-positive MBC who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. T-DM1 may be an effective new treatment for this patient population.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Immunotoxins; Lapatinib; Male; Maytansine; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).. Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m(2) twice daily on days 1-14 and docetaxel 75 mg/m(2) on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as ≥3rd line of therapy. All patients were evaluable for response and toxicity.. Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7-62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4-64.2), the median time to disease progression 9.3 months (range 1.2-58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %.. The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Docetaxel; Drug Administration Schedule; Fatigue; Female; Fever; Fluorouracil; Hand-Foot Syndrome; Humans; Middle Aged; Neoplasm Metastasis; Nervous System Diseases; Neutropenia; Remission Induction; Salvage Therapy; Taxoids; Treatment Outcome

Patients with metastatic breast cancer (MBC) with disease progression after anthracycline-and/or taxane-containing therapy need an effective drug regimen with low toxicity. Mitomycin C (MMC) and vinorelbine (VNR) are suitable candidates for combination therapy in the second-/third-line treatment of MBC. This study evaluates the safety and efficacy of an MMC/VNR combination chemotherapy in pretreated patients with MBC.. In a phase II trial, patients with anthracycline-and/or taxane-pretreated MBC were treated with MMC 8 mg/m(2) (day 1) and VNR 25 mg/m(2) (days 1 and 8) every 4 weeks for up to 6 cycles or until disease progression.. In 51 eligible patients, 13 (26%) partial remissions (PRs), 20 (39%) stable diseases (SDs) and 18 (35%) progressive diseases (PDs) were observed. The median progression-free survival (PFS) was 5.0 months. The main grade 3/4 toxicities were neutrocytopenia (41%), granulocytopenia (37%), and thrombocytopenia (4%). Other hematological and non-hematological toxicities were mostly mild.. The combination of MMC and VNR is an effective and relatively well-tolerated regimen for anthracycline- and/or taxane-pretreated patients with MBC and is suitable for outpatient therapy.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Evidence-Based Medicine; Female; Humans; Leukopenia; Middle Aged; Mitomycin; Taxoids; Treatment Failure; Treatment Outcome; Vinblastine; Vinorelbine

In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine.. Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval.. This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS).. Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%).. Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Female; Gemcitabine; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Survival Rate; Taxoids

Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2.. A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days.. Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2(+) disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%-23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%-30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted.. Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.

Topics: Adenocarcinoma; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Female; Humans; Medical Oncology; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Societies, Medical; Survival Analysis; Taxoids; United States

We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assessed after every two cycles of treatment. All of the patients had previously been treated with anthracyclines and taxanes. A total of 26 patients were enrolled in this study between April 2004 and August 2009. The median age of the patients was 47 years (range, 37 to 71 years), and 80.8% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Out of 24 evaluable patients, five partial responses were observed, giving an overall response rate of 20.8%, with a median response duration of 2.8 months. The median time to progression was 3.7 months (range, 0.5 to 22.6 months), and median overall survival duration was 10.4 months (range, 1.3 to 57.6 months). The major toxicities observed were neutropenia, anemia and peripheral neuropathy. Grade 3 or 4 hematologic toxicities included neutropenia in 18 patients (69.2%) and anemia in four patients (15.3%). Grade 1 or 2 peripheral neuropathy was observed in 11 patients (42.3%), however there were no cases of grade 3 or 4 peripheral neuropathy. The results of this study indicate that vinorelbine monotherapy was feasible regimen with manageable toxicities in patients with metastatic breast cancer who were previously exposed to anthracyclines and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice.. Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point.. Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9).. The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Treatment Outcome; Young Adult

Triple-negative breast cancer (TNBC) is characterized by lack of hormone receptors and HER-2 and shares many features with BRCA1-associated cancer. Preclinical data indicate cisplatin sensitivity, suggesting that these tumors may have defects in the BRCA1 pathway. The carboplatin and gemcitabine (CG) combination is active in unselected anthracycline/taxane pretreated metastatic breast cancer patients, so we carried out a phase II study to evaluate the activity of the CG combination in pretreated metastatic TNBC patients. From 10/2004 to 3/2009 we enrolled 31 patients. Median age was 57 years and 29 patients out of 31 had visceral involvement. The overall response rate (ORR) was 32% (1 complete response /9 partial responses), in addition 5 patients obtained stable disease for >12 weeks. After a median follow-up of 34 months, all patients progressed with a median time to progression of 5.5 months and median overall survival of 11 months. Dose reductions, delays and omissions occurred in 75 (60%), 36 (29%) and 22 (18%) cycles. Grade 3/4 neutropenia occurred in 17 and febrile neutropenia in 4 patients. Ten patients had Grade 3/4 thrombocytopenia. Non hematological toxicities were manageable. The CG combination is a reasonable option for the treatment of metastatic pretreated TNBC patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Deoxycytidine; Disease Progression; Female; Gemcitabine; Humans; Middle Aged; Neutropenia; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Watchful Waiting

NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2-positive breast cancer.. Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS).. Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis.. DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Middle Aged; Taxoids; Trastuzumab

Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.. Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.. Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.. Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Polyethylene Glycols; Survival Rate; Taxoids; Treatment Outcome

Effective treatment options for patients with metastatic breast cancer pretreated with or resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of ixabepilone plus capecitabine in both anthracycline-pretreated and resistant and taxane-resistant metastatic breast cancer of Chinese women.. Patients with measurable disease who had anthracycline and taxanes as prior neoadjuvant, adjuvant or metastatic therapy were treated with ixabepilone at 40 mg/m(2) intravenously on day 1 of 21-day cycle plus capecitabine 2,000 mg/m(2) orally on day 1 through 14 of a 21-day cycle. The primary end point was the objective response rate. The secondary end points were time to progression, overall survival, and toxicity profiles.. Twenty-one patients received 146 cycles with a median of 5 cycles (range 1-13 cycles) per patients. Fourteen patients (66.7%) had partial response, 5 patients (23.8%) had stable disease, and 2 patients (9.5%) had progressive disease. Median time to progression and duration of response were 6.2 and 6.0 months, respectively. The median overall survival was 16.7 months. Eight (38.1%) patients required dose reduction and 14 (66.7%) patients discontinued treatment for adverse effect. Grade 3/4 treatment-related events included fatigue (28.6%), peripheral sensory neuropathy (33.3%), neutropenia (61.9%), anemia (4.7%), hypokalemia (4.7%), hand and foot syndrome (19.0%) and infection (9.5%). Resolution of grade 3/4 peripheral neuropathy was reversible after a median period of 6 weeks.. Ixabepilone plus capecitabine demonstrated a clear activity and an acceptable safety profile in Chinese patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer, and the majority of patients completed 6 cycles of the therapy with manageable neuropathy toxicities.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asian People; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; China; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Prospective Studies; Survival Rate; Taxoids; Treatment Outcome

Recently, lower axillary lymph node retrieval after neoadjuvant chemotherapy was reported. We did not have this experience, and retrospectively analyzed our axillary lymph node dissections (ALNDs).. One hundred ninety-one patients who had ALND after neoadjuvant chemotherapy were compared with 192 patients with primary ALND after a positive sentinel node biopsy.. There were no differences in the mean number of nodes retrieved between the neoadjuvant group and the primary surgery group: 16.3 (range 4-38) and 15.8 (range 6-33), respectively (P = .4); or in the retrieval of fewer than 10 lymph nodes: 13/191 (7%) and 11/192 (6%) (P = .7). The number of cases with retrieval of more than 20 lymph nodes was higher in the neoadjuvant group: 42/191 (22%) versus 26/192 (13%) (P = .03). In the neoadjuvant group, 150/191 (79%) patients had residual lymph node metastasis after neoadjuvant chemotherapy.. Our results show the feasibility and need to remove enough lymph nodes to provide precise prognostic information and adequate local control.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Axilla; Biopsy, Fine-Needle; Breast Neoplasms; Bridged-Ring Compounds; Feasibility Studies; Female; Follow-Up Studies; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoadjuvant Therapy; Reproducibility of Results; Retrospective Studies; Taxoids; Time Factors; Young Adult

Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCβ and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC).. Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.. Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74).. Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Indoles; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

Using data from a recent randomized trial, we evaluated the cost effectiveness of ixabepilone plus capecitabine versus capecitabine alone in patients with predominantly metastatic breast cancer considered to be taxane-resistant and previously treated with or resistant to an anthracycline.. We developed a stochastic decision-analytic model to represent data collected in the trial on medical resource use, health-related quality of life, and clinical outcomes. Estimates of overall survival were conditional on level of tumor response. We assigned monthly costs and utility weights according to periods defined by the duration of study treatment, time from discontinuation of the study drug until disease progression, and from progression until death and were specific to the level of response and receipt of subsequent therapy. Medical resources were valued in 2008 US dollars. We performed Monte Carlo simulations and sensitivity analyses to evaluate model uncertainty.. Overall survival was significantly associated with level of tumor response (P < .001). Total costs were estimated at $60,900 for patients receiving ixabepilone plus capecitabine and $30,000 for patients receiving capecitabine alone. The estimated gain in life expectancy with ixabepilone was 1.96 months (95% CI, 1.36 to 2.64 months); the estimated gain in quality-adjusted survival was 1.06 months (95% CI, 0.09 to 2.03 months). The resulting incremental cost-effectiveness ratio was $359,000 per quality-adjusted life-year (95% CI, $183,000 to $4,030,000). In sensitivity analyses, the results were robust to changes in numerous inputs and assumptions.. Addition of ixabepilone to capecitabine adds approximately $31,000 to overall medical costs and affords approximately 1 additional month of quality-adjusted survival.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Drug Costs; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Quality-Adjusted Life Years; Taxoids

Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC).. MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate.. Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%.. Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

A multicenter, open-label, phase 2 study evaluated the efficacy and safety of intravenous vinflunine as third-line treatment in patients with progressing metastatic breast cancer (MBC) after failure of anthracycline- and taxane-based chemotherapy.. Fifty-six patients with MBC, relapsing after receiving 2 previous treatments for advanced disease, including both anthracyclines and taxanes, received 320 mg/m(2) of vinflunine once every 3 weeks (median number of 2.5 cycles, range: 1-13).. According to an independent radiologist, the response rate was 12.5% (95% CI: 5.2-24.1) and 14% (95% CI: 5.3-27.9) (6 partial responses) in the treated and evaluable populations, respectively. Disease control was achieved in 42.9% and 51.2% of the patients, respectively. Median progression-free survival was 2.6 months (95% CI: 1.6-4.0 months) with a median overall survival of 11.4 months (95% CI: 7.4-14.2 months). Duration of response was 6.8 months (95% CI: 5.6 months, upper limit not reached). Leukopenia was the most frequent hematologic toxicity, with grade 3/4 severity in 49.1% of the patients. Grade 3 neutropenia in 30.9%, grade 4 in 40.0% of patients, febrile neutropenia (5.4%), and 1 case of neutropenia infection (1.8%) were reported. Other grade 3 toxicities included anemia (5.5%), fatigue (14.3%), and constipation (7.1%), which were noncumulative. The adverse events associated with vinflunine were predictable and manageable.. Vinflunine is an active and well-tolerated agent as third-line treatment of patients with MBC after failure of anthracycline- and taxane-based therapy. These results warrant further investigation of vinflunine monotherapy or in combination for the treatment of MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Neoplasm Staging; Taxoids; Treatment Failure; Vinblastine

The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC).. A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle).. No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption.. Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

Our aim was to evaluate the activity and toxicity of capecitabine and cisplatin (CapCisp) combination in anthracycline- and taxane-pretreated metastatic breast cancer patients. Thirty-three patients, 20-61 years of age (median 41), were included. They received Cap 2,000 mg/m(2) on days 1-14 and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. Twelve nonprogressive patients continued single-agent Cap therapy until progression or until intolerable toxicity after Cisp cessation. The disease control rate in 154 cycles was 81.8%: complete response 3.0% (n = 1), partial response 48.5% (n = 16) and stable disease 30.3% (n = 10). The median time to disease progression was 6.3 months (95% CI 3.8-8.8). The median overall survival was 11.5 months (95% CI 6.9-16.1). The only grade 3 toxicity was neutropenia, observed in 4 patients (12.1%). CapCisp has an encouraging anti-tumor activity with a low toxicity rate in anthracycline- and taxane-pretreated metastatic breast cancer patients.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cisplatin; Deoxycytidine; Disease Progression; Drug Tolerance; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids

The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m(2) orally bid days 1-14 or vinorelbine 30 mg/m(2) i.v. days 1 and 8, both given every 3 weeks. The study was stopped due to poor accrual with 47 patients enrolled. Responses were seen in 2/23 patients treated with capecitabine (8.7%; 95% CI 1.1-29.0) and 3/24 patients treated with vinorelbine (12.5%; 95% CI 2.7-32.4). Median progression-free survival was 2.8 and 2.6 months, and median overall survival was 9.3 and 11.0 months, in the capecitabine and vinorelbine arms, respectively. There was more hematologic toxicity, neurotoxicity, and nausea/vomiting with vinorelbine and more diarrhea and hand-foot syndrome with capecitabine. The anti-tumor activity of capecitabine and vinorelbine seems to be comparable, but the toxicity profiles are different.

Topics: Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Middle Aged; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

To evaluate the efficacy and toxicity of a combination of intravenous vinorelbine and 5-fluorouracil (5-FU) given by continuous infusion in the treatment of metastatic breast cancer previously treated with anthracyclines and taxanes.. Sixty-one patients with metastatic breast cancer were treated with intravenous vinorelbine 30 mg/m2 on days 1 and 8 of each 21-day cycle together with 5-FU 200 mg/m2/day by continuous infusion. All had previously been treated with an anthracycline and 41% had also been previously treated with a taxane. All had normal haematological, renal and hepatic function and all but three had an Eastern Cooperative Oncology Group performance score of 2 or better.. The overall response rate by World Health Organization criteria was 46% (28 patients); excluding nine non-evaluable patients gave a response rate of 54%. In patients who had previously been treated with both an anthracycline and a taxane, a response rate of 50% was observed (12 of 24 patients). Severe toxicity was uncommon, as was toxicity attributable to infusional 5-FU. Myelosuppression was rarely severe, but was common and led to delay or dose reduction in 38% of treatments. Eleven patients (18%) were admitted with fever and/or neutropenia and one patient died. The median received dose intensity was vinorelbine 16 mg/m2/week and 5-FU 143 mg/m2/day.. The combination of vinorelbine and infusional 5-FU is active in metastatic breast cancer, including in patients previously treated with an anthracycline and a taxane. Toxicity is generally manageable, but myelosuppression is significant at this dose regimen. Recommended doses for routine clinical use are 5-FU 200 mg/m2/day and intravenous vinorelbine 30 mg/m2 days 1 and 15 on a 28-day cycle.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately active and extremely safe in patients with metastatic breast cancer previously treated with anthracycline and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids; Treatment Outcome

Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC).. Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis.. Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during >or= 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions.. Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Drug Administration Schedule; Fatigue; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Indoles; Middle Aged; Protein-Tyrosine Kinases; Pyrroles; Sunitinib; Survival Rate; Taxoids

Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC.. Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated.. One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%).. Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Diarrhea; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neutropenia; Prospective Studies; Taxoids; Time Factors; Treatment Outcome

XRP6258 is a novel taxoid with a low affinity for P-glycoprotein. This multicenter phase II study assessed the activity of XRP6258 in the treatment of taxane-resistant metastatic breast cancer (MBC).. XRP6258 was administered as a 1-h i.v. infusion every 3 weeks at 20 mg/m(2) (then, in the absence of severe toxicity, at 25 mg/m(2) from cycle 2). The primary end point was the objective response rate (ORR) assessed according to response evaluation criteria in solid tumours (RECIST) guidelines.. Seventy-one patients were enrolled. The median relative dose intensity was 0.98. The ORR was 14% (two complete, eight partial responses). Eighteen patients (25%) had stable disease of >3 months duration. At a median follow-up of 20.0 months, the median time to progression was 2.7 months, and the median overall survival 12.3 months. The most common grade 3/4 adverse events (AEs) were neutropenia (73%) and leucopenia (55%), with a low febrile neutropenia rate (3%) and infrequent grade 3/4, treatment-related, non-hematological AEs (<5% patients for any AE). Two deaths were reported, one related to study drug and one to unknown cause.. XRP6258 was active and well tolerated in this group of MBC patients with taxane-resistant disease. These results support the further clinical development of this agent.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer.. Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m2 IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m2 by IV infusion over 1 h on day 1 in 21 day cycles.. Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1-8.9 months) and 15 months (95% CI 10.5-19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred.. The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.

Topics: Adult; Aged; Alopecia; Anemia; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Infusions, Intravenous; Leukopenia; Middle Aged; Neoplasm Metastasis; Recurrence; Severity of Illness Index; Stomatitis; Survival Rate; Taxoids; Thrombocytopenia; Treatment Outcome

We examined if inclusion of a taxane and more prolonged preoperative chemotherapy improves pathologic complete response (pCR) rate in estrogen receptor (ER)-positive breast cancer compared with three to four courses of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC).. Pooled analysis of results from seven consecutive neo-adjuvant chemotherapy trials including 1079 patients was carried out. These studies were conducted at MD Anderson Cancer Center from 1974 to 2001. Four hundred and twenty-six (39.5%) patients received taxane-based neo-adjuvant therapy. pCR rates and survival times were analyzed as a function of chemotherapy regimen and ER status. Multivariate logistic and Cox regression analysis were carried out to identify variables associated with pCR and survival.. Patients with ER-negative cancer had higher overall pCR rate than patients with ER-positive tumors (20.1% versus 4.9%, P < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with and without a taxane (P < 0.001). In ER-positive patients, the pCR rates were 8.8% and 2.0% with and without a taxane (P < 0.001). In multivariate analysis, clinical tumor size (P < 0.001), ER-negative status (P < 0.001) and inclusion of a taxane (P = 0.01) were independently associated with pCR. For patients with pCR, survival was similar regardless of ER status or the type of regimen that induced pCR.. pCR rates increased for patients with both ER-positive and ER-negative tumors as regimens started to include a taxane and became longer. This indicates that a subset of patients with ER-positive breast cancer benefits from more aggressive chemotherapy, similarly to patients with ER-negative tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prognosis; Receptors, Estrogen; Survival Analysis; Taxoids; Tumor Burden

We conducted a multicenter phase II trial to determine the efficacy/safety of capecitabine and weekly paclitaxel, a combination with preclinical evidence of synergy, in patients with metastatic breast cancer (MBC) previously treated with a taxane.. Eligibility criteria included measurable MBC, history of every-3-week taxane therapy (adjuvant or for MBC), and no previous taxane on a weekly basis, capecitabine, or infusional 5-fluorouracil. Patients received capecitabine 825 mg/m2 per dose orally twice daily (1650 mg/m2 per day) on days 1-14 and weekly paclitaxel 80 mg/m2 intravenously on days 1 and 8, followed by a 1-week rest period (every-3-week cycle) until progression or intolerable toxicity. Fifty-four women were treated, most with previous every-3-week taxane exposure as adjuvant therapy (n=43) rather than for MBC (n=11). The median number of delivered cycles was 7, with dose modifications in 30 patients. The intent-to-treat objective response rate (primary study endpoint) was 59% (95% confidence interval, 46%-72%), including 7 complete and 25 partial responses.. Three patients had stable disease for>or=6 months, for a clinical benefit rate of 65% (95% confidence interval, 51%-76%). Median objective response duration, time to progression, and overall survival were 8.1 months, 8.4 months, and 21.6 months, respectively. Grade 3/4 treatment-related adverse events consisted of neutropenia (13%), anemia (2%), hand-foot skin reaction (20%), fatigue (7%), diarrhea (4%), nausea/vomiting (4%), and pain (2%). No patients developed grade 3/4 neuropathy.. Capecitabine and weekly paclitaxel were highly active with acceptable tolerability in patients with MBC previously treated with a taxane, consistent with our recently published experience in taxane-naive women with MBC.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Chemotherapy, Adjuvant; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Middle Aged; Paclitaxel; Taxoids

To evaluate the cardiovascular risk profile of a subset of patients with early-stage breast cancer treated with adjuvant taxane-anthracycline-containing chemotherapy and/or trastuzumab (Herceptin).. Twenty-six patients with breast cancer (mean, 20 months postchemotherapy) and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established cardiovascular disease (CVD) risk factors, body mass index, cardiorespiratory fitness, and left ventricular systolic function. All assessments were done within a 14-day period.. Cardiac abnormalities were suggested by left ventricular ejection fraction (LVEF) <50% in 8% of patients, LVEF remained >10% below pretreatment values in 38%, whereas 50% presented with resting sinus tachycardia. Brain natriuretic peptide was significantly elevated in 40% of patients and was correlated with LVEF (r = -0.72, P =or< 0.001). For the majority of CVD risk factors, similar proportions of patients and controls (35-60%) were classified as "undesirable." A significantly higher proportion of patients were classified with low cardiorespiratory fitness (46% versus 0%, P < 0.01), being overweight/obese (72% versus 50%, P < 0.05), and having resting sinus tachycardia (50% versus 0%, P < 0.01) compared with controls. Cardiorespiratory fitness and body mass index were correlated with CVD risk factors (r = -0.64 to 0.63, P < 0.05; r = -0.63 to 0.67, P < 0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen.. Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age-matched controls due to direct and indirect treatment-related toxicity.

Topics: Adult; Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Cardiovascular Diseases; Case-Control Studies; Chemotherapy, Adjuvant; Cross-Sectional Studies; Female; Humans; Middle Aged; Oxygen Consumption; Pilot Projects; Receptor, ErbB-2; Risk Assessment; Risk Factors; Stroke Volume; Tachycardia, Sinus; Taxoids; Trastuzumab

Cisplatin-gemcitabine is a synergistic chemotherapy (CT) combination highly proven in a broad spectrum of epithelial neoplasms and shows a non-cross-resistance profile with the most active drugs in metastatic breast cancer (MBC). We have conducted an exploratory study to determine if treatment with low doses of a combination of fixed-rate gemcitabine infusion and cisplatin was clinically meaningful in women relapsing after a minimum of 2 prior lines of CT for advanced disease (range 2-6), which had to have necessarily included both anthracyclines and taxanes. Another goal was to find the optimal individual schedule by adjusting frequency and dosage according to patient tolerability.. From May 2002 to November 2003, 22 patients with relapsed advanced BC and a minimum of two prior CT lines were offered treatment with gemcitabine (G) (initial dose 750 mg/m(2), or 600 mg/m(2) if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m(2), or 20 mg/m(2) in case of > or =3 prior CT lines) on days 1 and 8 of a 21-day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Further dose reductions were allowed as needed up to a maximum of three. Treatment continued until disease progression or intolerable toxicity. Median age was 54.5 years (35-75). Median Karnofsky was 90 (range 80-90). Median number of prior CT lines was 3 (2-6). 90.9% of patients had received adjuvant CT. All had prior anthracyclines and taxanes. Other agents used included 5-FU/eniluracil, MTA, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. 72.7% had received radiotherapy and 68.1% hormonal therapy (median 2 lines, range 1-4).. Partial responses (PR) were seen in 9.1% of patients and stable disease (SD) in 36.4%. Clinical Benefit Rate (PR+SD) was derived in 45.5% of patients. Median time to progression was 4 months (95% CI, 3-5) in general and 6 months (95% CI, 4-8) in patients with clinical benefit. Median survival for the entire group was 8 months (95% CI, 5-11) and 19 months when clinical benefit was obtained (95% CI, 11-25). Patients received a median of 8.5 CT administrations (range, 2-45). Forty-three percent of doses were delayed. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Cisplatin and gemcitabine doses were reduced in 75% and 62% of all cycles, respectively. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Toxicities grade >3 were neutropenia 35% and thrombocytopenia 15%. All other toxicities were grade 2 or less, including sensorial neuropathy (30%), asthenia (34%), nausea/vomiting (20%) and oral mucositis (15%). There were no treatment-related deaths. Reasons for discontinuation were progression (18 patients), death (3 patients) and patient decision (1 patient).. Weekly cisplatin-gemcitabine with flexible downwards individual tailoring is a safe and effective salvage treatment in heavily pretreated MBC patients with good PS.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Female; Gemcitabine; Humans; Middle Aged; Salvage Therapy; Secondary Prevention; Survival Analysis; Taxoids

Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.. Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.. Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

We compared trastuzumab alone therapy (A-group) (n=6) to trastuzumab plus taxane therapy (B-group) (n=12) in patients of advanced and metastatic breast cancers. The response rate of A-group was 33.3%. Six months after, A-group was switched to trastuzumab plus taxane therapy. The response rate of A-group after addition of taxane was improved to 83.3%. The mean duration of response was 6.8 months in A-group after addition of taxane. The response rate of B-group was 83.3%. The mean duration of response was 7.5 months in B-group. The combination therapy of trastuzumab and taxane therapy showed a high response rate. We think that it is possible to start trastuzumab alone therapy because A-group after addition of taxane showed a high response rate. There were no significant differences of immunosuppressive acidic protein (IAP) from the course of chemotherapy in all cases.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Humans; Immunotherapy; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Taxoids; Trastuzumab

Effective and tolerable regimens are sought specifically in patients who have been pretreated with anthracyclines and taxanes. Gemcitabine and cisplatin demonstrated synergistic activity in vitro and provides a new mechanism of drug interaction.. Previously treated patients with metastatic breast cancer (MBC) were enrolled in a multicentre phase II study. Treatment consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given on day 1 and 8 every 3 weeks.. Thirty-eight patients were recruited, all of whom had previously received chemotherapy (35 pretreated with taxanes, 33 pretreated with anthracyclines). A median of 5 cycles of the study treatment was delivered. There were 2 complete and 13 partial responses, for an overall response rate of 40% (95% confidence interval: 23-56%). Thirteen patients (35%) had stable disease. Tumour response appeared independent of previously applied chemotherapy. Median time-to-progression was 6 months and median overall survival was 13.5 months. Main toxicities were leucopenia and thrombocytopenia (grade 3/4 in 26 and 16% of cycles, respectively). Non-haematological toxicity was rarely severe.. Combination chemotherapy with gemcitabine and cisplatin given on 2 out of 3 weeks is well tolerated and active in heavily pretreated patients with MBC, even after prior exposure to anthracyclines and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Disease Progression; Female; Gemcitabine; Humans; Maximum Tolerated Dose; Middle Aged; Neoadjuvant Therapy; Salvage Therapy; Taxoids; Time Factors

To evaluate the relationship between apoptosis induced by chemotherapy and clinical response in breast cancer.. Apoptosis index (AI), mutant p53 and Bcl-2 protein expression were evaluated in 44 breast tumour samples from patients submitted to neoadjuvant chemotherapy. Objective response (OR) to primary chemotherapy was observed in 37 patients (84%) and no response (NR) in seven. AI was measured by the rate of apoptotic cells identified using morphological criteria. p53 and Bcl-2 protein expression were evaluated using an immunoperoxidase staining technique.. The median AI change observed between pre-chemotherapy AI and post-chemotherapy AI was 0.84 in the OR group and 0.01 in the NR group, (rho = 0.4; p = 0.006). There was no change in Bcl-2 protein expression following chemotherapy. In the OR group, p53 protein expression was positive in 41.6% of patients before and in 22.2% after chemotherapy (difference = 16.6%; p = 0.03). No change was detected in the NR group.. A positive correlation was found between the increase in AI and clinical response to neoadjuvant chemotherapy in locally advanced breast cancer.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Drug Resistance, Neoplasm; Epirubicin; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Middle Aged; Mutation; Neoadjuvant Therapy; Proto-Oncogene Proteins c-bcl-2; Taxoids; Tumor Suppressor Protein p53

Currently, there is no standard treatment for patients with anthracycline and taxane-refractory metastatic breast cancer (MBC). Capecitabine or vinorelbine plus cisplatin is an effective palliative regimen for taxane-refractory MBC. In this study, we analyzed the efficacy and toxicity of sequential therapy with capecitabine followed by biweekly vinorelbine plus cisplatin in 37 patients with anthracycline and taxane-refractory MBC in Taipei Veterans General Hospital.. Capecitabine (2,500 mg/m2 twice daily for 2 weeks, followed by 1 week of rest) was repeated every 3 weeks until the disease progressed. Patients then received biweekly vinorelbine (25 mg/m2) plus cisplatin (40 mg/m2) (arm A, n = 17) or best supportive care (BSC) (arm B, n = 20) in accordance with patient preference and clinical judgment. The clinical variables and response to capecitabine were well balanced in both arms.. The overall response rate to capecitabine was 32%, with a complete response rate of 5% and a partial response rate of 27%. Stable disease was achieved in an additional 46%. The disease control rate with capecitabine was 78%. Median progression-free survival and overall survival with capecitabine were 5.9 and 9.5 months, respectively. There was a trend toward better overall survival in arm A patients compared with arm B (BSC) patients, though statistical significance was not reached (10.4 vs. 7.4 months; p = 0.08); however, a significantly better overall survival rate was observed in the subgroup with capecitabine-controlled disease (10.8 vs. 6.9 months; p = 0.015). The safety profile of vinorelbine/cisplatin was acceptable: only 6% developed grade 4 neutropenia.. We suggest that sequential therapy is not necessarily effective compared with capecitabine alone, but is probably effective in patients initially controllable with capecitabine.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cisplatin; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Prospective Studies; Taxoids; Vinblastine; Vinorelbine

Locoregional breast cancer recurrence is characterized by a high rate of systemic and local re-recurrence. Data on concurrent radiochemotherapy (RCT) in these cases are scarce. The purpose of this study was to evaluate feasibility, toxicity and efficacy of local control of a radiotherapy combined with a chemotherapy containing a taxane.. Between May 1999 and November 2004, 36 women referred to the authors' clinic because of locoregional breast cancer recurrence that was either inoperable (n = 29) or resected (n = 7) received concurrent irradiation and taxane monotherapy weekly (TAX/RT; n = 28: paclitaxel 90 mg/m(2), n = 24, or docetaxel 35 mg/m(2), n = 4) or taxane + cisplatin therapy (TAX/CIS/RT; n = 8; paclitaxel 135 mg/m(2) d1 and cisplatin 20 mg/m(2) d1-5 q28).. Comparing TAX/RT with TAX/CIS/RT, the complete remission rate in patients with macroscopic tumor prior to RCT was significantly higher for TAX/RT than for TAX/CIS/RT (7/19 vs. 0/8; p = 0.046), but overall remission rates were comparable, i.e., partial remission: 11/20 versus 6/8 cases, stable disease (no change): 1/20 versus 2/8 cases, and response rate: 95% versus 75%, respectively. The cumulative local recurrence-free survival rate at 1 and 2 years post-treatment was 83% and 68% and that of systemic recurrence-free survival 56% and 29%, respectively. The main toxic reactions of third-degree and higher were dermatitis in TAX/RT (57% vs. 11% for TAX/CIS/RT) and leukocytopenia in TAX/CIS/RT (62% vs. 7% for TAX/RT).. Concurrent irradiation and taxane chemotherapy weekly, in particular with paclitaxel, is recommended due to response and acceptable side effects for treatment of inoperable locoregional breast cancer recurrence.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy; Taxoids; Treatment Outcome

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m(-2) q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed >6 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9-43.2%)). Among the responders, seven patients had relapsed during a period of <3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2-7.2), median progression-free survival was 3.7 months (95% CI: 2.8-4.2) and median overall survival was 14.3 months (95% CI: 9.2-19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Constipation; Disease Progression; Female; Humans; Leukopenia; Middle Aged; Nausea; Neutropenia; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine

The objective of this study was to assess the efficacy and safety of pemetrexed in pretreated patients with advanced-stage breast cancer.. Patients with advanced-stage or metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-2, and progressive or relapsed disease after treatment with regimens containing anthracyclines and taxanes were eligible. Pemetrexed 500 mg/m2 was administered as a 10-minute intravenous infusion on day 1 every 21 days.. Seventy-nine women were enrolled. After protocol amendment, 43 patients received folic acid and vitamin B12 supplementation to control pemetrexed-related toxicity. A median of 4 cycles (range, 1-23 cycles) was administered. Overall response rate was 9% (95% confidence interval, 3.7%-17.6%), median duration of response was 5.5 months, median progression-free survival was 3.1 months, and median survival was 10.5 months. Major grade 3/4 toxicities were lymphopenia (53.3%), neutropenia (36.4%), leukopenia (26.9%), and anemia (7.7%). In general, the toxicities were less frequent in patients who received vitamin supplementation than in those who did not receive vitamin supplementation.. The response to pemetrexed salvage treatment was low in this study of heavily pretreated patients with breast cancer. Pemetrexed was generally well tolerated in patients with previously treated breast cancer. Vitamin supplementation appeared to ameliorate toxicity.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Folic Acid; Glutamates; Guanine; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pemetrexed; Premedication; Salvage Therapy; Taxoids; Vitamin B 12; Vitamin B Complex

Few overlapping toxicities and oral formulations make capecitabine plus oral vinorelbine an attractive new combination for treating patients with breast cancer. An all-oral regimen minimizes inconvenience for the patient and saves medical resources.. To determine the recommended dose for this all-oral combination, we conducted a phase I study in 21 patients with metastatic breast cancer after failure of previous chemotherapy with anthracylines and/or taxanes for advanced disease. Capecitabine 1000 mg/m2 twice daily was given on days 2-7 and 9-14. Vinorelbine was administered at escalating doses of 40-80 mg/m2 on days 1 and 8 every 3 weeks. Dose escalation of vinorelbine was performed in cohorts of 3 patients, but the dose of vinorelbine could also be increased to the next level in the same patient after 3 cycles if there were no dose-limiting toxicities. In total, 173 cycles were administered (median, 8 cycles; range 1-21+ cycles).. Treatment was well tolerated: there were no grade 4 toxicities, and the only grade 3 toxicities in > 1 cycle were hand-foot syndrome and neutropenia (2% of cycles each). The maximum tolerated dose could not be determined using predefined criteria. However, in this heavily pretreated patient population, intrapatient vinorelbine dose escalation > 60 mg/m2 was rarely achieved. Thus, we considered vinorelbine 60 mg/m2 to offer the best dose level-toxicity ratio. At this dose, grade 3 toxicities occurred in only 7% of the 58 cycles administered. Among 19 evaluable patients, 7 exhibited response or stable disease lasting > 6 months, giving a clinical benefit rate of 37%. Duration of response in the 2 responding patients was 5 months and > 16 months.. The all-oral combination of capecitabine/vinorelbine is well tolerated and active in heavily pretreated patients. Oral vinorelbine 60 mg/m2 is recommended in combination with capecitabine 1000 mg/m2 twice daily for further evaluation.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Middle Aged; Prodrugs; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

To investigate the impact of histologic type invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) on response to primary chemotherapy (PC) and long-term outcome.. The study included 1,034 patients with stage II and III breast cancer who participated in six clinical trials of PC at our institution between 1985 and 2002. One hundred twenty-two patients (12%) had ILC and 912 (88%) had IDC. All patients received anthracycline-based PC, and 346 patients (33.5%) also received a taxane as part of PC. Pathologic complete response (pCR) was defined as no evidence of invasive disease in the breast and axillary lymph nodes.. The median patient age was 48 years (range, 18 to 79 years). Patients with ILC tended to be older (median age, 53 years v 47 years for patients with IDC) and have more hormone-receptor-positive tumors (92% v 62%; P < .001), lower nuclear grade (nuclear grade 3, 16% v 56%; P < .001), and higher stage at diagnosis (10% v 0% with stage IIIB or IIIC disease; P < .001). Patients with ILC were less likely to have a pCR (3% v 15%; P < .001) and had a larger number of involved axillary lymph nodes (41% v 26% had > 3 involved nodes; P = .001). At a median follow-up time of 70 months, ILC patients tended to have longer recurrence-free survival (P = .004) and overall survival (P = .001).. ILC is characterized by lower rates of pathologic response to PC but better long-term outcomes compared to IDC. pCR might not be a prognostic indicator for this group of patients.

Topics: Adolescent; Adult; Age Factors; Aged; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal; Carcinoma, Lobular; Disease-Free Survival; Humans; Lymph Nodes; Middle Aged; Neoplasms, Hormone-Dependent; Taxoids; Treatment Outcome

To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer.. Eligible patients had histologically confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained.. Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade >/=2: 4.5% and 37.5% in the 100 and 300 mg cohorts, respectively). Rash was reported by 26% of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease >/=24 weeks. All patients in the 300 mg cohort and 90% of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC(50) for VEGF inhibition in preclinical models.. ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Bridged-Ring Compounds; Diarrhea; Dose-Response Relationship, Drug; ErbB Receptors; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Piperidines; Quinazolines; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

This study was designed to evaluate the efficacy and safety of single-agent gemcitabine for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Eligible patients were required to have bidimensionally measurable MBC that had been treated with 2-4 prior chemotherapy regimens that included an anthracycline and a taxane. Gemcitabine was delivered at a dose of 800 mg/m2 on days 1, 8, and 15 of a 28-day cycle until evidence of disease progression.. Twenty-two patients were enrolled and included in the safety analysis; 18 patients were evaluable for response. The median age of patients was 54 years (range, 36-70 years). The mean number of prior chemotherapy regimens for metastatic disease was 2.3, and the mean dose of gemcitabine delivered was 911 mg/m2 (range, 600-1600 mg/m2).. Overall, gemcitabine was well tolerated with minimal grade 3 toxicities; the only grade 4 toxicity was 1 case of pulmonary embolus. Three patients had evidence of partial tumor regression (17%; 95% CI, 4%-41%), and 1 patient had a 41% decrease in tumor volume, including liver metastasis.. Gemcitabine is active and well tolerated as monotherapy given in heavily pretreated patients with MBC after anthracyclines and taxanes. The activity and safety reported in this trial are consistent with previous reports in similar patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Gemcitabine; Humans; Infusions, Intravenous; Liver Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Salvage Therapy; Skin Neoplasms; Soft Tissue Neoplasms; Survival Analysis; Taxoids; Treatment Outcome; Vomiting

Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC) represents a significant challenge to oncologists. The tumour-activated oral fluoropyrimidine, capecitabine, is the only treatment approved for these patients. Our study evaluated the efficacy, safety and impact on quality of life (QOL) of capecitabine in this setting. Patients (n=126) with anthracycline- and taxane-pretreated metastatic breast cancer received capecitabine 1250 mg/m(2) twice daily, days 1-14, followed by a 7-day rest period. Median time to progression was 4.9 months (95% Confidence Interval (CI): 4.0-6.4). Thirty-five patients (28%) achieved an objective response (95% CI: 20-36%), including five (4%) complete responses. Median overall survival was 15.2 months (95% CI: 13.5-19.6 months). Capecitabine demonstrated a favourable safety profile, with a low incidence of treatment-related grade 3/4 adverse events. The most common adverse events were hand-foot syndrome and gastrointestinal effects. QOL assessment showed that capecitabine treatment was associated with an increase in mean Global Health Score. Capecitabine is active, well tolerated and improves the QOL of patients with anthracycline- and taxane-pretreated metastatic breast cancer. Based on the consistently high activity demonstrated in clinical trials, capecitabine has become the reference treatment in this setting.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Quality of Life; Taxoids; Treatment Outcome

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.

Topics: Administration, Oral; Adult; Aged; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Metastasis; Prodrugs; Taxoids; Treatment Outcome

To compare the efficacy of pegylated liposomal doxorubicin (PLD) with that of a common salvage regimen (comparator) in patients with taxane-refractory advanced breast cancer.. Following failure of a first- or second-line taxane-containing regimen for metastatic disease, 301 women were randomly assigned to receive PLD (50 mg/m(2) every 28 days); or comparator-vinorelbine (30 mg/m(2) weekly) or mitomycin C (10 mg/m(2) day 1 and every 28 days) plus vinblastine (5 mg/m(2) day 1, day 14, day 28, and day 42) every 6 to 8 weeks. Patients were stratified before random assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only.. Progression-free survival (PFS) and overall survival (OS) were similar for PLD and comparator (PFS: hazard ratio [HR], 1.26; 95% CI, 0.98 to 1.62; P =.11; median, 2.9 months [PLD] and 2.5 months [comparator]; OS: HR, 1.05; 95% CI, 0.82 to 1.33; P =.71; median, 11.0 months [PLD] and 9.0 months [comparator]). In anthracycline-naïve patients, PFS was somewhat longer with PLD, relative to the comparator (n = 44; median PFS, 5.8 v 2.1 months; HR, 2.40; 95% CI, 1.16 to 4.95; P =.01). Most frequently reported adverse events were nausea (23% to 31%), vomiting (17% to 20%), and fatigue (9% to 20%) and were similar among treatment groups. PLD-treated patients experienced more palmar-plantar erythrodysesthesia (37%; 18% grade 3, 1 patient grade 4) and stomatitis (22%; 5% grades 3/4). Neuropathy (11%), constipation (16%), and neutropenia (14%) were more common with vinorelbine. Alopecia was low in both the PLD and vinorelbine groups (3% and 5%).. PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer, thereby representing a useful therapeutic option.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Liposomes; Middle Aged; Mitomycin; Neoplasm Metastasis; Salvage Therapy; Taxoids; Vinblastine; Vinorelbine

To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes. Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m2 and vinorelbine was given at the fixed dose of 25 mg/m2, both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m2 per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30-70) and median performance status (PS, ECOG score), 1 (range 0-2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively.. The optimal schedule for the combination was gemcitabine 800 mg/m2 and vinorelbine 25 mg/m2. The maximum tolerated dose of gemcitabine was 1000 mg/m2, with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3-9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28-57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone.. The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline-based schedules or with combinations of anthracyclines and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Combinations; Female; Gemcitabine; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Taxoids; Vinblastine; Vinorelbine

To model the cost-effectiveness of adopting capecitabine/docetaxel combination therapy in place of single-agent taxane therapy for women in the province of Ontario, Canada, receiving treatment for anthracycline-pretreated metastatic breast cancer.. Clinical effectiveness and economic data were combined in a population model, from the perspective of a universal health care system. Estimates of clinical effectiveness and medical resource utilization were derived prospectively during a phase III randomized controlled trial comparing single-agent docetaxel with capecitabine/docetaxel combination therapy. Population data were obtained from the Cancer Care Ontario Registry and provincial prescription claims data.. During 1999-2000, 542 patients were eligible for taxane monotherapy. As capecitabine/docetaxel treatment confers a median 3-month survival benefit compared with docetaxel monotherapy, the projected survival gain in these patients was 136 life-years. The results of the cost-effectiveness analysis demonstrate that the survival benefit provided by the addition of capecitabine to single-agent docetaxel is afforded at a small incremental cost of Canadian $3,691 per life-year gained. Hospitalization costs for treatment of adverse events were less for patients receiving capecitabine/docetaxel combination therapy than for those receiving docetaxel monotherapy. The results were robust for adjustments in treatment costs and adverse effects costs.. Due to its 3-month survival gain and small incremental treatment cost, capecitabine/docetaxel is judged to be a highly cost-effective treatment in anthracycline-pretreated advanced breast cancer. From the perspective of the Ontario health care system, the addition of capecitabine to docetaxel in this patient population is a clinically appropriate and economically acceptable treatment strategy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Budgets; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Docetaxel; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Neoplasm Metastasis; Ontario; Paclitaxel; Population Surveillance; Survival Analysis; Taxoids; Trastuzumab; Treatment Outcome; Vinblastine; Vinorelbine; Women's Health

Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen.. All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m(2) twice-daily for 14 days followed by a 7-day rest period.. One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand-foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths.. This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Confidence Intervals; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Probability; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes.. Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned.. Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61).. The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Paclitaxel; Survival Rate; Taxoids

Eniluracil (776C85), a potent inactivator of dihydropyrimidine dehydrogenase, allows fluorouracil (5-FU) to be administered orally on a schedule that simulates continuous-infusion 5-FU. The primary objective of this study was to estimate the objective tumor response rate of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer.. Patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto this open-label, phase II, multicenter study. Patients received orally administered 5-FU 1.0 mg/m(2) with eniluracil given in a 10:1 ratio (eniluracil:5-FU) twice daily for the first 28 days of each 35-day cycle.. Eighty-four patients were enrolled. Eight partial responses were observed in 84 patients (10%; 95% confidence interval [CI], 4.2% to 17.9%), and 20 patients (24%) had stable disease. The median duration of partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of progression-free survival and overall survival for all patients was 9.9 weeks and 40.4 weeks, respectively. Most adverse events were grade 1 or 2 in intensity. Diarrhea, nausea, malaise/fatigue, vomiting, and mucositis were the most common treatment-related nonhematologic adverse events. The most frequently occurring grade 3 or 4 treatment-related adverse events were malaise/fatigue and diarrhea, occurring in 17% and 7% of patients, respectively. The incidence of grade 3 or 4 hematologic toxicity was low. Grade 3 or 4 hyperbilirubinemia occurred in 17% of patients.. Eniluracil-5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. Treatment was convenient, and patient compliance was high.

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Patient Compliance; Taxoids; Treatment Outcome; Uracil

The purpose of this study was to determine the maximum tolerated dose (MTD) of infusional gemcitabine given in conjunction with intravenous (i.v.) cyclophosphamide, and to determine whether the regimen produced a response rate of at least 40% in patients with metastatic breast cancer who have been previously treated with taxanes. Patients received cyclophosphamide (600 mg/m2) i.v. followed immediately by gemcitabine (100, 150, or 200 mg/m2) given as a 24-hour infusion (every 3 weeks) using an accelerated dose-escalation schema. Dose-limiting toxicity was defined as a neutrophil nadir < 500/microL, platelet nadir < 50,000/microL, or > or = grade 2 nonhematologic toxicity (> or = grade 3 toxicity during the standard dose-escalation portion of the study). Twelve patients received a total of 32 cycles of therapy. The MTD of gemcitabine was 150 mg/m2. Dose-limiting toxicities at 200 mg/m2 included neutropenia and mucositis. One patient with lymphangitic lung metastases had a partial response (8%; 95% confidence intervals: 0%, 23%). This patient developed grade 4 transaminase and total bilirubin elevation that occurred after the sixth cycle of therapy. The study was terminated due to an insufficient number of responses. The MTD of gemcitabine given as a 24-hour infusion is 150 mg/m2 when used in conjunction with cyclophosphamide (600 mg/m2) every 3 weeks. This regimen is not likely to produce more than a 40% response rate in patients with metastatic breast cancer previously treated with taxanes.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bilirubin; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Infusions, Intravenous; Liver Neoplasms; Lung Neoplasms; Middle Aged; Survival Analysis; Taxoids; Treatment Outcome

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Taxoids

Phase II study evaluating efficacy and safety of combined oxaliplatin/fluorouracil (5-FU) in taxane-pretreated advanced and metastatic breast cancer (ABC) patients.. Sixty-four taxane- and anthracycline-pretreated (within 6 months of study entry) women were treated with oxaliplatin 130 mg/m(2) (2-hour intravenous [IV] infusion), day 1, and 5-FU 1,000 mg/m(2)/d (continuous IV infusion) days 1 to 4, every 3 weeks.. Median patient age was 51 years (range, 34 to 71 years), with a median of two involved organs (range, one to six organs), and metastases in the liver (70%), bone (47%), and lung (34%). Patients had a median of two prior chemotherapy regimens (range, one to six regimens), and 78% had previous hormonal therapy, with clinical taxane and anthracycline resistance in 53% and 34%, respectively. A total of 367 cycles were administered, with a median of six cycles/patient (range, one to 15 cycles). Sixty patients were assessable for response (World Health Organization criteria): 17 partial response, 26 stable disease, and 17 disease progression, giving an overall response rate of 27% (95% confidence interval, 16.3% to 39.1%), and 26% and 36% in taxane- and anthracycline-resistant populations, respectively, all responders having metastatic liver disease. Median time to progression was 4.8 months, and median overall survival was 11.9 months. Four treatment-related serious adverse events occurred, seven patients withdrew because of treatment-related toxicity. Hematotoxicity was prevalent but rarely severe, with grade 3-4 neutropenia, leukopenia, and thrombocytopenia in 34%, 19%, and 16% of patients, respectively, and a single episode of febrile neutropenia. One third of patients developed grade 2-3 peripheral neuropathy (oxaliplatin-specific scale), with grade 3 in only 8%.. This oxaliplatin/5-FU combination is effective with an excellent safety profile in anthracycline/taxane-pretreated ABC patients, showing encouraging activity in patients with anthracycline/taxane-resistance or visceral disease.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Safety; Survival Rate; Taxoids; Treatment Outcome

A phase II study was performed to investigate the efficacy and tolerability of gemcitabine as third-line chemotherapy for patients with metastatic breast cancer, previously treated with both an anthracycline- and taxane-containing regimen. Twenty-three patients were treated with gemcitabine 1200 mg/m2 in a 30-min infusion on day 1, 8 and 15 of a 28 day cycle. Seventy-four percent of the patients had visceral metastases. No complete or partial responses were observed. Six patients (26%) had stable disease with a median duration of 4.0 months. The median time to progression was 1.9 months and the median survival time was 7.8 months. Neutropenia grade 3 and 4 was observed in four patients (18%). Non-hematological toxicity grade 3 included nausea and vomiting in 14%, skin toxicity in 9% and elevation of transaminases in 23% of the patients. Gemcitabine is ineffective as third-line single agent therapy in patients failing anthracycline and taxane treatment for metastatic breast cancer.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Gemcitabine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Palliative Care; Taxoids; Treatment Failure

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase, the initial and rate limiting enzyme in the catabolism of fluorouracil. The current study was done to determine the objective tumour response of a 28-day oral regimen of eniluracil-fluorouracil in patients with advanced breast cancer.. This was a multicentre, phase II study in patients with anthracycline-refractory (AR) or anthracycline- and taxane-refractory (ATR) advanced breast cancer. Oral eniluracil (10 mg/m2) and fluorouracil (1 mg/m2) were taken twice daily for 28 days of each 35-day treatment course.. In this study, 106 patients received treatment: 62 patients in the AR stratum and 44 patients in the ATR stratum. The objective tumour response rate in the intent-to-treat population was 18% (95% confidence intervals (CI): 11%-27%), including three complete responses. The response rate was similar in both strata: 19% in the AR and 16% in the ATR stratum. The overall median duration of response was 23.6 weeks. The treatment was well tolerated with a low incidence of grade 3 or 4 toxicities that were considered attributable to study medication.. Treatment with oral eniluracil-fluorouracil was well tolerated by patients with advanced breast cancer. The efficacy data were comparable with those of other published studies in this group of refractory patients.

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Middle Aged; Taxoids; Treatment Outcome; Uracil

Estramustine phosphate (EMP) is an oral cytotoxic agent that depolymerizes tubuline, a mechanism of action that has been revisited during the last decade. Because of its lack of haematological toxicity and favourable tolerance profile, EMP is a good candidate for palliative chemotherapy. The aim of the study was to assess its tolerance and efficacy in advanced breast cancer after failure with usual regimens.. Patients with a life expectancy of at least 12 weeks and bi-dimensionally measurable disease having received at least 1 line of chemotherapy (including taxanes and/or anthracyclines) for advanced breast cancer (ABC) were eligible. EMP was given daily at a dose of 10 mg/kg until disease progression, unacceptable toxicity or patient refusal to continue chemotherapy.. Forty patients were included between June 1998 and December 1999. Patients had previously received one to eight chemotherapy regimens (median is two) for ABC. Twenty-two patients (55%) had visceral involvement and eighteen patients (45%) had osseous, chest wall or soft tissue metastases. Adverse events leading to early interruption of EMP were grade 2 allergy (n = 1), grade 2-3 nausea (n = 6), deep-vein thrombosis (n = 1), grade 3 sepsis (n = 1). One patient died at twenty-four weeks from pulmonary embolism, and another at fourteen weeks from unknown cause. Seven objective responses were observed (17.5%; 95% confidence interval (CI): 6%-30%). Median time to failure was 24 weeks (14-52+) in responding patients. All objective responses but one were observed in patients with visceral metastases. In 10 other patients (25%), disease remained stable with a median time to failure of 27 weeks (16-50); 6 of these experienced a decrease of consumption of analgesics or an improvement of performance status.. EMP is an active drug in ABC after failure with taxanes and anthracyclines, whose tolerance profile appears favourable.

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Resistance, Neoplasm; Estramustine; Female; Humans; Middle Aged; Salvage Therapy; Taxoids; Treatment Outcome

Currently, there is no gold standard for the treatment of patients with metastatic breast carcinoma who have experienced failure with anthracyclines and taxanes. A biologic rationale suggests that the mechanism of taxane resistance could be because of an excess of depolymerized tubulin that could enhance sensitivity to vinorelbine. The objective of the study was to assess the tolerance and efficiency of weekly vinorelbine in metastatic breast carcinoma after failure with taxanes.. Patients with measurable disease, a World Health Organization performance status of less than 3 and a life expectancy longer than 3 months were eligible. Persistent taxane-induced neuropathy higher than Grade 1 was an exclusion criterion. The initial planned dose was 30 mg/m(2)/week on an outpatient basis without granulocyte colony-stimulating factor (G-CSF). Neutrophil and platelet counts of 1.0 and 80 g/L, respectively, were required before each new injection; otherwise vinorelbine was delayed for 7 days with a dose reduction of 5 mg/m(2) at the second episode. The dose also was reduced if Grade 3 or 4 toxicity occurred. If the adverse event persisted or if the delay exceeded 14 days between 2 injections given at a dose of 20 mg/m(2), vinorelbine was definitively discontinued.. Between November 1997 and March 1999, 40 patients with a median age of 49 (range, 39-69) were enrolled. All of them had previously received anthracyclines and taxanes. Because of the delays in neutrophil recovery, the median dose intensity did not exceed 22.5 mg/m(2)/week (range, 11.25-30), and the initial planned dose of 30 mg/m(2)/week appeared unfeasible without G-CSF. The starting dose therefore was 25 mg/m(2)/week after the first 6 patients. Neutropenia led to fever in only three patients. Other severe toxicities were Grade 2-3 neuropathy (n = 5), Grade 2-3 ileus (n = 7), Grade 3 anemia (n = 4), and Grade 3 sepsis (n = 1). Objective responses were observed in 10 of 40 patients (25%), 7 of whom had visceral metastases and 4 who were refractory to taxanes (including 2 patients with liver involvement > 50%). The median time to failure was 6 months (range, 4-12) for responding patients. Disease stabilization was achieved in 9 patients (23%) for a median duration of 5 months (range, 4-6). The median survival duration for the whole population was 6 months (range, 2-18+).. Weekly vinorelbine is an active salvage therapy for metastatic breast carcinoma after failure with anthracyclines and taxanes, even in patients with taxane-refractory metastatic breast carcinoma. This confirms that vinorelbine and taxanes are not cross-resistant.

Topics: Adult; Aged; Anemia; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Intestinal Obstruction; Middle Aged; Neoplasm Metastasis; Neutropenia; Palliative Care; Salvage Therapy; Sepsis; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

Gemcitabine and vinorelbine have shown activity in breast cancer. A phase II trial was initiated in order to evaluate the response rate (RR) and time to progression (TTP) of the combination of the two drugs in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy.. Thirty-one patients were treated with the combination of gemcitabine 1000 mg/m2 days 1 + 8 and vinorelbine 30 mg/m2 days 1 + 8. The cycles were repeated every three weeks.. Of 27 evaluable patients 1 (4%, 95% confidence interval (95% CI): 0.1%-19%) achieved complete remission (CR), five (18%; 95% CI: 6%-38%) partial remission (PR), eleven (40%; 95% CI: 22%-61%) stable disease and ten patients progressed. The median duration of response was six months (range 4-10+) and the median duration of disease stabilization was five months (range 2-22+). With a median follow-up of 16 months (range 0.4-22+) the median TTP was 3.5 months (range 0.4-22+) and the median survival was 9.5 months (range 0.4-22+). Grade 3-4 toxicities were granulocytopenia 15 patients (48%), rash 3 patients (10%), neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%). In conclusion the combination of gemcitabine/vinorelbine in the doses administered in this group of patients had a response rate of 22% and needs to be further evaluated in metastatic breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Taxoids; Vinblastine; Vinorelbine

A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated.. Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours.. After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity.. Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Female; Humans; Infusions, Intravenous; Middle Aged; Paclitaxel; Taxoids

Taxanes form the mainstay of breast cancer therapy in the curative setting. Taxane-induced peripheral neuropathy (TIPN) is a common toxicity and confers significant morbidity with no validated therapies. Literature detailing TIPN is inconsistent in reporting its frequency, severity, risk factors, impact upon treatment course, and management practices.. A retrospective chart review was performed including 348 early-stage breast cancer patients undergoing weekly paclitaxel therapy between 2010 and 2020 in the adjuvant or neoadjuvant setting. The frequency, severity, and impact on treatment from TIPN were analyzed during treatment and at one year follow-up. Clinicopathological and patient factors were collected to identify potential risk factors.. 279 out of 348 patients (80.2%) developed TIPN of any grade. One-year follow-up was available for 232 of the original 279 TIPN patients (83.2%). Of these, 52 patients (22.4%) exhibited persisting TIPN of any grade. The presence and severity of TIPN during treatment was significantly associated with a lower median dose intensity (100% versus 82.5% for non-TIPN and all-grade TIPN respectively, p < 0.001). Neoadjuvant treatment (p = 0.038) and body surface area (BSA, p = 0.035) were independently associated with TIPN during treatment. Increased age (p < .001) and pre-treatment diabetes (p = 0.009) were associated with TIPN at one-year follow-up.. TIPN is common in breast cancer patients undergoing weekly paclitaxel therapy. TIPN results in patients receiving significantly lower dose intensity due to dose reductions and premature treatment cessation. Future prospective studies in similar cohorts are warranted, with a focus on long-term outcomes.

Topics: Breast Neoplasms; Female; Humans; Paclitaxel; Peripheral Nervous System Diseases; Prospective Studies; Retrospective Studies; Taxoids

Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC.. Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin.. In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options.. In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Carboplatin; Cost-Benefit Analysis; Doxorubicin; Female; Humans; Paclitaxel; Quality of Life; Taxoids

Taxane-induced peripheral neuropathy (TIPN) is a debilitating adverse effect of cancer treatments with taxanes which may require a reduction or discontinuation chemotherapy and affect clinical and survival outcomes. A number of factors have contributed to the increasing prevalence of TIPN. Nonetheless, limited knowledge exists of potential prechemotherapy blood-based biochemical factors associated with TIPN development.. We recruited breast cancer patients at seven cancer institutions in China. Participants aged 18 years or older with stage I to III breast cancer who scheduled to undergo primary neoadjuvant and adjuvant chemotherapy with taxanes were eligible. Eligible patients underwent patient-reported neuropathy assessments using the EORTC-CIPN20 questionnaire. Patients completed the questionnaire before commencing treatment and after every cycle. For every patient, we selected the highest TIPN toxicity score for analysis since the first cycle. The posttreatment TIPN severity was compared with blood-based biochemical factors within 30 days before commencing treatment. Independent samples t tests, Mann-Whitney U tests and linear regression were used to identify blood-based and clinical associations with TIPN development.. The study included 873 breast cancer participants who received paclitaxel, docetaxel or nanoparticle albumin-bound (nab)-paclitaxel. In the whole cohort, factors associated with higher TIPN toxicity scores were higher cumulative chemotherapy dose (β = 0.005; 95% CI, 0.004 to 0.006; P < .001), lower sodium ions (β = -0.24; 95% CI, -0.39 to -0.09; P = .002) and higher chloride ions (β = 0.30; 95% CI, 0.16 to 0.44; P < .001).. The findings suggest that breast cancer patients with a higher cumulative chemotherapy dose, lower pretreatment sodium ions, and higher pretreatment chloride ions receiving taxanes should receive closer monitoring to mitigate the development of short-term and long-term TIPN.

Topics: Breast Neoplasms; Chlorides; East Asian People; Female; Humans; Paclitaxel; Peripheral Nervous System Diseases; Taxoids

Breast cancer treatment is associated with adverse effects, which may delay return-to-work. Single nucleotide polymorphisms (SNPs) may influence the risk and severity of treatment toxicities, which in turn could delay return-to-work. We examined the association of 26 SNPs with return-to-work in premenopausal women with breast cancer.. Using Danish registries, we identified premenopausal women diagnosed with non-distant metastatic breast cancer during 2007‒2011, assigned adjuvant combination chemotherapy including cyclophosphamide and docetaxel. We genotyped 26 SNPs in 20 genes (ABCB1, ABCC2, ABCG2, CYP1A1, CYP1B1, CYP3A, CYP3A4, CYP3A5, GSTP1, SLCO1B1, SLCO1B3, ARHGEF10, EPHA4, EPHA5, EPHA6, EPHA8, ERCC1, ERCC2, FGD4 and TRPV1) using TaqMan assays. We computed the cumulative incidence of return-to-work (defined as 4 consecutive weeks of work) up to 10 years after surgery, treating death and retirement as competing events and fitted cause-specific Cox regression models to estimate crude hazard ratios (HRs) and 95% confidence intervals (CIs) of return-to-work. We also examined stable labor market attachment (defined as 12 consecutive weeks of work).. We included 1,964 women. No associations were found for 25 SNPs. The cumulative incidence of return-to-work varied by CYP3A5 rs776746 genotype. From 6 months to 10 years after surgery, return-to-work increased from 25 to 94% in wildtypes (n = 1600), from 17 to 94% in heterozygotes (n = 249), and from 7 to 82% in homozygotes (n = 15). The HR showed delayed return-to-work in CYP3A5 rs776746 homozygotes throughout follow-up (0.48, 95% CI 0.26, 0.86), compared with wildtypes. Estimates were similar for stable labor market attachment.. Overall, the SNPs examined in the study did not influence return-to-work or stable labor market attachment after breast cancer in premenopausal women. Our findings did suggest that the outcomes were delayed in homozygote carriers of CYP3A5 rs776746, though the number of homozygotes was low.

Topics: Breast Neoplasms; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Microfilament Proteins; Polymorphism, Single Nucleotide; Return to Work; Taxoids; Xeroderma Pigmentosum Group D Protein

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytics to describe taxane-associated CIPN risk.. We analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher's ratio (FR). We then ranked ordered those SNPs which discriminated CIPN-positive (CIPN +) from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross-validation (LOOCV).. Using aggregated genotype data obtained from the previously reported ECOG-5103 clinical trial (in which two different arrays were used, HumanOmniExpress (727,227 SNPs) and HumanOmni1-Quad1 (1,131,857 SNPs)), we identified a 267 SNP cluster which was associated with a CIPN + phenotype with an accuracy of 96.1%.. A cluster of SNPs was identified which prospectively discriminated patients most likely to develop symptomatic CIPN following taxane exposure as part of a breast cancer chemotherapy regimen. Validation using an independent patient cohort should be performed.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Genome-Wide Association Study; Humans; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; Taxoids

Taxanes are major drugs for metastatic breast cancer (MBC) treatment, and are generally well tolerated, making them attractive for therapeutic reintroduction (rechallenge) during metastatic course. In view of the paucity of current literature, we questioned the usefulness of taxane rechallenge in a population of patients previously treated with taxanes in a metastatic setting.. From the local database of a French cancer center, we retrospectively identified 756 patients diagnosed with ER+/HER2-, or triple negative MBC, and treated between 2008 and 2021. Among them, 58 patients (7.8%) were rechallenged with taxanes. Clinical characteristics, response rates, and survival were retrospectively evaluated and compared to patients who received taxanes only once.. Compared to non-rechallenged population, patients treated with taxane rechallenge were significantly younger, with better general status, and received more treatment. First taxane exposure led to better tumor response and was more frequently discontinued for reasons other than progression, compared to the non-rechallenged population. Taxane rechallenge led to an objective response rate of 27.6%, and a clinical benefit rate of 46.6%, with a median progression-free survival (PFS) of 5.7 months, and a median overall survival (OS) of 11.6 months. We also found a PFS2/PFS1 ratio >1.3 in 55.2% of the rechallenge population.. Although only a minority of MBC patients are concerned, taxane rechallenge appears to be a pragmatic option with an acceptable tolerance, and good efficacy, especially when these drugs have shown clinical activity earlier in the disease course, and/or have been stopped for reasons other than progression.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Neoplasms, Second Primary; Retrospective Studies; Taxoids; Treatment Outcome; Triple Negative Breast Neoplasms

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Taxoids; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with an aggressive clinical course. Adjuvant chemotherapy reduces the risk of recurrence and improves survival in patients with node-positive TNBC. The benefit of anthracycline plus taxane (ATAX) regimens compared with non-anthracycline-containing, taxane-based regimens (TAX) in older women with node-positive TNBC is not well characterised.. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1106 women with node-positive TNBC diagnosed at age 66 years and older between 2010 and 2015. We compared patient clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs). Kaplan-Meier survival curves were generated to estimate 3-year overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazard models were used to analyse OS and CSS while controlling for patient and tumour characteristics.. Of the 1106 patients in our cohort, 767 (69.3%) received adjuvant chemotherapy with ATAX (364/767, 47.5%), TAX (297/767, 39%) or other regimens (106/767, 13.8%). Independent predictors of which patients were more likely to receive ATAX versus TAX included more extensive nodal involvement (≥4), age, marital/partner status and non-cardiac comorbidities. There was a statistically significant improvement in 3-year CSS (81.8% versus 71.4%) and OS (70.7% versus 51.3%) with the use of any chemotherapy in our cohort (P < 0.01). Three-year CSS and OS for patients who received ATAX versus TAX were similar at 82.8% versus 83.7% (P = 0.80) and 74.2% versus 72.7% (P = 0.79), respectively. There was a trend towards improved CSS and OS in patients with four or more positive lymph nodes who received ATAX versus TAX (hazard ratio 0.66, 95% CI: 0.36-1.23, P = 0.19 and hazard ratio 0.68, 95% CI: 0.41-1.14, P = 0.14, respectively).. Among older women with node-positive TNBC, a majority of patients received adjuvant chemotherapy, which was associated with an improvement in CSS and OS. When compared with TAX chemotherapy, there was a trend towards better outcomes with ATAX for patients with ≥4 nodes.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Medicare; Taxoids; Triple Negative Breast Neoplasms; United States

Patients undergoing neoadjuvant chemotherapy (NC) for invasive breast cancer (IBC) need indicators to track their progress during treatment. The goal of this research is to learn how cyclin D1 works in conjunction with taxane and non-taxane therapy for people with IBC.. There were 31 examples divided into two groups, based on: those using a different type of NC (taxane- or non-taxane-based), and NC administration time (before or after). Tumor grade, age, PR, ER, Ki-67, HER2, and Cyclin D1 expression were among the factors considered. Using immunohistochemical labeling, we were able to categorize cyclin D1 levels according to a threshold value, and we supplemented this with data we found in our databases. To analyze the data, we used a modified linear model.. The expression of Cyclin D1 decreased after NC delivery (p=0.086). Cyclin D1 expression was reduced in the taxane group (p=0.792). The non-taxane group also saw no differences in outcomes (p = 0.065). There was a larger decrease in Cyclin D1 expression in the non-taxane group compared to the taxane group, but the difference was not statistically significant (p=0.200).. Cyclin D1 expression, even if the differences are not statistically significant, may be a prognostic indicator of NC reaction in IBC. The involvement of Cyclin D1 in NC warrants more research with bigger IBC sample sizes.

Topics: Breast Neoplasms; Cyclin D1; Female; Humans; Neoadjuvant Therapy; Prognosis; Receptor, ErbB-2

On the basis of the results from CLEOPATRA, pertuzumab plus trastuzumab and chemotherapy is the first-line standard of care for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, discrepancies have been reported between clinical trial and real-world outcomes. We report real-world outcomes for patients with HER2-positive MBC treated with first-line pertuzumab plus trastuzumab and a taxane in routine clinical practice in the United States.. A retrospective analysis was conducted using electronic health record-derived deidentified data from the Flatiron Health database. Patients were grouped according to the first taxane received (paclitaxel/nab-paclitaxel or docetaxel). Median real-world progression-free survival (rwPFS) and overall survival (rwOS) was estimated using Kaplan-Meier methodology. Subgroup analyses were conducted in patients treated with docetaxel who met CLEOPATRA's key eligibility criteria.. We included 1,065 patients; 313 patients received paclitaxel/nab-paclitaxel and 752 received docetaxel. Patients who received paclitaxel/nab-paclitaxel were older, had a worse Eastern Cooperative Oncology Group Performance Status, and had more recurrent metastatic disease compared with the docetaxel group. After adjustment for potential confounders, similar median rwPFS (inverse probability of treatment weighted average treatment effect for the treated [IPTW-ATT] hazard ratio [HR], 1.09; 95% CI, 0.9 to 1.3;. There was no statistically significant difference in real-world outcomes between patients treated with paclitaxel/nab-paclitaxel and those treated with docetaxel. Selecting patients using key CLEOPATRA eligibility criteria resulted in rwPFS and rwOS similar to those observed in CLEOPATRA, highlighting the importance of ensuring similar patient populations when comparing clinical trial and real-world data.

Topics: Breast Neoplasms; Docetaxel; Electronic Health Records; Female; Humans; Paclitaxel; Retrospective Studies; Taxoids; Trastuzumab

Taxane-associated acute pain syndrome (T-APS) is one of the most bothersome adverse effects caused by taxanes. We have previously reported the attenuating effect of dexamethasone (DEX) on T-APS and its risk factors under DEX prophylaxis. However, the appropriate DEX dosage administration remains unclear. Therefore, this study aimed to investigate whether DEX dose-dependently prevents T-APS in breast cancer patients.. The incidence of all-grade T-APS was 72.1% in 4 mg/day group and 48.5% in 8 mg/day group, which was significantly lowered by higher DEX dosage (P = 0.008). The severity of T-APS was also significantly reduced in 8 mg/day group (P = 0.02). These results were confirmed in the propensity score matching. Multivariate logistic analysis showed that higher DEX dosage was an independent T-APS preventive factor, whereas age < 55 years was a risk factor. Moreover, DEX-dosage-associated adverse effects similarly appeared in both groups.. Our study suggested that DEX dose-dependently prevents T-APS in breast cancer treatment. As understanding of the nature of T-APS and its appropriate management can significantly contribute to less onerous chemotherapy provision, further studies are required.

Topics: Acute Pain; Breast Neoplasms; Dexamethasone; Female; Humans; Middle Aged; Retrospective Studies; Taxoids

The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status.. Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status.. HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk.. HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Neoadjuvant Therapy; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Even though tamoxifen has significantly improved the survival of estrogen receptor positive (ER+) mammary carcinoma (MC) patients, the development of drug resistance with consequent disease recurrence has limited its therapeutic efficacy. Trefoil factor-3 (TFF3) has been previously reported to mediate anti-estrogen resistance in ER+MC. Herein, the efficacy of a small molecule inhibitor of TFF3 (AMPC) in enhancing sensitivity and mitigating acquired resistance to tamoxifen in ER+MC cells was investigated. AMPC induced apoptosis of tamoxifen-sensitive and resistant ER+MC cells and significantly reduced cell survival in 2D and 3D culture in vitro. In addition, AMPC reduced cancer stem cell (CSC)-like behavior in ER+MC cells in a BCL2-dependent manner. Synergistic effects of AMPC and tamoxifen were demonstrated in ER+MC cells and AMPC was observed to improve tamoxifen efficacy in tamoxifen-sensitive cells and to re-sensitize cells to tamoxifen in tamoxifen-resistant ER+MC in vitro and in vivo. Additionally, tamoxifen-resistant ER+MC cells were concomitantly resistant to anthracycline, platinum and fluoropyrimidine drugs, but not to Taxanes. Taxane treatment of tamoxifen-sensitive and resistant ER+MC cells increased TFF3 expression indicating a combination vulnerability for tamoxifen-resistant ER+MC cells. Taxanes increased CSC-like behavior of tamoxifen-sensitive and resistant ER+MC cells which was reduced by AMPC treatment. Taxanes synergized with AMPC to promote apoptosis and reduce CSC-like behavior in vitro and in vivo. Hence, AMPC restored the sensitivity of tamoxifen and enhanced the efficacy of Taxanes in tamoxifen-resistant ER+MC. In conclusion, pharmacological inhibition of TFF3 may serve as an effective combinatorial therapeutic strategy for the treatment of tamoxifen-resistant ER+MC.

Topics: Breast Neoplasms; Carcinoma; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Recurrence, Local; Tamoxifen; Taxoids; Trefoil Factor-3

The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer.. This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures.. DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression.. This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming.. Not applicable (non-interventional study). CRUK Internal Database Number 14232.

Topics: Adult; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; DNA Damage; Female; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nucleotidyltransferases; Taxoids; Treatment Outcome

Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and subjective measures of cognitive performance and well-being differ among older breast cancer survivors as a function of taxane-based chemotherapy treatment regimens.. Individual-level data were pooled and harmonized from two large prospective studies of older (greater than 60 years) breast cancer survivors. Assessments were conducted prior to systemic therapy and up to 36 months after. Cognitive performance was assessed with objective (working memory, processing speed, and executive functions) and subjective tests and physical, emotional, and functional well-being were also assessed.. One hundred and sixty-seven (M age = 67.3 years) women with 116 receiving chemotherapy with taxanes and 51 without taxanes contributed data. Declines in subjective cognition for both groups were significant between pre-treatment and 12-month follow-up. Significant improvements were seen on a measure of objective cognition (working memory) from 12 to 36 months. Measures of well-being improved from prior to systemic therapy to 12 months. Longitudinal changes across all measures did not vary as a function of receipt of taxane-based treatment.. Older women who received treatment with taxanes did not have greater declines in cognitive performance or well-being than women receiving other chemotherapy regimens. Despite older cancer survivors being at greater risk for negative outcomes, treatment with taxane-based chemotherapies does not appear to exacerbate these health consequences.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Cognition; Female; Humans; Prospective Studies; Quality of Life; Taxoids

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Endosomes; Female; Humans; Taxoids; Triple Negative Breast Neoplasms

Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.. We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.. Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98).. Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cohort Studies; Cytochrome P-450 CYP3A; Denmark; Docetaxel; Female; Humans; Liver-Specific Organic Anion Transporter 1; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Taxoids

Taxane-based chemotherapy agents, such as docetaxel and paclitaxel, are used for treating a wide range of cancers. Although much has been published on adverse events related to taxanes, data on ocular outcomes with these very important drugs are scant.. To quantify the risk of 3 mutually exclusive ocular adverse events of epiphora, cystoid macular edema (CME), and optic neuropathy with taxane-based chemotherapy agents by undertaking a large pharmacoepidemiologic study.. This retrospective cohort study design used a private health-claims database from the US that captures health information of more than 150 million enrollees. The study team created a cohort of new users of women with cancer who were taking taxane-based chemotherapy (docetaxel or paclitaxel) and new users of tamoxifen as controls. Study members were observed to the first incidence of each of the 3 mutually exclusive outcomes. An analysis of taxane-only users was also undertaken.. Tamoxifen (unexposed) and taxanes (ie, paclitaxel and docetaxel) as the exposed.. First diagnosis of (1) epiphora, (2) cystoid macular edema (CME), or (3) optic neuropathy ascertained using International Statistical Classification of Diseases and Related Health Problems, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.. Among the 18 219 users in the epiphora analysis and optic neuropathy analysis, there were 1824 taxane users (paclitaxel and docetaxel) (age, mean [SD], 62.1 [12.7] years) and 16 395 tamoxifen users (age, mean [SD], 54.6 [12.8] years), respectively. The crude hazard ratio (HR) for epiphora was 5.55 (95% CI, 2.99-10.29) and adjusted HR was 5.15 (95% CI, 2.79-9.54). For optic neuropathy, the crude HR was 4.43 (95% CI, 1.10-17.82) and the adjusted HR was 4.44 (95% CI, 1.04-18.87). Among the 18 433 users in the CME analysis, there were 1909 taxane users (paclitaxel and docetaxel) (age, mean [SD], 62.5 years) and 16 524 tamoxifen users (age, mean [SD], 54.6 years). The crude HR for CME comparing taxane users with tamoxifen users was 1.37 (95% CI, 0.72-2.60) and adjusted HR was 1.33 (95% CI, 0.70-2.53). The HRs for epiphora and CME in the taxane cohort during the time of exposure compared with the period prior to use of the drugs were 2.86 (95% CI, 1.11-7.39) and 2.27 (95% CI, 0.68-7.54), respectively.. In a cohort of women who were using taxane chemotherapy agents, there was an association with elevated risk for epiphora, CME, and optic neuropathy. Ophthalmologists and oncologists should be aware of these adverse events in women with breast cancer who receive these drugs.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Child; Docetaxel; Female; Humans; Lacrimal Apparatus Diseases; Macular Edema; Middle Aged; Optic Nerve Diseases; Paclitaxel; Retrospective Studies; Tamoxifen; Taxoids

HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR). Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Patient factors that predict DR continue to be elucidated.. This is a retrospective study of patients with de novo HER2 + MBC. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor, and initial treatment were analyzed.. 96 patients with de novo HER2 + MBC, 28 with DR, and 68 with progression were identified. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p = 0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p < 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p = 0.002.) Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab.. Nearly a third of patients with de novo HER2 + MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. Among patients with DR, indefinite trastuzumab administration is the norm.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoplasm Metastasis; Neoplasms, Second Primary; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab; Treatment Outcome

Dramatic improvements in cancer survival have occurred in the last decade, but the quality of life for many survivors is compromised due to severe, long-lasting, and often irreversible side effects of chemotherapy. The neurological side effects, chemotherapy induced peripheral neuropathy (CIPN) and cancer related/induced cognitive impairment (CRCI/CICI), are under-recognized and can occur after chemotherapy, immunotherapy, or radiation. The cellular mechanisms underlying these neurological side effects are poorly understood and there are no effective treatments or preventions, other than reduction or termination of cancer therapy. In our preliminary prospective, non-interventional study to examine the side effects of chemotherapy in patients with breast cancer (NCT03872141), patients with breast cancer who received standard of care single agent weekly taxane-based chemotherapy were assessed at baseline, midpoint, and end of treatment for neurological and cognitive changes and for blood levels of potential protein biomarkers (n = 13). CIPN and CRCI both showed an increase in severity with accumulating taxane and these changes were compared to protein alternations over the course of treatment. Using peripheral blood collected from patients (n = 10) during chemotherapy and tested with an antibody array curated by the MD Anderson RPPA Core), we found that 19 proteins were increased, and 12 proteins decreased over 12 weeks of treatment. Among those downregulate were proteins known to be critical for neuronal viability and function including GRB2 (growth factor receptor-bound protein 2) and NCS1 (neuronal calcium sensor 1). Concurrently, proteins associated with apoptosis, including BAK1 (Bcl-1 homologous antagonist/killer), were upregulated. These results support the proposal that CIPN and CRCI increase with increasing taxane exposure, and identified several proteins that are altered with taxane exposure that could be implicated in their pathogenesis. In conclusion, our study provides evidence for progressive neurological changes and the rationale to investigate the molecular basis for these changes with the goal of target identification for mitigation of these neurological side effects.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cognition; Female; Humans; Peripheral Nervous System Diseases; Prospective Studies; Quality of Life; Receptors, Growth Factor; Taxoids

Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR; ypT0/isypN0), and the secondary endpoints were breast pathologic complete response (bpCR; ypT0/is) and axillary pathologic complete response (apCR; ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H + P + taxane + carboplatin (TcbHP), 94 with H + P + taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H + P + taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P = .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.

Topics: Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Cyclophosphamide; Female; Hormones; Humans; Neoadjuvant Therapy; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab

The prevention of chemotherapy-induced alopecia still represents an urgent need for every day clinical practice. In this regard, this prospective single-center study included breast cancer (BC) patients who underwent a scalp cooling device (Dignicap

Topics: Adult; Alopecia; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Female; Humans; Paclitaxel; Prospective Studies; Scalp; Taxoids

Understanding the detailed symptom spectrum of chemotherapy-induced peripheral neuropathy (CIPN) could facilitate shared decision-making and promote early intervention.. To compare the symptom spectrum of patient-reported CIPN associated with nab-paclitaxel, paclitaxel, and docetaxel treatments among patients with breast cancer.. This prospective cohort study was conducted at 9 medical centers across China from 2019 to 2021. Participants included hospitalized women diagnosed with invasive breast cancer, assessed with overlap propensity score weighting. Data were analyzed from from December 2021 to May 2022.. Treatment with nab-paclitaxel-, paclitaxel-, or docetaxel-based regimens.. Patient-reported CIPN on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire: CIPN 20-item instruments, consisting of sensory, motor, and autonomic scales. Multiple regression models were adjusted for baseline patient, tumor, and treatment characteristics.. Of 1234 participants, the mean (SD) age was 50.9 (10.4) years, and 295 patients (23.9%) received nab-paclitaxel, 514 patients (41.7%) received paclitaxel, and 425 patients (34.4%) received docetaxel. The nab-paclitaxel group mostly reported numbness in hands or feet related to sensory symptoms (83 patients [81.4%]), while the paclitaxel and docetaxel groups reported mainly motor (eg, weakness in legs: 60 patients [47.2%] in the paclitaxel group; 52 patients [44.4%] in the docetaxel group) and autonomic (eg, blurred vision: 58 patients [45.7%] in the paclitaxel group; 51 patients [43.6%] in the docetaxel group) symptoms. Patients reported motor symptoms earlier than sensory abnormalities, with a median of 0.4 (95% CI, 0.4-2.3) weeks in the nab-paclitaxel group, 2.7 (95% CI, 1.7-3.4) weeks in the paclitaxel group, and 5.6 (95% CI, 3.1-6.1) weeks in the docetaxel group. After overlap propensity score weighting and compared with the nab-paclitaxel group, the risks of patient-reported CIPN were lower in the paclitaxel (hazard ratio [HR], 0.59 [95% CI, 0.41-0.87]; P = .008) and the docetaxel (HR, 0.65 [95% CI, 0.45-0.94]; P = .02) groups. Similarly, patients who received paclitaxel (HR, 0.44 [95% CI, 0.30-0.64]; P < .001) or docetaxel (HR, 0.52 [95% CI, 0.36-0.75]; P < .001) reported less sensory discomfort compared with those who received nab-paclitaxel. However, the risk of patients in the paclitaxel or docetaxel groups reporting motor (paclitaxel: HR, 0.76 [95% CI, 0.52-1.11]; P = .15; docetaxel: HR, 0.69 [95% CI, 0.47-1.01]; P = .05) and/or autonomic (paclitaxel: HR, 1.00 [95% CI, 0.68-1.49]; P = .98; docetaxel: HR, 0.88 [95% CI, 0.59-1.30]; P = .52) symptoms was not lower than that in the nab-paclitaxel group.. In this cohort study of women with invasive breast cancer, nab-paclitaxel was associated with more severe CIPN than either paclitaxel or docetaxel. In addition to sensory symptoms, the risk of motor and autonomic abnormalities was not low among these 3 taxanes, and patients-reported motor symptoms even earlier than sensory symptoms. These findings may facilitate early detection and intervention for CIPN in taxane treatments for breast cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cohort Studies; Docetaxel; Female; Humans; Middle Aged; Paclitaxel; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Prospective Studies; Quality of Life; Taxoids

Neoadjuvant chemotherapy before mastectomy helps reduce tumor burden and pathologic response in breast cancer. Limited evidence exists regarding how neoadjuvant chemotherapy impacts outcomes following microvascular breast reconstruction. This study examines the effects of neoadjuvant chemotherapy regimens and schedules on microvascular breast reconstruction complication rates and also assesses the effects of neoadjuvant chemotherapy on circulating immune cells related to wound healing.. Patients who underwent neoadjuvant chemotherapy and microvascular breast reconstruction at Yale New Haven Hospital between 2013 and 2018 were identified. Demographic variables, oncologic history, chemotherapy regimens, and complication profiles were collected. Chemotherapy regimens were stratified by inclusion of anthracycline and order of taxane administration. Chi-square, Fisher's exact, and t tests were used for univariate analysis. Multivariate binary logistic regression was used to control for covariates.. One hundred patients met inclusion criteria. On multivariate analysis, the administration of taxane first in an anthracycline-containing chemotherapy sequence was associated with increased complications (OR, 3.521; p = 0.012), particularly fat necrosis (OR, 2.481; p = 0.040). In the logistic regression model evaluating the effect of the taxane-first regimen on complication rates, the area under the curve was estimated to be 0.760 (p < 0.0001), particularly fat necrosis 0.635 (p < 0.05). The dosage of chemotherapy, number of days between neoadjuvant chemotherapy completion and surgery, and number of circulating immune cells did not significantly differ among patients who experienced complications.. Taxane-first, anthracycline-containing neoadjuvant chemotherapy regimens were associated with increased complications, particularly fat necrosis. The increased postreconstruction complication risk must be weighed against the benefits of taxane-first regimens in improving tumor outcome.. Therapeutic, III.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Mammaplasty; Mastectomy; Middle Aged; Neoadjuvant Therapy; Postoperative Complications; Surgical Flaps; Taxoids; Treatment Outcome

Current guidelines recommend harvesting ≥3 sentinel nodes if sentinel lymph node biopsy (SLNB) alone is considered after neoadjuvant therapy (NAT) for initially node-positive (cN+) breast cancer. We attempted to investigate factors predicting one or two sentinel lymph nodes harvested to be accepted for SLNB alone after NAT in initially cN + patients.. Overall, 157 patients who received NAT (clinically T1-3/N1-2/M0) and underwent SLNB were identified from a prospectively maintained database. Significant factors were identified using a multiple logistic regression model.. The overall SLN identification rate was 83.4%. Failed SLN identification was associated with a 2-day protocol using a single tracer (odds ratio: 0.331 [95% confidence interval {CI}: 0.132-0.830], p = 0.018), age >52 years (0.345 [0.131-0.913], p = 0.032), and lobular histology (0.156 [0.026-0.944], p = 0.043). The overall false-negative SLNB rate was 14.7%. Its increased risk was associated with radioactivity count >530 for any SLN during SLNB (96.4 [4.00-2320], p = 0.005), age ≥57 years (34.2 [1.92-610], p = 0.016), and taxane use (105 [1.02-10700], p = 0.049); its decreased risk was associated with more harvested SLNs (0.191 [0.054-0.669], p = 0.01) and dual tracers (0.101 [0.012-0.843], p = 0.034). A predictive model using these factors achieved an area under the curve of 0.935 (95% CI: 0.878-0.991).. When taxane was administered during NAT, the false-negative rate was predicted at <5% for patients aged <57 years, if 1-2 SLNs were harvested using dual tracers, and when the count of every SLN was lower than 530 after NAT in cN + breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Bridged-Ring Compounds; Databases, Factual; Female; Humans; Middle Aged; Neoadjuvant Therapy; Risk Assessment; Sensitivity and Specificity; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Taiwan; Taxoids; Young Adult

This study aimed to investigate level fluctuations of serum biomarkers that are associated with cardiotoxicity risk, such as high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein-B (Apo-B) in response to chemotherapy treatment for breast cancer.. The serum levels of hs-CRP and Apo-B were evaluated in 56 breast cancer patients with main inclusion criteria: HER2 negative and who received adjuvant chemotherapy AC [A: Adriamycin, C: Cyclophosphamide] or AC→T [A: Adriamycin, C: Cyclophosphamide, T: Taxane] regimes at early II (n = 26) and late IV (n = 30) clinical stages by using particle enhanced turbidimetric assay.. The results of this study suggest that a high level of pre-treatment hs-CRP is a good prognostic marker in comparison to Apo-B. Moreover, the AC-T chemotherapy regime treatment in both early and late stages exhibited a significantly higher level of hs-CRP compared to that in the AC regime. Hs-CRP was significantly elevated in the early stage in comparison to the late stage among cancer patients, meanwhile Apo-B behaved inversely. Furthermore, the results showed that hs-CRP levels were significantly higher in late-stage cancer patients compared with those in early-stage in both chemotherapy regimens groups. On the other hand, Apo-B showed no significant differences.. Monitoring hs-CRP level changes in comparison to Apo-B can be used to assist the side effect risk difference among different chemotherapy regimens, and staging reflecting a positive correlation between them more notable in the late stage.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apolipoproteins B; Biomarkers; Breast Neoplasms; Bridged-Ring Compounds; C-Reactive Protein; Cardiotoxicity; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Female; Humans; Middle Aged; Risk Assessment; Taxoids

Taxanes are a class of chemotherapeutic agents with common associated dermatologic adverse events, such as skin hyperpigmentation, hand-foot skin syndrome, paronychia and onycholysis. Taxane-induced scleroderma is rare. Few cases with skin findings resembling systemic sclerosis, have been reported after the administration of these agents. We report two cases with stage IV breast cancer, aged 66 and 71 years, who developed sclerodermic skin lesions in their extremities after starting treatment with placlitaxel and nabplaclitaxel respectively.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Scleroderma, Systemic; Taxoids

To maximize the effect of perioperative chemotherapy in breast cancer, it is critical to keep the relative dose intensity (RDI) high. While bi-weekly doxorubicin and cyclophosphamide, dose-dense AC (ddAC), instead of tri-weekly conventional AC (cAC) followed by a taxane has been adopted as standard perioperative chemotherapy, postponement or discontinuation are sometimes experienced during ddAC or subsequent taxane phase. This study aimed at evaluating whether ddAC, compared to cAC, was associated with reduced RDI.. We compared ddAC and cAC, both followed by a taxane, for perioperative breast cancer regarding the proportion of completion of planned treatment (%completion), defined as an RDI ≥85% for both AC and taxane phases.. There was no remarkable difference between the groups in patient characteristics after propensity score matching (n=46 in ddAC, and n=86 in cAC). The %completion was similar between the groups (67.4% vs. 65.1%). Most other endpoints related to RDI were similar between groups. The incidence of pneumonia was higher in the ddAC group (13% vs. 3%) including one Pneumocystis jiroveci pneumonia.. ddAC followed by a taxane can be considered with sufficient supportive measures and precautions for pneumonia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Doxorubicin; Female; Humans; Propensity Score; Taxoids

Chemotherapy-induced alopecia (CIA) is a common and quite distressing adverse effects of chemotherapy. There are few detailed observational studies of CIA or of the impact of age on CIA. We performed a prospective observational study to investigate the prevalence and degree of CIA, including CIA of eyebrows, eyelashes, and body, and we examined patient's recovery from CIA, focusing on age-depending effects.. We analyzed 68 female Japanese patients with breast cancer (median age 53 years, range 29-76 years) who received perioperative adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide (FEC) and taxane. A questionnaire was administered at the point of chemotherapy completion and 6 and 12 months after chemotherapy completion.. CIA occurred in all patients, with severe hair loss irrespective of age. CIA occurred mainly in the scalp but also in the eyebrows, eyelashes, and body for most of the patients. There were significant associations between the patient's age and the onset of hair regrowth in the eyebrows, eyelashes, and body. The onset of eyebrows, eyelash, and body hair growth were significantly shorter in the premenopausal patients. Any hair changes (e.g., thinned diameter, softer texture, curlier structure) were reported by 85.3% of the patients.. Severe CIA occurred in all 68 patients who received FEC and taxane chemotherapy. The present findings provide the first data demonstrating that age was not associated with the degree or incidence of hair loss, but age affected the recovery from CIA. These results contribute more accurate information provision and insights regarding the proper treatment of CIA.

Topics: Adult; Age Factors; Aged; Alopecia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Epirubicin; Eyebrows; Eyelashes; Female; Fluorouracil; Humans; Japan; Middle Aged; Premenopause; Prevalence; Prospective Studies; Scalp; Self Report; Taxoids; Treatment Outcome

This study aimed to prospectively explore severity and prevalence of chemotherapy-induced peripheral neuropathy (CIPN) and examine the correlation between clinician-assessed (objective) and patient-reported (subjective) CIPN in breast cancer survivors receiving taxane.. This was a prospective, longitudinal study. Purposive sampling was adapted to enroll women newly diagnosed with breast cancer and about to receive taxane. The CIPN was assessed after breast cancer diagnosed and before chemotherapy (T1), before cycle 1 to 4 taxane infusion (T2 to T5), and after chemotherapy completion (T6 to T8). Total Neuropathy Score-clinical version (TNSc), Identification Pain Questionnaire (ID pain), Functional Assessment of Cancer Therapy-Taxane subscale (FACT-Tax), and Peripheral Neuropathy Scale (PNS) were utilized for measuring CIPN. Descriptive statistics, Pearson correlation coefficient, and generalized estimating equation were used to analyze data.. A total of 88 participants were included. Both clinician-assessed and patient-reported CIPN gradually increased between T1 and T6 and mildly decreased at T7 and T8. Fifty-five participants (62.5%) experienced CIPN at T8. Weak-to-moderate correlations between subjective and objective CIPN were found at T6 to T8 (r = 0.272-0.533, p < 0.05). The change of TNSc, FACT-Tax, and PNS were significant over time. However, the significant change of neuropathic pain was only found at T6.. The change of CIPN prevalence and severity were significant over time in survivors newly diagnosed with breast cancer. Specifically, the severest and highest CIPN was detected at chemotherapy completion. Survivors remained suffering from CIPN 3 months after chemotherapy completion. Besides, mild to moderate correlations between clinician-assessed and patient-reported CIPN were identified.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Cancer Survivors; Female; Humans; Longitudinal Studies; Middle Aged; Peripheral Nervous System Diseases; Prospective Studies; Taxoids

Multi-gene prognostic signatures of long non-coding RNAs (lncRNAs) provide new insights into mechanisms of HER2-negative breast cancer development and progression, and predict distant relapse-free survival (DRFS) of patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. The aim of this study was to develop such a multi-lncRNAs signature. Optimal multiple candidate signature lncRNAs associated with DRFS were firstly identified by a univariate Cox proportional hazard regression survival analysis and a robust likelihood-based survival analysis of the GEO dataset GSE25055. A nine-lncRNA prognostic risk score model Risk Score = 0.0289 × EXP

Topics: Adult; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Neoadjuvant Therapy; Predictive Value of Tests; Receptor, ErbB-2; Recurrence; Retrospective Studies; RNA, Long Noncoding; Survival Rate; Taxoids

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents, Immunological; Breast Neoplasms; Bridged-Ring Compounds; CD4-Positive T-Lymphocytes; Cyclophosphamide; Cytokines; Dendritic Cells; Doxorubicin; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Granzymes; Humans; Immune System; Immunity, Mucosal; Interferons; Interleukin-12; Mice; Neoadjuvant Therapy; Nitric Oxide; Receptor, ErbB-2; Streptomycin; Taxoids; Trastuzumab; Treatment Outcome; Tumor Microenvironment; Vancomycin

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-β1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-β1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-β1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-β1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

Topics: Adult; Aged; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Cytokines; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Taxoids; Zoledronic Acid

The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.. The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile.. The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups.. Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab; Vinorelbine

Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy.. A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage.. Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed.. Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient.. ISRCTN 46099296.

Topics: Aged; Aged, 80 and over; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy; Female; Humans; Patient Satisfaction; Propensity Score; Prospective Studies; Quality of Life; Survival Analysis; Taxoids; Trastuzumab; Treatment Outcome

The optimal time to deliver adjuvant chemotherapy has not been defined.. A retrospective study of consecutive patients receiving adjuvant anthracycline and/or taxane 1993-2010. Primary endpoint included 5-year disease-free survival (DFS) in patients commencing chemotherapy <31 versus ≥31 days after surgery. Secondary endpoints included 5-year overall survival (OS) and sub-group analysis by receptor status.. We identified 2003 eligible patients: 1102 commenced chemotherapy <31 days and 901 ≥31 days after surgery. After a median follow-up of 115 months, there was no difference in 5-year DFS rate with chemotherapy <31 compared to ≥31 days after surgery in the overall population (81 versus 82% hazard ratio (HR) 1.15, 95% confidence interval (95% CI) 0.92-1.43, p = 0.230). The 5-year OS rate was similar in patients who received chemotherapy <31 or ≥31 days after surgery (90 versus 91%, (HR 1.21, 95% CI 0.89-1.64, p = 0.228). For 250 patients with triple-negative breast cancer OS was significantly worse in patients who received chemotherapy ≥31 versus <31 days (HR = 2.18, 95% CI 1.11-4.30, p = 0.02).. Although adjuvant chemotherapy ≥31 days after surgery did not affect DFS or OS in the whole study population, in TN patients, chemotherapy ≥31 days after surgery significantly reduced 5-year OS; therefore, delays beyond 30 days in this sub-group should be avoided.

Topics: Adult; Anthracyclines; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Male; Middle Aged; Retrospective Studies; Survival Analysis; Taxoids; Time Factors; Treatment Outcome; United Kingdom

Increased plasma aldehyde dehydrogenase 1 (ALDH1) levels have been proposed to predict cancer chemoresistance. However, studies have reported inconsistent results, depending on the type of cancer cells used.. This study aimed to investigate the correlation between plasma levels of ALDH1 and chemotherapy responses to the taxane-adriamycin-cyclophosphamide (TAC) regimen in breast cancer patients.. Thirty breast cancer patients who underwent chemotherapy using the TAC regimen were included in this study. Blood sampling was performed before chemotherapy was initiated and after the first and third cycles of chemotherapy administration. After 3 cycles of chemotherapy, patients were categorized as non-responsive if the tumor size was reduced <30%, if the tumor size remained the same or increased, or if any new tumors were discovered. Patients were defined as responsive after 3 cycles of chemotherapy if the tumor mass disappeared, if the tumor size was reduced by at least 30% of the initial size and if no new tumors were found.. Among the 30 patients, only five were responsive to the TAC regimen. The clinical response to TAC was not correlated with the patient's age, cancer grading, or tumor stage. A change in the ALDH1 levels was observed after the third cycle of TAC administration, with significantly higher ALDH1 levels observed in responsive compared with non-responsive patients (p < 0.05).. The results of this study may indicate a role for ALDH1 in chemoresponsiveness, rather than chemoresistance, for the TAC regimen in breast cancer patients. Further research remains necessary to confirm this result.

Topics: Adult; Aged; Aldehyde Dehydrogenase 1 Family; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Bridged-Ring Compounds; Congresses as Topic; Cyclophosphamide; Doxorubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Taxoids

The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making.. Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear.. We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients.. Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients).. Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Topics: Adult; Anthracyclines; Antineoplastic Agents; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Clinical Decision-Making; Combined Modality Therapy; Female; Humans; Lymph Node Excision; Lymphedema; Mastectomy; Middle Aged; Nomograms; Radiotherapy; Retrospective Studies; Risk Factors; Taxoids; Trastuzumab

There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2 years after the breast cancer diagnosis.. A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test.. A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age ≤ 50 years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not.. Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast; Breast Neoplasms; Bridged-Ring Compounds; Cancer Survivors; Chemotherapy, Adjuvant; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Middle Aged; Proportional Hazards Models; Risk Assessment; Risk Factors; Taxoids; Trastuzumab

Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence.. To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality.. An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019.. Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis.. The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method.. The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55).. Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.

Topics: Adult; Anthracyclines; Antineoplastic Agents; Body Composition; Breast Neoplasms; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Female; Humans; Medication Adherence; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Taxoids

Due to advances in anticancer treatment and supportive care, patients increasingly complained about nonphysical side effects of chemotherapy and targeted therapy in recent years. Therefore, continuous assessment of side effects and patients' perceptions is important. The aim of this study was to evaluate the identification and severity of side effects perceived by ovarian cancer (OC) and breast cancer (BC) patients undergoing contemporary anticancer therapy.. Between 2015 and 2017, consecutive chemo-naïve OC and BC patients were enrolled in this prospective cohort study. Interviews were performed 12 ± 3 weeks after start of anticancer therapy, and patients were asked to select and rank, according to severity, 72 physical or nonphysical symptoms potentially related to their treatment. Data were analyzed with descriptive statistics.. Forty-five OC patients and 98 BC patients completed the interview. Sleeping difficulties were ranked as the most troublesome symptom, followed by concerns about family or partner, and loss of hair. Alopecia was the most predominant side effect for BC patients, whereas OC patients were highly afflicted by numbness in limbs. Chemotherapy alone or in combination with targeted therapy caused pronounced sleep disturbances. Prolonged taxane treatment led to shortness of breath and numbness in limbs. Vomiting was ranked by one and nausea by eight women among the five most bothersome symptoms.. Sleep disturbances have lately emerged as the most severe problem in women with OC or BC receiving anticancer therapy. Concerns about family and partner were ranked second in the current study and first in previous investigations.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Middle Aged; Nausea; Ovarian Neoplasms; Perception; Prospective Studies; Sleep Wake Disorders; Taxoids; Trastuzumab; Vomiting; Young Adult

The APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study.. The APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed.. A total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation.. Diarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antidiarrheals; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Diarrhea; Disease-Free Survival; Female; Humans; Incidence; Mastectomy; Middle Aged; Multicenter Studies as Topic; Progression-Free Survival; Prospective Studies; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Severity of Illness Index; Taxoids; Trastuzumab

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication related to taxanes. Underlying mechanisms are not completely understood and no specific treatment exists. We investigated the role of nerve conduction studies (NCS) and of serum osteopontin (OPN) measurement as a means to stratify the risk of developing taxane-induced neuropathy (TIN).. We enrolled 50 women with breast cancer treated with taxanes (docetaxel or paclitaxel) in a 3-month prospective study. They were evaluated before chemotherapy (time-point T0) and followed up at 1 (T1) and 3 (T2) months with clinical examinations/scales, quality of life (QoL) questionnaires, NCS, and serum OPN dosages.. A reduction of sural and superficial peroneal sensory action potentials was seen at T1, with a progression at T2 (P<0.001). In contrast, a significant impact of neuropathic symptoms on QoL only occurred at T2 (P<0.01). OPN levels at T0 inversely correlated to axonal loss in the sural nerve (T0-T2, P<0.01). OPN levels at T0 were lower in the intermediate and poor outcome patient subgroups, compared to the good outcome subgroup, as specifically defined (P<0.05).. Lower limb NCS changes occurred earlier than the detrimental effects of TIN on patients' QoL. Low serum OPN levels before chemotherapy may represent a novel biomarker of TIN risk.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Neural Conduction; Osteopontin; Peripheral Nervous System Diseases; Prospective Studies; Taxoids

Paclitaxel is one of the most effective chemotherapy drugs for breast cancer worldwide but 20‑30% patients show primary resistance to the drug. Screening and identification of markers that facilitate effective and rapid prediction of sensitivity to paclitaxel is therefore an urgent medical requirement. In the present study, G protein signaling modulator 2 (GPSM2) mRNA levels were significantly associated with taxane sensitivity in experiments based on the Gene Expression Omnibus (GEO) online database. Immunohistochemical analysis consistently revealed a significant association of GPSM2 protein levels with paclitaxel sensitivity in breast cancer patients. Knockdown of GPSM2 reduced the sensitivity of breast cancer cells to paclitaxel via regulation of the cell cycle. Animal experiments further corroborated our in vitro findings. These results suggest that GPSM2 plays an important role in breast cancer resistance, supporting its utility as a potential target for improving drug susceptibility in patients as well as a marker of paclitaxel sensitivity.

Topics: Aged; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; MCF-7 Cells; Mice; Middle Aged; Paclitaxel; RNA, Messenger; Taxoids; Xenograft Model Antitumor Assays

Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established.. We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m. We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference.. ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Furans; Hemangiosarcoma; Humans; Ketones; Taxoids; Treatment Outcome

Taxanes are cornerstones of cancer chemotherapy and can be used for the treatment of various tumors, including breast cancer. Taxane-associated peripheral neuropathy is a common adverse effect of taxanes, leading to discontinuation of drug therapy, affecting drug treatment outcomes, and severely affecting patients' quality of life. This consensus addresses and recommends the pathogenesis, clinical features, associated risk factors, diagnostic evaluation, prevention, and treatment of taxane-related peripheral neuropathy. It is hoped that this consensus will standardize the current management of taxane-related peripheral neuropathy in China and improve clinicians' understanding of taxane-related peripheral neuropathy, thereby improving patient outcomes and improving patient quality of life.. 紫杉类药物是肿瘤化学治疗的基石药物，可用于包括乳腺癌在内的多种肿瘤的治疗。紫杉类药物相关周围神经病变是紫杉类药物的常见不良反应，可导致药物治疗中止，影响药物治疗结局，且严重影响患者的生活质量。《紫杉类药物相关周围神经病变规范化管理专家共识》针对紫杉类药物相关周围神经病变的发病机制、临床特点、相关危险因素、诊断评估、预防和治疗等展开阐述和推荐。希望本共识可规范当前国内紫杉类药物相关周围神经病变的管理，提高临床医师对紫杉类药物相关周围神经病变的认识，从而改善患者的治疗结局，提高患者生活质量。.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; China; Consensus; Humans; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Practice Guidelines as Topic; Quality of Life; Taxoids

Topics: Adult; Aged; Antineoplastic Agents; Arm; Breast Neoplasms; Bridged-Ring Compounds; Coloring Agents; Female; Humans; Indocyanine Green; Lymph Node Excision; Lymphedema; Middle Aged; Retrospective Studies; Taxoids

To comprehensively describe patient-reported, functional and neurophysiological outcomes to elucidate the phenotypic profile of taxane-induced neuropathy.. Taxane-treated patients (n = 47) completed cross-sectional bilateral clinical and sensory assessments and nerve conduction studies. Patients reported symptom severity via Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx13) questionnaire.. Symptoms of neuropathy were reported by 81% of patients. On clinical examination, 62% had 2 or more abnormalities, with 20% indicating significant symptomatic and objective neuropathy. Nerve conduction studies were consistent with a sensory predominant axonal neuropathy. However, features more typical of entrapment neuropathy were also present in > 50%, which were not associated with overall severity of chemotherapy-induced peripheral neuropathy (CIPN) or clinical risk factors.. There is considerable variation in CIPN phenotypes associated with taxane-treatment. Understanding their clinical associations may assist in identification of patients at risk of severe neurotoxicity. This would enable treatment modification decisions but also limit early cessation of effective anti-cancer treatment in patients with less severe neurological sequelae.. Understanding the CIPN phenotype may inform treatment decisions which could impact clinical and survival outcomes.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Electrodiagnosis; Female; Humans; Middle Aged; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Phenotype; Taxoids; Urogenital Neoplasms

Although chemotherapy-induced congestive heart failure (CHF) is a well-known adverse event in cancer survivors, the long-term risk of standard low-dose anthracycline has not yet been reported. This study aimed to investigate the long-term effects of standard anthracycline on late CHF in breast cancer survivors.. A nationwide retrospective cohort study was conducted using the national insurance claims data for nearly 98% of Korean citizens. Between Jan 2010 and Dec 2015, a total of 56,338 newly diagnosed female breast cancer survivors were included.. The total number of person-years was 199,648 and the incidence rate of late CHF was 3.57 per 1000 person-years. In multivariate analysis according to the subject's age at diagnosis, only in the 50-59 age group, anthracycline-based [hazard ratio (HR) 1.765, 95% confidence interval (CI) 1.206-2.583] and taxane plus anthracycline-based regimens (HR 1.816, 95% CI 1.192-2.768) significantly increased the risk of late CHF. In the 50-59 age group, standard low-dose anthracycline significantly increased the risk of late CHF (HR 1.627, 95% CI 1.080-2.451) in Cox proportional hazard regression models. In competing risk model with recurrence and in-hospital death as competing risks, standard low-dose anthracycline was a significant risk factor for late CHF [subdistribution hazard ratio (SHR) 1.553, 95% CI 1.029-2.340].. This nationwide study showed that standard chemotherapy with low-dose anthracycline is a risk factor for late-onset CHF in breast cancer survivors who were in their 50 s at breast cancer diagnosis. Long-term monitoring of late CHF should be considered in these younger breast cancer survivors.

Topics: Age Factors; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cancer Survivors; Female; Heart Failure; Humans; Incidence; Middle Aged; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Factors; Taxoids

Febrile neutropenia (FN) is one of the most concerning complications of chemotherapy, and its prediction remains difficult. This study aimed to reveal the risk factors for and build the prediction models of FN using machine learning algorithms. Medical records of hospitalized patients who underwent chemotherapy after surgery for breast cancer between May 2002 and September 2018 were selectively reviewed for development of models. Demographic, clinical, pathological, and therapeutic data were analyzed to identify risk factors for FN. Using machine learning algorithms, prediction models were developed and evaluated for performance. Of 933 selected inpatients with a mean age of 51.8 ± 10.7 years, FN developed in 409 (43.8%) patients. There was a significant difference in FN incidence according to age, staging, taxane-based regimen, and blood count 5 days after chemotherapy. The area under the curve (AUC) built based on these findings was 0.870 on the basis of logistic regression. The AUC improved by machine learning was 0.908. Machine learning improves the prediction of FN in patients undergoing chemotherapy for breast cancer compared to the conventional statistical model. In these high-risk patients, primary prophylaxis with granulocyte colony-stimulating factor could be considered.

Topics: Aged; Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Febrile Neutropenia; Female; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Inpatients; Logistic Models; Machine Learning; Male; Middle Aged; Republic of Korea; Risk Factors; Taxoids

Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer.. A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The phenotypes were confirmed with alternative expression in vitro and in vivo. Molecular mechanisms were investigated using global phosphoprotein arrays and expression microarrays. Global microarray analysis was performed to determine TAOK3 and genes that induced paclitaxel resistance.. A serine/threonine kinase gene, TAOK3, was identified from 724 screened kinase genes. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Ectopic downregulation of TAOK3 resulted in paclitaxel-resistant breast cancer cells sensitize to paclitaxel treatment in vitro and in vivo. The expression of TAOK3 also was correlated to sensitivity to two other anti-microtubule drugs, eribulin and vinorelbine. Our TAOK3-modulated microarray analysis indicated that NF-κB signaling played a major upstream regulation role. TAOK3 inhibitor, CP43, and shRNA of NF-κB both reduced the paclitaxel resistance in TAOK3 overexpressed cells. In clinical microarray databases, high TAOK3 expressed breast cancer patients had poorer prognoses after adjuvant chemotherapy.. Here we identified TAOK3 overexpression increased anti-microtubule drug resistance through upregulation of NF-κB signaling, which reduced cell death in breast cancer. Therefore, inhibition of the interaction between TAOK3 and NF-κB signaling may have therapeutic implications for breast cancer patients treated with anti-microtubule drugs. Video abstract.

Topics: Animals; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Mice, Inbred NOD; Mice, SCID; Microtubules; NF-kappa B; Paclitaxel; Prognosis; Protein Serine-Threonine Kinases; RNA, Small Interfering; Signal Transduction; Taxoids

Breast cancer is the most common cancer among women. Localized breast cancer treatments involve taxanes which are often responsible for acute peripheral neuropathy. The persistence of taxane-induced peripheral neuropathy (TIPN) is scarcely described among elderly women. A monocenter historical cohort study including all women over 65 years of age treated between 2001 and 2016 with a taxane-based chemotherapy for localized breast cancer was carried out at the Paul Strauss Regional Comprehensive Cancer Center. All cases included were followed up for at least 2 years, deaths from causes unrelated to TIPN were excluded. We report on the frequency and risk factors and establish a prognostic score of persistent Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 TIPN. Among the 302 included patients, 21% and 9% developed persistent TIPN of grade 2 and 3, respectively. Two patients died from complications of grade 3 TIPN. Risk factors of persistent grade 2 and higher neuropathy included age (P < .0001), body mass index (P < .0001), and diabetes (P = .0093). Persistent TIPN was more frequent with paclitaxel than docetaxel (OR = 5.43; P < .0001). Patients presenting all four major risk factors had a 97.2% probability of developing long-term symptoms against 1.2% for patients showing no risk factor. We therefore identified 3 prognostic groups. TIPN is a frequent and sometimes severe persistent side effect of breast cancer treatment among elderly women with a major impact on health-related quality of life. Chemotherapy regimens without taxane could therefore be a valid option in elderly patients with neurotoxicity risk factors.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Female; Humans; Paclitaxel; Peripheral Nervous System Diseases; Quality of Life; Taxoids

Taxane acute pain syndrome (TAPS) is a clinically significant side-effect of taxane chemotherapy, often described as arthralgia and myalgia that occurs 2-3 days after infusion. The aim of this study was to assess pain descriptors used by patients during their experience of TAPS.. A clinical prospective cohort study was conducted on breast cancer patients who had not received prior chemotherapy and were asked to complete diaries on three consecutive docetaxel treatment cycles on days 1-7, 14, and 21 (acute phase). Questionnaires to assess pain severity, descriptors of pain, and the interference in activities due to pain were adapted from the Brief Pain Inventory and the McGill Pain Questionnaire. Telephone questionnaire follow-up was done at 1, 3, 6, 9, and 12 months following docetaxel (delayed phase).. The most commonly used descriptor for acute and chronic pain was "aching" (90-96%). However, in the delayed phase of the study, "burning" (32-50%), "radiating" (39-48%), and "sharp" (40-69%) were used more often. In both acute and chronic pain phases, most patients experienced moderate/severe pain regardless of the location. Pain in cycle 1 was predictive of pain in subsequent taxane cycles (p < 0.0001). Pain in cycle 3 was predictive of chronic pain (p < 0.002).. The descriptors used by patients experiencing chemotherapy-induced pain (ChIP) may be reflective of the underlying mechanisms. It is suspected that TAPS initiates as an acute inflammatory pain, which over time develops into neuropathic pain, known as chemotherapy-induced peripheral neuropathy (CIPN). However, the subjective pain experience varies from patient to patient.

Topics: Acute Pain; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Prospective Studies; Taxoids

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15-4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41-5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26-9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asian People; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Female; Germ-Line Mutation; Humans; Middle Aged; Neoadjuvant Therapy; Prevalence; Taxoids; Tumor Suppressor Protein p53; Young Adult

Internationally, there has recently been growing interest in the use of neoadjuvant pertuzumab and trastuzumab in patients with non-metastatic HER-2 positive breast cancer following the NEOSPHERE trial in 2012. However, pertuzumab is currently not funded by the Pharmaceutical Benefits Scheme (PBS) in Australia for use in this setting. The authors sought to assess the clinical and pathological response rates at the time of surgery in patients who received neoadjuvant dual anti-HER2 and taxane therapy in a multidisciplinary breast cancer unit.. A retrospective case series of all patients treated with the neoadjuvant therapy, and who had definitive surgery was conducted. Demographic data, size, grade, tumor type, receptor status prior to neoadjuvant treatment, pathological complete response (pCR) rates, and adverse effects were analyzed.. Nineteen patients were included in the study. Sixty-eight percent of all patients achieved pCR, of which 54% further demonstrated no residual ductal carcinoma in situ. Eight patients (42%) had N1 disease pretreatment, of these 88% demonstrated total pCR in the axilla and the breast. Most adverse effects to treatment were manageable grade 1-2 side effects.. This is the first reported Australian experience using neoadjuvant dual anti-HER2 and taxane therapy for HER-2 positive nonmetastatic breast cancer. The authors have demonstrated favorable pCR rates for invasive disease compared to the NEOSPHERE trial (68% vs 46%), with reasonable patient tolerability. Larger collaborative data sets are required to fully evaluate correlation of pCR with survival outcomes, and cost-effectiveness. National funding models need to be considered.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Retrospective Studies; Taxoids

Adding taxane to an anthracycline-based regimen improves survival in node-positive breast cancer patients, as shown by clinical trials and meta-analyses. However, no studies have analyzed the number of metastatic lymph nodes in patients with estrogen receptor (ER)-positive cancer. This study investigated whether adding a taxane to an anthracycline-based regimen improved prognosis in node-positive, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients in a real-world setting.. Using Japanese Breast Cancer Society registry data, we compared disease-free survival (DFS) of patients with ER-positive, HER2-negative breast cancer, excluding those receiving neoadjuvant chemotherapy, between those who received an anthracycline-based regimen followed by a taxane-based regimen (A + T) and those who received only an anthracycline-based regimen (A w/o T), stratified by lymph node status. A Cox proportional hazards model was used to evaluate DFS in both groups.. There were 4566 eligible patients with ER-positive, HER2-negative breast cancer. During the median follow-up period of 60 months, there were 481 recurrences and 149 deaths. There was no significant difference in DFS between the A + T and A w/o T groups among patients with 1-3 positive nodes, while there was a significant difference among patients with ≥ 4 positive nodes.. In patients with ER-positive, HER2-negative breast cancer, adding taxane to an anthracycline regimen did not improve DFS in patients with metastasis in 1-3 lymph nodes. We considered that the group without the addition of taxane might be present in patients with ER-positive, HER2-negative lymph node metastases.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Japan; Lymphatic Metastasis; Middle Aged; Prognosis; Receptor, ErbB-2; Registries; Societies, Medical; Taxoids

Topics: Breast Neoplasms; Bridged-Ring Compounds; Female; Genotype; Humans; Neoadjuvant Therapy; Polymorphism, Single Nucleotide; Prognosis; Solute Carrier Organic Anion Transporter Family Member 1B3; Taxoids

Women with early-stage breast cancer may still have a future child wish, while chemotherapy may impair fertility. To pursue on fertility preservation shortly after breast cancer diagnosis is complex. This review holds a critical reflection on all topics that need to be counseled to give them the opportunity to make a well-informed decision before starting any oncological treatment.. A comprehensive literature review was performed on papers published in English language on breast cancer in young women, risk of chemotherapy-induced infertility, fertility preservation techniques, impact of possible mutation carriership, and future pregnancy outcome.. Below 40 years of age, the risk of permanent chemotherapy-induced ovarian function failure is approximately 20%, where taxanes do not significantly add to this risk. Overall, 23% of reported women who performed fertility preservation by cryopreserving oocytes or embryos returned for embryo transfer. Of these, 40% gave live birth. Both fertility preservation in women diagnosed with breast cancer and pregnancy after treatment seem safe with respect to breast cancer survival. Women who have a genetic predisposition for breast cancer like BRCA gene mutation should also be informed about the possibility of pre-implantation genetic diagnosis.. Women with an early stage of breast cancer and a possible future child wish should be referred to an expertise center in breast cancer, fertility preservation, and genetics in this complex decision-making process, shortly after diagnosis.

Topics: Adult; Breast Neoplasms; Bridged-Ring Compounds; Child; Cryopreservation; Early Detection of Cancer; Female; Fertility; Fertility Preservation; Genetic Counseling; Humans; Infertility, Female; Oocyte Retrieval; Oocytes; Ovulation Induction; Pregnancy; Taxoids; Young Adult

The St. Gallen Consensus 2017 recommended neoadjuvant therapy as a standard of care in stage II-III HER2-positive (HER2+) early breast cancer (EBC). Today, the neoadjuvant approach has become even more clinically relevant, as pathological complete response (pCR) status can not only be used to predict patient outcome, but also to escalate anti-HER2 therapy after surgery, based on the recently published results from the KATHARINE trial. Based on the NEOSPHERE results, dual antibody blockade together with chemotherapy has become the neoadjuvant standard. The chemotherapy backbone consists either of an anthracycline-taxane sequence or of an anthracycline-free regimen such as docetaxel and carboplatin. Adjuvant anti-HER2 therapy is then chosen based on initial tumor burden and pCR status. A multidisciplinary approach right from the beginning guarantees optimal treatment results for patients with HER2+ EBC. Emerging strategies will include early response markers (e.g. biomarkers, molecular imaging) as well as novel targeted agents (e.g. immunotherapy) in order to individualize systemic therapy in HER2-positive EBC. Neoadjuvant and adjuvant therapy thus represent components of an integrated, continuous strategy in HER2+ EBC allowing therapy adaptation according to individual tumor response. Refining the treatment algorithm with further de-escalation and escalation approaches will hopefully lead to better chances for cure as well as reduced short- and long-term toxicities in HER2-positive early breast cancer.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Meta-Analysis as Topic; Neoadjuvant Therapy; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids; Treatment Outcome

An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC.. This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes.. Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC.. Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; Middle Aged; Neoplasms, Second Primary; Netherlands; Receptors, Estrogen; Risk Factors; Taxoids; Trastuzumab

In adjuvant settings of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, anthracycline-based chemotherapy followed by taxane and trastuzumab is a standard regimen. Recent studies have reported the use of anthracycline-free adjuvant chemotherapy in selected HER2-positive breast cancer patients. We conducted a single-center retrospective study to identify the characteristics of HER2-positive breast cancer patients for whom anthracyclines can be safely omitted.. A total of 238 women were diagnosed with HER2-positive breast cancer and treated with neoadjuvant and/or adjuvant chemotherapy between January 1, 2008 and December 31, 2015 at Keio University Hospital. They were divided in two cohorts: an "anthracycline" cohort of 112 anthracycline-treated women and a "no anthracycline" cohort of 126 anthracycline-untreated women. Survival outcomes were estimated by Kaplan-Meier method.. The 3-year disease-free survival rates in the no-anthracycline and anthracycline cohorts were 91.3% and 93.1%, respectively (P = 0.692). After using a statistical method with inverse probability of treatment weighting to minimize the selection bias, no significant differences were observed between the two cohorts (adjusted hazard ratio for disease-free survival: 1.042; P = 0.909). Stratified by tumor size, no significant differences were observed between the two cohorts in the cT1N0 and cT2N0 subsets (P = 0.516 and P = 0.579, respectively). The recurrence rate was low among patients who achieved pathological complete response after receiving neoadjuvant chemotherapy with or without anthracyclines.. Our study suggests that anthracyclines can be safely omitted in selected patients with HER2-positive breast cancer, who have cT1N0 or cT2N0 and achieved pathological complete response after receiving neoadjuvant chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab

While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely.. This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival.. The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006).. This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Outcome Assessment, Health Care; Oxonic Acid; Patient Participation; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Tegafur; Treatment Outcome

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; G(M1) Ganglioside; Humans; Peripheral Nervous System Diseases; Taxoids

Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials.. Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies.. From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m. Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Autopsy; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Comorbidity; Female; Germany; Heart Failure; Humans; Middle Aged; Patient Safety; Pneumonia; Prospective Studies; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Sepsis; Taxoids

In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses.. OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted.. The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm.. These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Kaplan-Meier Estimate; Neoplasm Metastasis; Neoplasm Staging; Odds Ratio; Receptor, ErbB-2; Taxoids; Trastuzumab; Treatment Outcome

Pertuzumab, when combined with trastuzumab and chemotherapy, is a highly active human epidermal growth factor receptor 2 (HER2), targeting agent in the neoadjuvant, adjuvant and first-line metastatic HER2-positive breast cancer setting. The efficacy of late-line (after first/second-line) pertuzumab in combination with trastuzumab and chemotherapy is unknown.. To establish pertuzumab efficacy by performing an audit of patients who received pertuzumab after first-line HER2 directed therapy. We sought to establish whether efficacy differed by clinicopathological factors.. The primary endpoint was progression-free survival (PFS) and the secondary endpoint, overall survival (OS). Clinicopathological factors, PFS and OS data were collated and clinicopathological factors associated with PFS were evaluated using Cox regression models.. Fourteen women were identified. Six (43%) had hormone receptor (HR) negative and eight (57%) had HR-positive, metastatic HER2-positive breast cancer. Median follow up was 22.8 months, median prior lines of therapy were 5 (range: 1-9). Median time from diagnosis of metastatic disease to receiving pertuzumab was 4.5 years (range: 4.2-5.8). All patients received initial chemotherapy with pertuzumab and trastuzumab (taxane-based 71%). Median PFS was 9 months (95% confidence interval [CI]: 7-not estimable [NE]) and median OS was not reached (95% CI, 16 months-NE). Univariable analysis demonstrated that HR-negative patients had a significantly longer PFS than HR-positive patients (hazard ratio = 0.11; 95% CI, 0.01-0.88; P = 0.04).. This small cases series reports a favorable PFS and OS for pertuzumab with trastuzumab and chemotherapy in the later line metastatic setting. This finding warrants further study.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Australia; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab

Many studies were performed to explore the correlation between taxane-based chemotherapy and the risk of breast cancer-related lymphedema (BCRL), however, with inconsistent results. Hence, the purpose of this study is to evaluate whether taxane-based chemotherapy is a risk factor for BCRL.. A comprehensive systematic search of clinical trials published in the PubMed, Embase and the Cochrane Library databases will be conducted to identify eligible studies up to the date of December 31, 2018. We will employ risk ratios with 95% confidence intervals (95% CIs) to estimate the correlations between taxane-based chemotherapy and BCRL. Meta-analysis will be performed using Stata SE version 12.0 software.. The results of this systematic review and meta-analysis will provide a high-quality synthesis of existing evidence of the correlations between taxane-based chemotherapy and the risk of BCRL.. The protocol will provide updated evidence for the use of taxane-based chemotherapy in postoperative breast cancer patients.. It is not necessary for ethical approval because it is based on published studies. The protocol will be disseminated in a peer-reviewed journal or presented at a topic-related conference.. This systematic review protocol has been registered with a number of CRD42019123989.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Lymphedema; Meta-Analysis as Topic; Research Design; Risk Factors; Systematic Reviews as Topic; Taxoids

Eyebrow and eyelash loss (madarosis) is a common and distressing side effect of chemotherapy for which no protective strategies have yet been developed. The purpose of this study was to develop an overview of perceptions and experiences of women undergoing taxane-based treatment for early breast cancer.. A total of 25 women with a diagnosis of invasive early breast cancer participated in a focus group (n = 5), ages ranging from 35 to 64 (median 50), all had completed therapy with a taxane-based chemotherapy treatment. This focus group used targeted questions to explore participants' perceptions and experience of madarosis during and following chemotherapy and identified issues associated with impact of madarosis on quality of life (QoL). Thematic analysis was conducted to identify important issues experienced by participants.. Seven themes emerged from the data: (1) timing of regrowth and permanent changes, (2) meaning/importance of eyebrow/eyelashes, (3) preparedness/information given, (4) impact of the hair loss of self, (5) impact of hair loss on others, (6) physiological side effects of loss of eyebrows/eyelashes, and (7) management of loss of eyebrows/eyelashes. In addition, participants noted physical symptoms of eye irritation during their treatment that they attributed to madarosis.. This study highlights the significant impact of madarosis on patients, providing the first published analysis of patient's attitude and perception of eyelash and eyebrow loss during chemotherapy. Further research in this area is required and will be benefitted from the development of a dedicated instrument/questionnaire that can capture and measure the impact of madarosis on QoL and allow development of clinical trial strategies.

Topics: Adult; Alopecia; Australia; Breast Neoplasms; Bridged-Ring Compounds; Eyebrows; Eyelashes; Female; Focus Groups; Humans; Middle Aged; Perception; Qualitative Research; Quality of Life; Racial Groups; Surveys and Questionnaires; Taxoids

The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome.. Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression.. The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p < 0.001), nodal involvement (>cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p < 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p < 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p < 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p < 0.001) and in the HER2-negative patients (OR 1.99; p < 0.001). Patients with PgR-negative disease had significantly worse outcome (p < 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS.. ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer.

Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids

Obesity may negatively affect survival in breast cancer (BC), but studies are conflicting, and associations may vary by tumor subtypes and race/ethnicity groups.. In a retrospective review, we identified 273 women with invasive BC administered Adriamycin/Taxane-based neoadjuvant chemotherapy from 2004 to 2016 with body mass index (BMI) data at diagnosis. Obesity was defined as BMI ≥30. Associations between obesity and event-free survival (EFS), using STEEP events, and overall survival (OS), using all-cause mortality, were assessed overall and stratified by tumor subtype [[Hormone Receptor Positive (HR+)/HER2-, HER2+, and Triple-Negative Breast Cancer (TNBC])] in our diverse population.. Median follow-up was 32.6 months (range 5.7-137.8 months). Overall, obesity was associated with worse EFS (HR 1.71, 95% CI 1.03-2.84, p = 0.04) and a trend towards worse OS (p = 0.13). In HR+/HER2- disease (n = 135), there was an interaction between obesity and hormonal therapy with respect to OS but not EFS. In those receiving tamoxifen (n = 33), obesity was associated with worse OS (HR 9.27, 95% CI 0.96-89.3, p = 0.05). In those receiving an aromatase inhibitor (n = 89), there was no association between obesity and OS. In TNBC (n = 44), obesity was associated with worse EFS (HR 2.62, 95% CI 1.03-6.66, p = 0.04) and a trend towards worse OS (p = 0.06). In HER2+ disease (n = 94), obesity was associated with a trend towards worse EFS (HR 3.37, 95% CI 0.97-11.72, p = 0.06) but not OS. Race/ethnicity was not associated with survival in any subtype, and there were no interactions with obesity on survival.. Obesity may negatively impact survival, with differences among tumor subtypes.

Topics: Adult; Aged; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Doxorubicin; Ethnicity; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant Therapy; Obesity; Prognosis; Retrospective Studies; Taxoids; Triple Negative Breast Neoplasms

It is well known that BRCA1 and BRCA2 play a central role in DNA repair, but the relationship between BRCA1 and BRCA2 mRNA expression and response to neoadjuvant chemotherapy in sporadic breast cancer patients has not been well established. Here, we investigate the association between BRCA1 or BRCA2 mRNA expression levels and pathological response in 674 BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant chemotherapy. BRCA1 and BRCA2 mRNA expression were assessed using quantitative real-time polymerase chain reaction in core biopsy breast cancer tissue obtained prior to the initiation of neoadjuvant chemotherapy. A total 129 patients (19.1%) achieved pathological complete response (pCR) after neoadjuvant chemotherapy. Among patients treated with anthracycline-based chemotherapy (n = 531), BRCA1 mRNA low expression patients had a significantly higher pCR rate than intermediate or high BRCA1 mRNA expression groups (24.6% vs 16.8% or 14.0%, P = .031) and retained borderline significance (OR = 1.54, 95% CI = 0.93-2.56, P = .094) in multivariate analysis. Among the 129 patients who received a taxane-based regimen, pCR rate showed no differences in BRCA1 low, intermediate, and high mRNA level subgroups (19.6%, 26.8% and 21.4%, respectively; P = .71). BRCA2 mRNA level was not associated with pCR rate in the anthracyline-based treated subgroup (P = .60) or the taxane-based regimen subgroup (P = .82). Taken together, our findings suggested that BRCA1 mRNA expression could be used as a predictive marker in BRCA1/2 mutation-negative breast cancer patients who received neoadjuvant anthracycline-based treatment.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoadjuvant Therapy; Real-Time Polymerase Chain Reaction; Taxoids; Treatment Outcome

Among harmful effects of chemotherapy is the reduction of ovarian function. The aim was to determine the serum levels of FSH, LH, estradiol and AMH after chemotherapy followed by endocrine therapy in breast cancer patients.. The study included 40 premenopausal hormone receptor-positive breast cancer patients aged 33-50 years. Anthracycline-based chemotherapy received 14/40 while anthracycline-taxane combination received 26/40 of patients, followed by tamoxifen (30/40) or tamoxifen plus goserelin (10/40). All of them experienced chemotherapy-induced secondary amenorrhea. Hormone levels were determined by ELISA. Statistics included Spearman's test, Mann-Whitney test and multiple linear regression analysis.. Undetectable AMH levels were observed in 62.5 and 33.3% of patients with time period < 2 and ≥ 2 years from completion of chemotherapy to sample collection. Median levels of hormones for patients treated with anthracycline-based compared to anthracycline-taxane therapy were: 15.5 vs. 22.3 IU/L for FSH; 10.9 vs. 13.6 IU/L for LH; 55.5 vs. 39.5 pg/mL for estradiol; 0.11 vs. 0.11 ng/mL for AMH. The multiple linear regression showed that: women who received goserelin had significantly lower FSH; those with shorter time from completion of chemotherapy to sample collection had significantly higher LH and lower estradiol; younger women had higher AMH levels.. The ovarian function was recovered from chemotherapy-induced secondary amenorrhea with time elapsed since the completion of adjuvant chemotherapy. It may be less disrupted in patients who received anthracycline-based chemotherapy and goserelin plus tamoxifen, as well.

Topics: Adult; Amenorrhea; Anti-Mullerian Hormone; Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Estradiol; Female; Follicle Stimulating Hormone; Goserelin; Humans; Inhibins; Luteinizing Hormone; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Ovary; Premenopause; Serbia; Tamoxifen; Taxoids

Several regimens for which efficacy was established in randomized controlled trials are recommended in current treatment guidelines for early breast cancer. However, knowledge on use and effectiveness of commonly administered chemotherapeutic agents in real-life care and across all breast cancer subtypes is limited.. The prospective, multicentre German TMK cohort study (Tumour Registry Breast Cancer) recruited patients in 148 oncology outpatient-centres. Data from 1650 patients who completed adjuvant chemotherapy were analysed regarding treatment regimens and taxane use from 2007 to 2014. The association of patient characteristics with application of taxane-free regimens was examined with a multivariate regression model.. The preferred adjuvant treatment shifted from fluorouracil, anthracycline and cyclophosphamide containing regimens to anthracycline/taxane combinations. Taxane use increased for all subtypes, and the greatest rise was among node-negative patients. Older age, node-negativity, lower grading, HR-positive/HER2-negative subtype and earlier start year of therapy were significantly associated with taxane-free therapy.. Treatment with anthracycline/taxane-based chemotherapy in Germany has been rising for every subtype. The increased taxane use reflects updated guideline recommendations over the past decade. Cohort studies like the TMK provide insight into real-life treatment of patients outside of clinical trials.

Topics: Age Factors; Aged; Ambulatory Care; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Germany; Humans; Longitudinal Studies; Middle Aged; Prospective Studies; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Registries; Taxoids; Time Factors; Treatment Outcome

Chemotherapy for early breast cancer is associated with a small risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The aim of this study was to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens.. Patients diagnosed with stage I to III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. The development of AML/MDS, chemotherapy use, and comorbidities were identified with International Classification of Diseases, Ninth Revision and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics, cumulative incidences, and Cox proportional hazards models to estimate the hazard of AML/MDS after adjustments for clinically relevant covariates.. In all, 92,110 patients were included; after a median follow-up of 85 months, the overall rates per 1000 person-years were 0.65 for AML and 1.56 for MDS. Patients who received an anthracycline (A) or anthracycline and taxane (A+T) regimen were more likely to develop AML (hazard ratio [HR] for A, 1.70; 95% confidence interval [CI], 1.16-2.50; HR for A+T, 1.68; 95% CI, 1.22-2.30) or MDS (HR for A, 2.18; 95% CI, 1.70-2.80; HR for A+T, 1.62; 95% CI, 1.29-2.03) than patients who did not receive chemotherapy. Patients using docetaxel and cyclophosphamide (TC) were not at increased risk for AML or MDS.. Adjuvant chemotherapy is associated with a small but significant increase in the risk of AML and MDS, especially with regimens that include A. Longer follow-up is needed to confirm that risk is not increased with the recently adopted TC regimen. Cancer 2018;124:899-906. © 2017 American Cancer Society.

Topics: Acute Disease; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Female; Humans; Leukemia, Myeloid; Medicare; Myelodysplastic Syndromes; Neoplasm Staging; Registries; Risk Factors; SEER Program; Taxoids; Texas; United States

Primary angiosarcoma of the breast is a rare entity with incidence of less than 0.05% of all malignant breast neoplasms. It occurs in young females without any associated risk factors. The tumor behaves aggressively and has a poor prognosis compared to invasive ductal carcinoma.. It was a retrospective observational study done at a tertiary cancer center from January 2012 to December 2016. The medical records of patients diagnosed with primary breast angiosarcoma were reviewed for the study. Clinicopathological profile, treatment, and the outcomes were analyzed.. Four patients were diagnosed with primary breast angiosarcoma out of 2560 breast cancer patients seen over a period of 5 years. Two had metastatic disease at presentation. Among four patients, two underwent surgery of the primary tumor, whereas, all received chemotherapy either as adjuvant or palliative setting. One patient received adjuvant radiation therapy. Three patients received 2nd line and one received 3rd line chemotherapy on disease progression. After a median follow-up of 18 months one patient was surviving on 3rd line chemotherapy with trabectedin. Other three succumbed to disease after progression.. Due to a small number of this malignancy randomized studies are difficult to perform and optimum treatment strategy still need to be defined.

Topics: Adult; Breast; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Dioxoles; Female; Hemangiosarcoma; Humans; India; Middle Aged; Prognosis; Radiotherapy, Adjuvant; Retrospective Studies; Survival Rate; Taxoids; Tertiary Care Centers; Tetrahydroisoquinolines; Trabectedin; Treatment Outcome

Given their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy.. Patients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups.. RL patients were more frequently HR-positive, less likely to have visceral metastases (P < .001 for both) and had more frequently received (neo)adjuvant hormone therapy or trastuzumab than CLEOPATRA patients (P = .004 and P < .001, respectively). The median number of anti-HER2 cycles was 8 vs 24 and the median number of cycles was 7 vs 8 for docetaxel in the RL versus CLEOPATRA population, respectively. Adverse reactions of all grades were less frequent in RL. Median PFS was 27.8 months in the RL population and the treatment was equally effective in all patients' subgroups.. This study provides compelling evidence that pertuzumab, trastuzumab and a taxane are effective and safe also in a clinical scenario.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Female; Humans; Italy; Middle Aged; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab; Treatment Outcome; Young Adult

Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy.. This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates.. A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009).. This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Topics: Adult; Aged; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Cognitive Dysfunction; DNA, Mitochondrial; Fatigue; Female; Humans; Logistic Models; Middle Aged; Neoplasm Staging; Taxoids

Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions.. Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected.. Eighty-one of 85 patients who did not undergo infusion HSR after 2 cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51 years (range 27-74 years). Only 16% of the patients had a BMI greater than 30 kg/m. Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Dexamethasone; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Middle Aged; Paclitaxel; Premedication; Retrospective Studies; Taxoids

Decreased expression of p27. We investigated 226 cases of breast cancer from Kangbuk SMC between 2000 and 2005. Levels of p27. Low p57. Low p27

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Female; Humans; Immunohistochemistry; Middle Aged; Prognosis; Survival Analysis; Taxoids; Tissue Array Analysis

This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting.. This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics.. In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events.. In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Female; Furans; Humans; Ketones; Middle Aged; Taxoids; Treatment Outcome

Peripheral neuropathy is a common complication of cancer treatment impairing quality of life and function. This study explored the impact of a complementary and integrative medicine (CIM) program on taxane-induced peripheral neuropathy (TIPN).. Taxane-treated female patients with breast and gynecological cancer reporting TIPN-related symptoms were referred to an integrative physician, followed by patient-tailored CIM treatments (acupuncture with/without other modalities). Assessment of study outcomes at 6 to 12 weeks was conducted using the Measure Yourself Concerns and Wellbeing, which documented free-text narratives about patients' experience during the CIM treatment process. Content was analyzed using ATLAS.Ti software.. Of the 125 patients treated with taxanes, 69 had been referred for CIM treatment of TIPN-associated symptoms. Multidisciplinary narrative analysis identified 2 groups of CIM-treated patients: those with an apparently moderate improvement in symptoms (n = 35) and those with either only an apparent mild or no improvement at all. For 10 patients, assessment of their response to treatment was unclear. The 2 identified groups had similar demographic, cancer-related, and quality of life-related parameters at baseline. Content analysis of patients with an apparent moderate improvement suggested a short-term (24-48 hours) effect with acupuncture treatment, either alone or combined with manual, mind-body, and anthroposophic music therapies. Symptoms showing improvement included paresthesia and numbness.. Acupuncture and other CIM therapies may result in a short-term and transitory reduction in TIPN-related symptoms.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Complementary Therapies; Female; Genital Neoplasms, Female; Humans; Integrative Medicine; Middle Aged; Peripheral Nervous System Diseases; Precision Medicine; Taxoids

Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 2-3 days after taxane-based chemotherapy and lasting up to 7 days. In the absence of validated tools, many studies use the presence of both the myalgia and arthralgia components of the Common Terminology Criteria for Adverse Events (CTCAE) to define TAPS. The present study prospectively evaluated the frequency, severity, and impact of TAPS in patients with breast or prostate cancer.. In this prospective, non-randomized study, patients with breast or prostate cancer commencing taxane-based chemotherapy completed the CTCAE (version 4.03), the Functional Assessment of Cancer Therapy-Taxane (FACT-T), and Brief Pain Inventory (BPI) questionnaires at baseline and once between days 5 and 7 of each chemotherapy cycle.. From March 2015 to April 1, 2016, 75 patients (breast n = 66, prostate n = 9) were enrolled; 83% received docetaxel and 16% paclitaxel and 1% withdrew. After the first cycle of taxane, TAPS was reported by 25/69 (36.2%) patients; a further 8/69 (18.2%) reporting TAPS after a subsequent chemotherapy treatment. Overall incidence of TAPS was 33/75 (44%). While associated with detrimental scores on FACT-T and BPI as well as increased use of analgesics in 63% (21/33) of patients with TAPS, TAPS did not lead to alterations in chemotherapy dosing.. TAPS is common after taxane-based chemotherapy, and its presence is associated with reduced quality of life and increased analgesic requirements. Prospective patient-reported outcome assessments are crucial to help individualize treatment strategies and improve management of TAPS.

Topics: Acute Pain; Arthralgia; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Male; Middle Aged; Myalgia; Prospective Studies; Prostatic Neoplasms; Quality of Life; Syndrome; Taxoids

Chemotherapy for breast cancer induces alopecia, representing a major source of patient distress. This study assesses whether a scalp-cooling device is effective in reducing chemotherapy-induced alopecia, and assesses adverse treatment effects.. A prospective observational study including women with breast cancer undergoing chemotherapy and scalp cooling using a Paxman device. The primary efficacy end points were: successful hair preservation (no hair loss; <30% hair loss not requiring a wig; or <50% hair loss not requiring a wig) at the completion of chemotherapy. Secondary end points included adverse effects such as headache, pain, nausea or dizziness.. The study enrolled 131 participants. Mean patient age was 49.8 years; 74% received anthracycline/taxane-based chemotherapy and 26% received taxane-monotherapy based chemotherapy. Hair preservation was successful in 102 women who underwent scalp cooling (71.0%; 95% CI = 63-79%). Only adverse events related to device use were collected, representing 7% (95% CI = 3-11%) of cases.. Scalp cooling is effective in preventing hair loss among breast cancer patients undergoing standard chemotherapy treatment, and has minimal adverse effects.

Topics: Alopecia; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cryotherapy; Female; Humans; Middle Aged; Prospective Studies; Scalp; Taxoids; Treatment Outcome

Patients with breast cancer who have a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have improved survival. We hypothesize that once pCR has been achieved, there is no difference in subsequent postsurgical recurrence-free survival (RFS), whichever NACT regimen is used.. Data from patients with breast cancer who achieved pCR after NACT between 1996 and 2011 were reviewed. RFS was estimated by the Kaplan-Meier method, and differences between groups were assessed using log-rank testing. Cox proportional hazards regression analysis adjusted for age, menopausal status, stage, grade, tumor subtype, and adjuvant endocrine HER2-targeted radiation treatment.. Among 721 patients who achieved pCR after NACT, 157 (21.8%) were hormone receptor-positive (HR), 310 (43.3%) were HER2-amplified, and 236 (32.7%) were triple-negative; 292 (40.5%) were stage IIA, 153 (21.2%) were stage IIB, 78 (10.8%) were stage IIIA, 66 (9.2%) were stage IIIB, and 132 (18.3%) were stage IIIC. Most patients (367 [50.9%]) had been treated with adriamycin-based chemotherapy plus taxane (A + T), 56 (7.8%) without taxane (A no T), 227 (31.5%) with HER2-targeted therapy, and 71 (9.8%) provider choice. Median follow-up was 7.1 years. Adjuvant chemotherapy was employed in 196 (27%) patients, adjuvant endocrine in 261 (36%), and adjuvant radiation in the majority (559 [77.5%]). There was no statistically significant difference in RFS by NACT group. Adjusted RFS hazard ratios, comparing each treatment with the reference group A + T, were 1.25 (95% CI 0.47-3.35) for A no T, 0.90 (95% CI 0.37-2.20) for HER2-targeted therapy, and 1.28 (95% CI 0.55-2.98) for provider choice.. These data suggest that postsurgical RFS is not significantly influenced by the choice of NACT or cancer subtype among patients achieving pCR.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Doxorubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Taxoids

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates; Mice; Phosphatidylinositol 3-Kinases; PTEN Phosphohydrolase; Receptor, ErbB-2; Signal Transduction; Taxoids; Trastuzumab; Xenograft Model Antitumor Assays

Vascular endothelial growth factor (VEGF) has been shown to induce neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that chemotherapy reduces circulating VEGF levels and leads to cognitive decline among patients. This multicenter longitudinal study aimed to evaluate the impact of chemotherapy on VEGF levels and the association between VEGF levels and cognitive function.. A total of 145 early-stage breast cancer patients were recruited and assessed before chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). At each time point, plasma VEGF levels were assessed using a multiplex immunoassay. Cognitive function was assessed using both Functional Assessment of Cancer Therapy-Cognitive Function, Version 3 (FACT-Cog), and Headminder (a computerized, web-based neuropsychologic battery).. Generally, we observed higher-than-baseline plasma VEGF levels after the start of chemotherapy (P < .001). Among patients receiving anthracycline-based chemotherapy, the median plasma VEGF levels were significantly higher at T2 (T2: 37.3 pg/mL vs. T1: 21.3 pg/mL; P < .001) and T3 (T3: 35.5 pg/mL vs. T1: 21.3 pg/mL; P < .001) than at baseline. Plasma VEGF levels were not associated with chemotherapy-associated cognitive impairment.. Breast cancer patients experience an increasing trend in plasma VEGF levels during chemotherapy, and the regimen types may have a differential effect on circulating VEGF levels. Furthermore, changes in plasma VEGF levels during chemotherapy were not associated with cognitive impairment. VEGF may play a minor role in mediating the occurrence of chemotherapy-associated cognitive impairment.

Topics: Adult; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cognitive Dysfunction; Female; Humans; Longitudinal Studies; Middle Aged; Taxoids; Vascular Endothelial Growth Factor A

To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas.. Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.).. In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups.. Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR- breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cohort Studies; Female; Gene Dosage; Humans; Membrane Proteins; Middle Aged; Neoadjuvant Therapy; Oncogene Proteins; Organoplatinum Compounds; Taxoids; Triple Negative Breast Neoplasms

Tumour biology, physiologic features such as growth fraction and physical features such as size may influence response of breast cancer to neoadjuvant chemotherapy. Molecular biology is an established basis for predicting response and selecting neoadjuvant chemotherapy. Whether physical characteristics such as size should influence chemotherapy regimen is inconclusive and has not been adequately studied in developing countries.. To determine the relationship between breast tumour size and response to neoadjuvant chemotherapy and hence define the role of tumour size during selection of neoadjuvant chemotherapy regimen for locally advanced breast cancer.. Records of women managed at the University of Ilorin Teaching Hospital, Ilorin Nigeria, with neoadjuvant chemotherapy (NAC) for locally advanced breast cancer were reviewed between January 2013 and June 2015. Data was analyzed as 2 subgroups; primary tumour ≥100mm as group 1 and primary tumour ≥100mm as group 2. Primary outcome was 50% reduction in tumour size. Comparison was by chi-square test of independence at p value 0.05.. 57 records were reviewed (group1=24, group2=33). Majority (37( 65%)) were premenopausal. Mean age was 47.9 ± 13.1 (range 28-85). NAC was either taxane or anthracycline based regimen. Median chemotherapy dose was 4 (range 2-6). Widest diameter of tumours was 30mm to 180mm (mean 96 ±3.8mm, median 100mm). Mean tumour diameter for groups 1 and 2 was 7.2 ±1.6mm and 12.2± 2.9mm respectively. 50% reduction in tumour size was 45.8% and 6.0% for groups 1 and 2 respectively (p=0.0001).. There was relationship between breast tumour size and response to neoadjuvant chemotherapy at a cut-off of 10mm. Well-designed prospective studies are required to confirm this relationship.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Middle Aged; Neoadjuvant Therapy; Nigeria; Retrospective Studies; Taxoids; Treatment Outcome; Tumor Burden

To identify surrogate markers for prognosis of breast cancer patients with non-pathological complete response (non-pCR) to neoadjuvant chemotherapy (NAC), our investigation focused on the serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA15-3) as well as clinicopathological factors both before and after NAC.. A total of 185 breast cancer patients treated with NAC were recruited. Serum carcinoembryonic antigen and CA15-3 were measured at baseline and at completion of NAC.. Among the non-pCR cancers (n = 142), the disease-free survival (DFS) of patients with CA15-3-low at baseline (3-year DFS: 0.908, n = 73) was significantly better than of those with CA15-3-high (3-year DFS: 0.681, n = 69, P = .0134). Multivariable analysis demonstrated that baseline CA15-3 levels (hazard ratio: 3.31, 95% confidence interval: 1.28-10.23; P = .0122) and residual invasive size (hazard ratio: 4.47, 1.26-28.39; P = .0171) were significant independent factors for DFS. The combination of these factors proved to be an accurate predictor for DFS regardless of breast cancer subtypes.. The combination of residual invasive size and serum CA15-3 levels at baseline seems to be a significant and independent surrogate marker of poor outcome for patients with non-pCR. These findings suggest that these markers may be useful for identifying patients with inferior prognosis and candidates for additional adjuvant treatments.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Ki-67 Antigen; Mucin-1; Neoadjuvant Therapy; Preoperative Care; Prognosis; Taxoids; Trastuzumab

Background and aims Breast cancer is the most prevalent adult cancer worldwide. A broader use of screening for early detection and adjuvant systemic therapy with chemotherapy has resulted in improved survival rates. Taxane-containing chemotherapy is one of the cornerstones of the treatment. However, taxane-containing chemotherapy may result in acute chemotherapy-induced nociceptive and neuropathic pain. Since this pain may be an additional burden for the patient both during and after taxane chemotherapy, it is important to rapidly discover and treat it. There is yet no gold standard for assessing taxane-induced pain. In the clinic, applying multiple methods for collecting information on pain may better describe the patients' pain experiences. The aim was to document the pain during and after taxane through the contribution of different methods for collecting information on taxane-induced pain. Fifty-three women scheduled for adjuvant sequential chemotherapy at doses of ≥75 mg/m2 of docetaxel and epirubicin were enrolled in the study. Methods Prospective pain assessments were done on a visual analog scale (VAS) before and during each cycle of treatment for about 5 months, and using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire's (EORTC-QLQ-C30) two pain questions at baseline, 3 months, and 12 months. Participants scoring pain on the VAS >30 and undergoing an interview also colored their pain on a body image during treatment and at 12 months. Results Surprisingly widespread, intense pain was detected using a multi-method approach. The colored body image showed pain being perceived on 51% of the body surface area during treatment, and on 18% 12 months after inclusion. In general, the pain started and peaked in intensity after the first cycle of taxane. After Cycle 3, most women reported an increase in pain on the VAS. Some women continued to report some pain even during the epirubicin cycles. The VAS scores dropped after the last chemotherapy cycle, but not to the baseline level. At baseline, 3 months and 12 months after inclusion, the women who estimated VAS >30 reported higher levels of pain on the pain questions of the EORTC-QLQ-C30. Conclusions This study contributes information on how different pain assessment tools offer different information in the assessment of pain. The colored body image brings another dimension to pain diagnostics, providing additional information on the involved body areas and the pa

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Docetaxel; Epirubicin; Female; Humans; Middle Aged; Pain; Pain Measurement; Prospective Studies; Taxoids

Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Topics: Aldehyde Dehydrogenase; Animals; ATP Binding Cassette Transporter, Subfamily B; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Chemokine CCL20; Chemotherapy, Adjuvant; Disease Progression; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplastic Stem Cells; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Prognosis; Protein Kinase C; Remission Induction; Taxoids; Treatment Outcome; Triple Negative Breast Neoplasms; Up-Regulation

Metastatic breast cancer (MBC) rest an incurably disease associated with bad prognosis and a median overall survival of 23-31 months. There are several treatment options including chemotherapy and sometimes endocrine therapy. Currently, there is no standard treatment for patients with MBC who have already benefited from anthracyclines and taxanes therapy. Many drugs like capecitabine, eribulin, gemcitabine, vinorelbin and liposomal doxorubicin are conventionally used as monotherapy. One important complication from MBC is life threating visceral crisis that needs a fast-effective treatment.. We report here a case of an evolution of metastatic breast cancer with lymphangitic carcinomatosis after taxane based chemotherapy and endocrine therapy. This 37-year-old woman was referred to our hospital with complaints of dyspnea and dry cough. There was clinical concern for visceral crisis and a chemotherapy with eribulin was initiated. Pulmonary lymphangitic carcinomatosis disappeared and the patient achieved a good partial response.. We reported a case of rapid, positive treatment response using eribulin on metastatic breast cancer with visceral crisis and we could quoted others. Therefore, eribulin may be an appropriate chemotherapeutic option in instances requiring rapid symptom control.

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Female; Furans; Humans; Ketones; Lung Neoplasms; Taxoids

Women treated with chest radiation for Hodgkin lymphoma (HL) have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. This small retrospective study identified 15 patients, noting that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation.. Women treated for Hodgkin lymphoma (HL) with chest radiation have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer.. Women with breast cancer diagnosed from 1986-2015 after radiation for HL were identified from hospitals and clinics in St. Paul and Minneapolis, Minnesota. Patient, tumor and treatment characteristics, and clinical outcomes were abstracted from medical records and summarized using descriptive statistics. Chemotherapy was defined as tolerated if all scheduled doses and cycles were completed without deviation from the initial plan, with lack of grade 3 or higher toxicity attributable to chemotherapy in categories including blood, cardiac, gastrointestinal, fatigue and pain.. Forty-two patients with breast cancer and prior radiation for HL were identified, 15 of which received chemotherapy for breast cancer. We noted 75% tolerability of taxane-based and 100% tolerability of anthracycline-based chemotherapy, suggesting that most patients with prior radiation for HL tolerate chemotherapy for breast cancer. A subset of patients (N = 7) in this study were also treated with chemotherapy for HL prior to breast cancer diagnosis, and 86% (6 of 7) also tolerated chemotherapy for breast cancer.. Treatment of breast cancer is strongly influenced by prior treatment of HL. Although this study was small and did not meet statistical significance, the data suggest that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. Larger studies comparing specific chemotherapy dosing schedules are needed to address this complicated population.

Topics: Adult; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cancer Survivors; Cohort Studies; Female; Hodgkin Disease; Humans; Minnesota; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Pilot Projects; Radiotherapy; Retrospective Studies; Taxoids

The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment.. Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900).. The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05).. Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer.. ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Diet; Female; Humans; Middle Aged; Peripheral Nervous System Diseases; Quality of Life; Self Report; Taxoids

Recent clinical, randomized and observational studies showed that eribulin, an analogous of Halichondrin B, was beneficial and well-tolerated in heavily pretreated metastatic breast cancer patients. Here, we aim to evaluate the effectiveness and safety of eribulin in taxane-refractory metastatic breast cancer patients.. In this subanalysis of the ESEMPIO study database, we selected 91 subjects with well-defined taxane refractoriness and complete data available.. 41 patients (45.2%) showed clinical benefit; one complete response (2.2%) and 16 partial responses (17.6%) were observed. Median progression-free survival and median overall survival were 3.1 and 11.6 months, respectively. The most experienced adverse event was asthenia/fatigue (58%), followed by neutropenia (30%). The treatment-related toxicity led to eribulin-dose reduction in 19 patients and suspension in nine.. This study shows that eribulin is effective and well tolerated also in taxane-refractory patients in clinical practice.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Furans; Humans; Ketones; Middle Aged; Multicenter Studies as Topic; Retreatment; Taxoids; Treatment Outcome

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several commonly used chemotherapy drugs including taxanes, vinca alkaloids, and platinum compounds. Development of CIPN is highly variable, both in self-reported symptoms and functional consequences, and can be severe enough to alter dose intensity.. To describe the natural histories of both patient-reported symptoms of CIPN and functional impairments in breast cancer patients undergoing taxane-based chemotherapy.. Thirty-three breast cancer patients (32 female/1 male; 47.8 ± 11.2 years; n = 17 stage II/n = 16 stage III) were enrolled. Patients completed self-reports of symptoms and function (e.g., EORTC QLQ-CIPN20) and objective measures of physical function (i.e., balance and gait testing) in an outpatient oncology clinic at five timepoints: (1) baseline-prior to starting chemotherapy, (2-4) before starting subsequent chemotherapy cycles, and (5) 1-3 months after receiving their last taxane infusion.. Significant negative changes in both patient-reported outcomes and objective functional measures were observed. Decreased balance was observed after the first chemotherapy cycle (28% increase in medial-lateral excursion of the center of pressure, p = 0.016) and progressed with cumulative exposure (43% increase, p < 0.001). Patients also demonstrated slower walking speeds (5% decrease, p = 0.003) as they progressed through treatment. These functional deficits were mirrored with increased patient-reported symptom severity for all EORTC QLQ-CIPN20 subscales (all p < 0.05).. This study longitudinally assessed patient-reported outcomes concurrently with balance and gait testing in patients undergoing taxane therapy. Taxane treatment was associated with the development of clinically relevant problems in both CIPN symptoms and patient function.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Female; Gait; Humans; Male; Middle Aged; Neoplasm Staging; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Postural Balance; Self Report; Taxoids; Treatment Outcome

Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pretreatment DOS functional maps for predicting LABC response to NAC.. Locally advanced breast cancer patients (n=37) underwent DOS breast imaging before starting NAC. Breast tissue parametric maps were constructed and texture analyses were performed based on grey-level co-occurrence matrices for feature extraction. Ground truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS textural features computed on volumetric tumour data before the start of treatment (i.e., 'pretreatment') to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naive Bayes, and k-nearest neighbour classifiers.. This study demonstrated that the pretreatment DOS texture features can predict breast cancer response to NAC and potentially guide treatments.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Female; Hemoglobins; Humans; Middle Aged; Neoadjuvant Therapy; Oxygen; Predictive Value of Tests; ROC Curve; Spectrum Analysis; Taxoids; Tomography, Optical; Trastuzumab; Tumor Burden

We studied the effect of neoadjuvant chemotherapy (NAC) ± trastuzumab on the ductal carcinoma in situ (DCIS) component in patients with locally advanced breast cancer who achieved pathological complete response (pCR).. The diagnostic biopsies of 92 consecutive breast cancer patients that were treated with neoadjuvant chemotherapy (NAC) ± trastuzumab were evaluated for the presence of DCIS. Upon completion of NAC, the surgical specimens were evaluated for complete eradication of both the invasive and non-invasive cancer in the breast. The pretreatment mammograms were evaluated for the presence of microcalcifications and compared to the mammograms that were obtained upon completion of therapy prior to surgery.. Thirty of 92 patients (33%) had a substantial component of DCIS in the pretreatment biopsy. Thirty nine patients (42%) achieved pCR: 22 (56%) following NAC + trastuzumab, 17 (32%) following chemotherapy only. Ten of 30 patients (33%) with DCIS component achieved pCR: 4 received chemotherapy only, in 6 trastuzumab was added. Multiple microcalcifications on the pretreatment mammograms were observed in 3 of 10 patients with DCIS who achieved pCR. No reduction in the area of calcifications was observed following NAC.. DCIS may be completely eradicated by NAC ± trastuzumab. However, associated microcalcifications probably persist. Patients with locally advanced breast cancer with substantial DCIS may still opt for NAC and breast conservation as the DCIS component may respond and even completely disappear following NAC. Residual widespread microcalcifications after NAC do not necessarily indicate residual cancer. Larger studies are needed to direct the surgical management of these patients.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma in Situ; Carcinoma, Ductal, Breast; Female; Humans; Mammography; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Taxoids; Trastuzumab; Treatment Outcome

Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-naïve patients (TN-group) in order to investigate the possibility of trastuzumab resistance.. Patients treated with first-line HER2-targeted-containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves and multivariable Cox proportional hazards models.. Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96],. First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.. Evidence on the efficacy of palliative trastuzumab-based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab-based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane-treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision-making after short progression-free intervals on trastuzumab-containing regimens in the palliative setting.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Palliative Care; Proportional Hazards Models; Receptor, ErbB-2; Taxoids; Trastuzumab

Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21).. We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA).. Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients.. In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.

Topics: Adult; Amenorrhea; Anti-Mullerian Hormone; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Neoadjuvant Therapy; Taxoids; Time Factors

Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified.. Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3-10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients' medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed.. Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24-45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28-54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias.. Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted.

Topics: Adult; Antineoplastic Agents; Blood Pressure; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; China; Female; Humans; Lipids; Middle Aged; Premenopause; Retrospective Studies; Tamoxifen; Taxoids; Weight Gain; Young Adult

One of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs) are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1). In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs) than the non-resistant cells.. Two isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.. MCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, but more sensitive to colchicine compared to MCF-7CC cells. PARP cleavage assay further demonstrated that all of the MTAs induced apoptosis of the MCF-7 cells. However, again, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, and more sensitive to colchicine compared to MCF-7CC cells. Live imaging demonstrated that the microtubule dynamics of MCF-7TXT cells were less sensitive to vinca alkaloids, and more sensitive to colchicine. MCF-7TXT cells were also noted to be more sensitive to other CSBAs including 2MeOE2, ABT-751 and phosphorylated combretastatin A-4 (CA-4P).. Docetaxel-resistant MCF-7TXT cells have demonstrated cross-resistance to vinca alkaloids, but appear to be more sensitive to CSBAs (colchicine, 2MeOE2, ABT-751 and CA-4P) compared to non-resistant MCF-7CC cells. Taken together these results suggest that CSBAs should be evaluated further in the treatment of taxane resistant breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Chromatin; Colchicine; Docetaxel; Drug Resistance, Neoplasm; Humans; MCF-7 Cells; Microtubules; Taxoids; Vinca Alkaloids

This analysis was performed to assess the impact of early intervention following prospective surveillance using bioimpedance spectroscopy (BIS) to detect and manage breast cancer-related lymphedema (BCRL).. From 8/2010 to 12/2016, 206 consecutive patients were evaluated with BIS. The protocol included pre-operative assessment with L-Dex as well as post-operative assessments at regular intervals. Patients with L-Dex scores >10 from baseline were considered to have subclinical BCRL and were treated with over-the-counter (OTC) compression sleeve for 4 weeks. High-risk patients were defined as undergoing axillary lymph node dissection (ALND), receiving regional nodal irradiation (RNI), or taxane chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy (CDP).. Median follow-up was 25.9 months. Overall, 17% of patients had one high-risk feature, 8% two, and 7% had three. 9.8% of patients were diagnosed with subclinical BCRL with highest rates seen following ALND (23 vs. 7%, p = 0.01). Development of subclinical BCRL was associated with ALND and receipt of RNI. At last follow-up, no patients (0%) developed chronic, clinically detectable, BCRL. Subset analysis was performed of the 30 patients undergoing ALND. Median number of nodes removed was 18 and median number of positive nodes was 2. 77% received taxane chemotherapy, 62% axillary RT, and 48% had elevated BMI. Overall, 86% of patients had at least one additional high-risk feature, 70% at least two, and 23% had all three. Seven patients (23%) had abnormally elevated L-Dex scores at some point during follow-up. To date, none has required CDP.. The results of this study support prospective surveillance utilizing BIS initiated pre-operatively with subsequent post-operative follow-up measurements for the detection of subclinical BCRL. Intervention triggered by subclinical BCRL detection with an elevated L-Dex score was associated with no cases progressing to chronic, clinically detectable BCRL even in very high-risk patients.

Topics: Adult; Aged; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Dielectric Spectroscopy; Female; Humans; Lymph Node Excision; Lymph Nodes; Lymphedema; Middle Aged; Postoperative Period; Risk Factors; Taxoids

We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study.. The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding.. In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocol-recommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups.. The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Combinations; Female; Humans; Middle Aged; Oxonic Acid; Prognosis; Receptor, ErbB-2; Taxoids; Tegafur; Young Adult

We experienced 2 cases in which eribulin mesylate was effective for taxane-resistant advanced breast cancer. Case 1: A 65- year-old woman was diagnosed with advanced breast cancer(T4cN2aM0, stage III B)and treated with chemotherapy(nabpaclitaxel). Bone metastasis was observed; then, she sequentially received epirubicin and cyclophosphamide, nab-paclitaxel, and bevacizumab and paclitaxel. However, lung metastases appeared, and we changed the regimen to eribulin mesylate. We administered 11 courses of eribulin mesylate before bone marrow metastasis appeared. Eribulin mesylate was effective for more than 1 year. Case 2: A 77-year-old woman was diagnosed with advanced breast cancer(T4bN3cM1, stage IV), and liver and pleural metastasis were observed during an examination at the first visit. Four courses of nab-paclitaxel were administered, but because of the increase in pleural effusion, we changed the regimen to eribulin mesylate. Thirteen courses of eribulin mesylate were administered before the disease progressed. The progression-free survival was 9.53 months. Through the 2 cases in which eribulin mesylate was effective for taxane-resistant advanced breast cancer, the effect of eribulin mesylate compared to taxane was clinically inferred.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Furans; Humans; Ketones; Neoplasm Staging; Taxoids; Treatment Outcome

This retrospective observational study contains advanced or metastatic breast cancer female patients who pretreated with anthracycline and/or taxane received eribulin(ERI)mesylate. The primary endpoint was the progressionfree survival(PFS)and secondary endopoints were objective response rate(ORR), clinical benefit rate(CBR), overall survival (OS), and post-progression survival(PPS).. A total of 32 patients underwent chemotherapy cycles(median 3; range 1-9 cycles). The ORR was 15.6% and the CBR was 31.3%. The median PFS, OS and PPS were 2.9 months, 8.5 months, 5.6 months respectively. The OS, PPS for relative dose intensity(RDI)<85% and RDI≥85% were 7.2 months, 3.4 months and 14.5 months, 11.4 months, respectively(p=0.005, 0.004). In multivariate analysis for OS and PPS, the visceral disease, total dose of ERI and RDI correlated with OS and PPS. The most frequent treatment-related Grade 3/4 adverse events was neutropenia( 56%). No Grade 3 and 4 peripheral sensory neuropathy was occurred.. ERI exhibited efficacy and tolera- bility in patients with heavily pretreated A/MBC. The total dose and RDI of ERI would induce favorable effect for prognosis.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Resistance, Neoplasm; Furans; Humans; Ketones; Middle Aged; Neoplasm Staging; Retrospective Studies; Taxoids; Treatment Outcome

This study was performed to determine optimal radiation dose in pN1 breast cancer patients who received breast conserving surgery (BCS) and anthracycline plus taxane (AT)-based chemotherapy.. Retrospective chart reviews were performed in 1,147 patients who were treated between January 2006 and December 2010. The impact of radiation dose on treatment outcomes was evaluated.. Median follow-up time was 66 months. The 5-year rate of disease-free survival (DFS) was 93.2%. Larger tumor size (> 20 mm), positive lymphovascular invasion, high histologic grade, and high ratio of positive nodes (> 0.1) were significantly associated with inferior DFS. By using the 4 factors related to DFS, patients were categorized into high-risk (with ≥ 3 factors) and low-risk (with < 3 factors) groups. In the high-risk group, higher radiation dose (> 60.3 GyEQD2) was significantly associated with better DFS than the lower dose (≤ 60.3 GyEQD2). However, the radiation dose did not impact DFS in the low-risk group.. Dosing of radiation affects the outcome of post-BCS radiotherapy in pN1 breast cancer. Doses of over 60.3 GyEQD2 were associated with better outcome in the high-risk patients.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Dose-Response Relationship, Radiation; Female; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Mastectomy, Segmental; Middle Aged; Radiation Dosage; Retrospective Studies; Taxoids; Young Adult

Elderly breast cancer patients are affected by poorer quality of life (QoL) compared to younger patients. Because QoL has a relevant impact on guideline-adherent treatment, elderly breast cancer patients are often undertreated, especially with regard to adjuvant chemotherapy, and overall survival is decreased. Thus, understanding the impact of chemotherapy on QoL in elderly patients is crucial. This study compared QoL in patients aged < 65 years and 65 to 70 years receiving adjuvant chemotherapy as a secondary outcome in the prospective randomized multicenter ADEBAR trial.. Patients with lymph node-positive breast cancer were prospectively randomized for either sequential anthracycline-taxane or epirubicin/fluorouracil/cyclophosphamid chemotherapy (FEC) therapy. QoL was assessed at baseline (t1), before cycle 4 FEC, and cycle 5 epirubicin/cyclophosphamid-docetaxel (EC-DOC) (t2), 4 weeks after chemotherapy (t3), and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23). We compared patients aged < 65 years and 65 to 70 years with respect to QoL and discontinuation of chemotherapy.. A total of 1363 patients were enrolled onto the ADEBAR trial, with 16.7% of the patients aged 65 to 70 years. In elderly patients, Eastern Cooperative Oncology Group performance status was higher and global health status and physical functioning were lower at baseline. Global health status decreased between t1 and t3 by 7 points in patients < 65 years and by 11 points in patients 65 to 70 years, and physical functioning decreased in the same period by 13.4 points in patients aged < 65 years and by 15.9 points in patients 65 to 70 years. In both groups, at t4 global health status exceeded baseline by 6 points, and physical functioning was 1.3 points under baseline in patients < 65 years old and 3 points under baseline in patients 65 to 70 years. There was a trend to more fatigue in elderly patients and to more nausea and vomiting while receiving chemotherapy in younger patients at t3. There was a higher dropout rate in patients aged 65 to 70 years (25.7%) than in patients aged < 65 years (16.2%).. There were only small or trivial differences in QoL in patients aged < 65 years versus 65 to 70 years who were receiving adjuvant chemotherapy, although the dropout rate from chemotherapy was notably higher in elderly breast cancer patients.

Topics: Adolescent; Adult; Age Factors; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Cyclophosphamide; Docetaxel; Epirubicin; Female; Fluorouracil; Humans; Longitudinal Studies; Middle Aged; Multicenter Studies as Topic; Patient Compliance; Practice Guidelines as Topic; Prospective Studies; Quality of Life; Surveys and Questionnaires; Taxoids; Young Adult

Locally advanced breast cancer (LABC) is a major problem, especially in developing countries. The standard treatment for LABC is neoadjuvant chemotherapy, with or without anti-Her2 therapy, followed by surgery, radiotherapy, and adjuvant systemic treatment if appropriate. However, there are few data in the literature addressing alternatives when neoadjuvant chemotherapy fails to reduce the tumour for surgery.. We conducted a retrospective study including all patients who had non-metastatic LABC treated with neoadjuvant chemotherapy and who were not eligible for surgical resection; these patients were submitted to salvage radiotherapy (RTX) between January 2000 and December 2012 at the Brazilian National Cancer Institute.. Fifty-seven patients were included, with a median age of 51 (23-72) years. The most frequent clinical stages were IIIA and IIIB, corresponding to 19.3% and 70.2%, respectively; mean tumour size was 8.74 (3-18) cm, and 44 patients (77.2%) had nodal involvement. Chemotherapeutic regimens containing anthracyclines were prescribed to 98.2% of the patients. Fifteen patients (26.3%) received taxanes and anthracyclines. Radiation dose was 50 Gy divided into 25 fractions; 43 patients (75.4%) had their tumours downsized by RTX and underwent mastectomy. Overall survival (OS) was 38 (23-52) months. Patients who were submitted to surgery had an OS of 49 (28-70) months and those who were not eligible for mastectomy after radiotherapy had an OS of 18 (9-27) months.. This retrospective study confirms that RTX is an effective treatment to downsize LABC tumours with low or no response to chemotherapy, thereby enabling surgical resection which may improve overall patient outcome.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Disease-Free Survival; Dose Fractionation, Radiation; Female; Humans; Mastectomy; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Retrospective Studies; Salvage Therapy; Survival Rate; Taxoids; Tumor Burden; Young Adult

Even if neoadjuvant chemotherapy (NACT) and oncoplastic techniques have increased the breast conserving surgery rate, mastectomy is still a standard for multifocal or extensive breast cancers (BC). In the prospect of increasing breast reconstruction, an alternative therapeutic protocol was developed combining NACT with neoadjuvant radiation therapy (NART), followed by mastectomy with immediate breast reconstruction (IBR). The oncological safety of this therapeutic plan still needs further exploration. We assessed pathological complete response (pCR) as a surrogate endpoint for disease free survival.. Between 2010 and 2016, 103 patients undergoing mastectomy after NACT and NART were recruited. After CT and RT were administrated, a completion mastectomy with IBR by latissimus dorsi flap was achieved 6 to 8 weeks later. pCR was defined by the absence of residual invasive disease in both nodes and breast. Histologic response was analyzed for each immunohistochemical subset.. pCR was obtained for 53.4% of the patients. This pCR rate was higher in hormonal receptor negative (HER2 and triple negative) patients when compared to luminal tumours (69.7% vs 45.7%, p=0.023).. The pCR rate found in this study is higher than those published in studies analyzing NACT (12.5%-27.1%). This can be explained by the combination of anthracycline and taxane, the use of trastuzumab when HER2 was overexpressed but also by RT associated to NACT.. Inverting the sequence protocol for BC, requiring both CT and RT, allows more IBR without diminishing pCR and should therefore be considered as an acceptable therapeutic option.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Carcinoma In Situ; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Immunohistochemistry; Mammaplasty; Mastectomy, Segmental; Middle Aged; Neoadjuvant Therapy; Organ Sparing Treatments; Radiotherapy, Adjuvant; Receptor, ErbB-2; Surgical Flaps; Taxoids; Time Factors; Treatment Outcome

This study was conducted to evaluate the impact of supraclavicular lymph node radiotherapy (SCNRT) on N1 breast cancer patients receiving post-lumpectomy whole-breast irradiation (WBI) and anthracycline plus taxane-based (AT) chemotherapy.. We performed a case-control analysis to compare the outcomes of WBI and WBI plus SCNRT (WBI+SCNRT). Among 1,147 patients with N1 breast cancer who received post-lumpectomy radiotherapy and AT-based chemotherapy in 12 hospitals, 542 were selected after propensity score matching. Patterns of failure, disease-free survival (DFS), distant metastasis-free survival (DMFS), and treatment-related toxicity were compared between groups.. A total of 41 patients (7.6%) were found to have recurrence. Supraclavicular lymph node (SCN) failure was detected in three patients, two in WBI and one in WBI+SCNRT. All SCN failures were found simultaneously with distant metastasis. There was no significant difference in patterns of failure or survival between groups. The 5-year DFS and DMFS for patients with WBI and WBI+SCNRT were 94.4% versus 92.6% (p=0.50) and 95.1% versus 94.5% (p=0.99), respectively. The rates of lymphedema and radiation pneumonitis were significantly higher in the WBI+SCNRT than in the WBI.. We did not find a benefit of SCNRT for N1 breast cancer patients receiving AT-based chemotherapy.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Case-Control Studies; Combined Modality Therapy; Female; Humans; Lymphatic Metastasis; Mastectomy, Segmental; Middle Aged; Neoplasm Staging; Postoperative Care; Prognosis; Radiotherapy Dosage; Radiotherapy, Adjuvant; Survival Analysis; Taxoids; Treatment Outcome

The purpose of this study was to evaluate the impact of postmastectomy radiotherapy (PMRT) on loco-regional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) in pT1-2N1 patients treated with taxane-based chemotherapy.. We retrospectively reviewed the medical data of pathological N1 patients who were treated with modified radical mastectomy and adjuvant taxane-based chemotherapy in 12 hospitals between January 2006 and December 2010.. We identified 714 consecutive patients. The median follow-up duration was 69 months (range, 1 to 114 months) and the 5-year LRRFS, DFS, and OS rates were 97%, 94%, and 98%, respectively, in patients who received PMRT (PMRT [+]). The corresponding figures were 96%, 90%, and 96%, respectively, in patients who did not receive PMRT (PMRT [-]). PMRT had no significant impact on survival. Upon multivariable analysis, only the histological grade (HG) was statistically significant as a prognostic factor for LRRFS and DFS. In a subgroup analysis of HG 3 patients, PMRT (+) showed better DFS (p=0.081).. PMRT had no significant impact on LRRFS, DFS, or OS in pT1-2N1 patients treated with taxane-based chemotherapy. PMRT showed a marginal benefit for DFS in HG 3 patients. Randomized studies are needed to confirm the benefit of PMRT in high risk patients, such as those with HG 3.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Staging; Postoperative Care; Radiotherapy, Adjuvant; Recurrence; Retrospective Studies; Survival Analysis; Taxoids; Treatment Failure; Treatment Outcome; Young Adult

Despite the scientific evidence undoubtedly influencing current guidelines on the management of metastatic Breast cancer (mBC), marketing research data suggests this may not be reflected in EU prescribing behavior. Specifically we would like to understand the use of combination chemotherapy vs monotherapy in mBC patients.. This study is based on IMS Oncology Analyzer™, a web-based physician panel survey set-up by IMS Health, a global company which specializes in health care information including market research data. Analysis was carried out on prescribing behavior reflected in marketing research data from IMS source (from MAT Q42013 till MAT Q32014) and comparing the data with the current guidelines recommendation in mBC (ESO-ESMO 2nd international consensus guidelines).. Despite the recommendation provided by current ESMO guidelines on mBC treatments, indicating the sequential use of single cytotoxic agents is a considerable alternative to standard multidrug chemotherapy regimens, marketing research data suggests this may not be reflected in EU prescribing behavior.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Prescriptions; Europe; Female; Humans; Marketing; Neoplasm Metastasis; Practice Guidelines as Topic; Taxoids

Chemotherapy-induced alopecia is a common and distressing adverse effect. In previous studies of scalp cooling to prevent chemotherapy-induced alopecia, conclusions have been limited.. To evaluate whether use of a scalp cooling system is associated with a lower amount of hair loss among women receiving specific chemotherapy regimens for early-stage breast cancer and to assess related changes in quality of life.. A prospective cohort study conducted at 5 US medical centers of women with stage I or II breast cancer receiving adjuvant or neoadjuvant chemotherapy regimens excluding sequential or combination anthracycline and taxane (106 patients in the scalp cooling group and 16 in the control group; 14 matched by both age and chemotherapy regimen). The study was conducted between August 2013 and October 2014 with ongoing annual follow-up for 5 years.. Use of a scalp cooling system. Scalp cooling was initiated 30 minutes prior to each chemotherapy cycle, with scalp temperature maintained at 3°C (37°F) throughout chemotherapy and for 90 minutes to 120 minutes afterward.. Self-estimated hair loss using the Dean scale was assessed 4 weeks after the last dose of chemotherapy by unblinded patient review of 5 photographs. A Dean scale score of 0 to 2 (≤50% hair loss) was defined as treatment success. A positive association between scalp cooling and reduced risk of hair loss would be demonstrated if 50% or more of patients in the scalp cooling group achieved treatment success, with the lower bound of the 95% CI greater than 40% of the success proportion. Quality of life was assessed at baseline, at the start of the last chemotherapy cycle, and 1 month later. Median follow-up was 29.5 months.. Among the 122 patients in the study, the mean age was 53 years (range, 28-77 years); 77.0% were white, 9.0% were black, and 10.7% were Asian; and the mean duration of chemotherapy was 2.3 months (median, 2.1 months). No participants in the scalp cooling group received anthracyclines. Hair loss of 50% or less (Dean score of 0-2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%-75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P < .001). Three of 5 quality-of-life measures were significantly better 1 month after the end of chemotherapy in the scalp cooling group. Of patients who underwent scalp cooling, 27.3% (95% CI, 18.0%-36.6%) reported feeling less physically attractive compared with 56.3% (95% CI, 31.9%-80.6%) of patients in the control group (P = .02). Of the 106 patients in the scalp cooling group, 4 (3.8%) experienced the adverse event of mild headache and 3 (2.8%) discontinued scalp cooling due to feeling cold.. Among women undergoing non-anthracycline-based adjuvant chemotherapy for early-stage breast cancer, the use of scalp cooling vs no scalp cooling was associated with less hair loss at 4 weeks after the last dose of chemotherapy. Further research is needed to assess outcomes after patients receive anthracycline regimens, longer-term measures of alopecia, and adverse effects.. clinicaltrials.gov Identifier: NCT01831024.

Topics: Adult; Aged; Alopecia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Headache; Humans; Hypothermia, Induced; Medical Illustration; Middle Aged; Neoadjuvant Therapy; Photography; Prospective Studies; Quality of Life; Scalp; Taxoids

Anagen effluvium with reversible scalp alopecia is a known side effect of chemotherapy. However, there are an increasing number of reports in the literature documenting permanent alopecia in patients treated with taxanes.. We sought to describe the clinicopathologic features in breast cancer patients who underwent treatment with taxanes and adjuvant hormonal chemotherapy.. We reviewed the clinical and histopathologic information of a cohort of 10 patients treated with taxanes and adjuvant hormonal chemotherapy.. We have observed 3 types of clinical patterns of alopecia (types A, B, and C), and have validated the histopathologic features showing alopecia areata-like and female pattern hair loss.. The study was based on a small sample size and retrospective retrieval of clinical information and histopathologic review of posttreatment slides.. We hypothesize a clinicopathologic model of hair follicle cycle disruption in response to the chemoinflammatory and hormonal insults to the hair follicles resulting in permanent alopecia. Clinicopathologic correlation is paramount to the understanding of the morphobiologic pathways in chemotherapy-induced alopecia caused by taxanes and adjuvant hormonal treatment.

Topics: Aged; Alopecia; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Hair Follicle; Humans; Middle Aged; Retrospective Studies; Taxoids

Taxanes such as docetaxel belong to a group of microtubule-targeting agents (MTAs) that are commonly relied upon to treat cancer. However, taxane resistance in cancerous cells drastically reduces the effectiveness of the drugs' long-term usage. Accumulated evidence suggests that the mechanisms underlying taxane resistance include both general mechanisms, such as the development of multidrug resistance due to the overexpression of drug-efflux proteins, and taxane-specific mechanisms, such as those that involve microtubule dynamics. Because taxanes target cell microtubules, measuring microtubule dynamic instability is an important step in determining the mechanisms of taxane resistance and provides insight into how to overcome this resistance. In the experiment, an in vivo method was used to measure microtubule dynamic instability. GFP-tagged α-tubulin was expressed and incorporated into microtubules in MCF-7 cells, allowing for the recording of the microtubule dynamics by time lapse using a sensitive camera. The results showed that, as opposed to the non-resistant parental MCF-7CC cells, the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitive to docetaxel treatment, which causes the resistance to docetaxel-induced mitotic arrest and apoptosis. This paper will outline this in vivo method of measuring microtubule dynamic instability.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Diagnostic Imaging; Docetaxel; Drug Resistance, Neoplasm; Female; Humans; Microtubules; Taxoids; Tubulin; Tumor Cells, Cultured

The addition of pertuzumab to trastuzumab and taxane therapy was shown to be an effective first-line treatment for patients with HER2-positive metastatic breast cancer.. Describe the progression-free survival of pertuzumab, trastuzumab, and taxane therapy for previously treated HER2-positive metastatic breast cancer.. This case-series reviews 19 patients with metastatic breast cancer receiving treatment with pertuzumab, trastuzumab, taxane after progression and exposure to previous lines of HER2-directed therapy. Progression-free survival and adverse effects such as changes in ejection fraction and episodes of neutropenic fever were assessed.. The median progression-free survival of pertuzumab, trastuzumab, taxane therapy for previously treated metastatic breast cancer was 4.1 months. The mean baseline left ventricular ejection fraction change experienced by patients was -1%. Neutropenic fever events were not encountered.. Pertuzumab, trastuzumab, and taxane therapy seems to confer progression-free survival benefit for previously treated metastatic breast cancer. The use of the dual anti-HER2 antibodies, pertuzumab and trastuzumab, in addition to cytotoxic chemotherapy agents for previously treated metastatic breast cancer should be further evaluated.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Female; Humans; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Taxoids; Trastuzumab

The objective of this study was to explore the relationship between β3-tubulin expression and sensitivity to taxane-based neoadjuvant chemotherapy in primary breast cancer patients. A total of 48 local advanced breast cancer patients that received taxane-containing neoadjuvant chemotherapy were studied. The levels of β3-tubulin expression were tested by immunohistochemistry before chemotherapy and at the end of cycles 2, 4 and 6. The correlation between the efficacy of the chemotherapy and β3-tubulin expression and changes in β3-tubulin expression over the course of chemotherapy was examined. β3-tubulin protein expression before chemotherapy was significantly and negatively correlated with the response rate. The overall response rate was 31.8 % in the high β3-tubulin expression group, whereas it was 84.6 % in the low β3-tubulin expression group. At the end of cycles 2, 4 and 6 during the treatment course, the average expression rates of β3-tubulin were showed an increasing trend with β3-tubulin expression level at the end of cycle 4 being significantly different from that before chemotherapy. Nine patients that had a low β3-tubulin expression level preneoadjuvant chemotherapy changed to a high β3-tubulin expression level postneoadjuvant chemotherapy, and they had lower response rate than patients with consistent low. In conclusion, β3-tubulin is a good predictor of chemosensitivity to taxane for breast cancer, and the change of its expression level during chemotherapy may be an important cause of secondary resistance to taxane. Detection of β3-tubulin expression before and throughout the chemotherapy will help with selection of the chemotherapy treatment plan.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy; Female; Humans; Immunohistochemistry; Middle Aged; Prospective Studies; Taxoids; Treatment Outcome; Tubulin

Breast cancer is characterized by molecular heterogeneity, and four major breast cancer subtypes have been identified, each characterized by significant differences in survival, prognosis, and response to therapy. We have studied the effects of docetaxel treatment on apoptosis and survivin expression in four breast cancer cell lines: MCF7 (luminal A: estrogen receptor-positive and progesterone receptor-positive, ErbB2-negative), BT474 (luminal B: estrogen receptor/progesterone receptor/ErbB2-positive), SKBR3 (HER2-like: estrogen receptor/progesterone receptor-negative, ErbB2-positive), and MDA-MB231 (basal-like: estrogen receptor/progesterone receptor/ErbB2-negative). We demonstrated that docetaxel-induced apoptosis and survivin upregulation (MCF7 p = 0.002, BT474 p = 0.001, SKBR3 p = 0.001) in luminal A/B and HER2-like cells, while it induced mainly necrosis and a lower rate of survivin upregulation (MDA-MB231 p = 0.035) in basal-like cells. Wortmannin, a p-Akt inhibitor, was able to revert surviving upregulation and, at the same time, induced an increase of docetaxel-dependent apoptosis, suggesting that reduced levels of survivin can sensitize tumor cells to apoptosis. These data show that the analyzed breast cancer cell lines respond differently to docetaxel, depending on their receptor expression profile and molecular phenotype. Yet, these data confirm that one of the pathways involved in taxane-related chemoresistance is the upregulation of survivin. Further studies on the molecular mechanisms of chemoresistance and on the different modalities of apoptosis induced by chemotherapeutic agents are requested to better understand how cancer cells evade cell death, in order to design new kind of anticancer agents and survivin could represent a future target for this kind of research.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; MCF-7 Cells; Phenotype; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survivin; Taxoids; Up-Regulation

Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15-40% increase in in vitro trastuzumab-mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activity.

Topics: Animals; Antibodies, Blocking; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Cells, Cultured; Docetaxel; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins; Histocompatibility Antigens Class I; Humans; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Mice, SCID; NK Cell Lectin-Like Receptor Subfamily K; Reverse Transcriptase Polymerase Chain Reaction; Taxoids; Trastuzumab; Xenograft Model Antitumor Assays

Left ventricular ejection fraction (LV-EF), despite its high feasibility, is not sensitive enough to detect early and subtle LV systolic dysfunction during oncologic treatments. Therefore, we used systolic global longitudinal strain (GLS) by speckle tracking echocardiography to verify whether early LV systolic dysfunction induced by adjuvant therapy in early breast cancer patients at low risk for cardiotoxicity can be reversed. Thirty patients (aged 53 ± 11 y) with no previous cardiac and oncologic disease who were receiving adjuvant trastuzumab and taxane (group HER2+, n = 15) or taxane only (group HER2-, n = 15), after treatment with anthracyclines, were studied. LV-EF and GLS were measured at baseline, after anthracyclines (end of week 7 or 8), short term after trastuzumab and/or taxane (end of week 18) and after completion of therapy. Significant LV systolic dysfunction was defined as a relative reduction in GLS of >10% with respect to baseline values. Mean and individual LV-EFs did not change significantly during the oncologic treatment and after completion of therapy, although GLS varied significantly. In particular, during the course of therapy, four patients in the trastuzumab-docetaxel HER2+ subgroup and two patients in the taxane HER2- subgroup had a relative decrease (>10%) in GLS. However, after the end of adjuvant treatment, strain modification was fully or partially reversible. Speckle tracking echocardiography is more sensitive than LV-EF in recognizing subtle myocardial impairment during adjuvant chemotherapy. However, in patients at low risk for cardiotoxicity, these alterations may be reversible and not associated with clinically significant cardiotoxicity or late development of decreased LV-EF.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Heart Ventricles; Humans; Middle Aged; Taxoids; Trastuzumab; Treatment Outcome; Ultrasonography, Mammary; Ventricular Dysfunction, Left

Bone morphogenetic protein receptor type IB (BMPRIB) is one osteogenesis factor, which function in breast cancer has been rarely explored until recently. In the clinical study presented here, involving a cohort of 368 invasive ductal carcinoma (IDC) patients, we identified that patients with low expression of BMPRIB exhibited poor prognosis, especially in the luminal B subtype. We also provided the first piece of evidence that low level of BMPRIB was a promoting factor for breast cancer patients to develop bone metastasis, but not lung, liver or brain. The first of its kind, we reported that patients with high expression of BMPRIB exhibited favorable prognosis by a retrospective analysis consisting of 168 patients treated with TE (taxane and anthracycline) regimens. And the patients with high expression of BMPRIB were more sensitive to TE regimens in the detection of 32 paired pre-neoadjuvant and post-neoadjuvant specimens. Overall, our study concluded that low expression of BMPRIB indicated poor prognosis of breast cancer and was insensitive to taxane-anthracycline chemotherapy. Our findings also lay a foundation to help clinicians improve identification of patients for TE regimens by BMPRIB in the era of precision medicine.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Morphogenetic Protein Receptors, Type I; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Taxoids

Few studies have reported reproductive outcomes after breast cancer chemotherapy. The relationship between anti-Müllerian hormone (AMH) concentrations and the occurrence of subsequent pregnancies in women after chemotherapy for breast cancer was investigated. Women aged 18-43 years treated with chemotherapy for invasive breast cancer between May 2005 and January 2011 were retrospectively identified. Exclusion criteria were previous gonadotoxic treatment, oophorectomy or hysterectomy. Measurement of AMH took place before, during chemotherapy and at distant time points after the end of chemotherapy (4 months to 5.5 years). Seventeen out of 134 patients experienced 28 spontaneous pregnancies (median follow-up: 59 months). Neither baseline AMH (divided into quartiles) nor end-of-chemotherapy AMH (detectable versus undetectable) were significantly associated with the occurrence of pregnancy. Chemotherapy regimen with anthracyclines was associated with a greater probability of pregnancy compared with a taxane-containing regimen (hazard ratio 4.75; (95% CI 1.76 to 12.8); P = 0.002). Five-year disease-free survival and overall survival rates were 60% (95% CI: 51 to 70; relapse, n = 48) and 88% (95% CI 82 to 95; deaths, n = 21), respectively. AMH did not predict the occurrence of pregnancy. Additional studies assessing ovarian reserve and reproductive outcomes after breast cancer are required.

Topics: Adolescent; Adult; Anthracyclines; Anti-Mullerian Hormone; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Fertility Preservation; Humans; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Retrospective Studies; Survival Analysis; Taxoids

The purpose of this study is to identify risk factors for transient lymphedema (TLE) and persistent lymphedema (PLE) following treatment for breast cancer.. A total of 1,073 patients who underwent curative breast surgery were analyzed. TLE was defined as one episode of arm swelling that had resolved spontaneously by the next follow-up; arm swelling that persisted over two consecutive examinations was considered PLE.. At a median follow-up period of 5.1 years, 370 cases of lymphedema were reported, including 120 TLE (11.2%) and 250 PLE (23.3%). Initial grade 1 swelling was observed in 351 patients, of which 120 were limited to TLE (34%), while the other 231 progressed to PLE (66%). All initial swelling observed in TLE patients was classified as grade 1. In multivariate analysis, chemotherapy with taxane and supraclavicular radiation therapy (SCRT) were associated with development of TLE, whereas SCRT, stage III cancer and chemotherapy with taxane were identified as risk factors for PLE (p < 0.05). The estimated incidence of TLE among initial grade 1 patients was calculated using up to three treatment-related risk factors (number of dissected axillary lymph nodes, SCRT, and taxane chemotherapy). The approximate ratios of TLE and PLE based on the number of risk factors were 7:1 (no factor), 1:1 (one factor), 1:2 (two factors), and 1:3 (three factors).. One-third of initial swelling events were transient, whereas the other two-thirds of patients experienced PLE. Estimation of TLE and PLE based on known treatment factors could facilitate prediction of this life-long complication.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Female; Humans; Lymph Node Excision; Lymphedema; Mastectomy; Middle Aged; Neoplasm Staging; Prognosis; Radiotherapy; Risk Factors; Taxoids

The purpose of this study is to evaluate the predictive performance of magnetic resonance imaging (MRI) markers in breast cancer patients by subtype. Sixty-four patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy were enrolled in this study. Each patient received a dynamic contrast-enhanced (DCE-MRI) at baseline, after 1 cycle of chemotherapy and before surgery. Functional tumor volume (FTV), the imaging marker measured by DCE-MRI, was computed at various thresholds of percent enhancement (PEt) and signal-enhancement ratio (SERt). Final FTV before surgery and percent changes of FTVs at the early and final treatment time points were used to predict patients' recurrence-free survival. The full cohort and each subtype defined by the status of hormone receptor and human epidermal growth factor receptor 2 (HR+/HER2-, HER2+, triple negative) were analyzed. Predictions were evaluated using the Cox proportional hazard model when PEt changed from 30% to 200% in steps of 10% and SERt changed from 0 to 2 in steps of 0.2. Predictions with high hazard ratios and low p-values were considered as strong. Different profiles of FTV as predictors for recurrence-free survival were observed in each breast cancer subtype and strong associations with survival were observed at different PEt/SERt combinations that resulted in different FTVs. Findings from this retrospective study suggest that the predictive performance of imaging markers based on FTV may be improved with enhancement thresholds being optimized separately for clinically-relevant subtypes defined by HR and HER2 receptor expression.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Pharmacological; Breast Neoplasms; Bridged-Ring Compounds; Contrast Media; Cyclophosphamide; Doxorubicin; Female; Gene Expression; Humans; Image Enhancement; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Taxoids; Tumor Burden

To prospectively evaluate individual functional MRI metrics for the early prediction of pathological complete response (pCR) to neo-adjuvant chemotherapy (NAC) in breast cancer.. Thirty-two women (median age 52 years; range 32-71 years) with biopsy proven breast cancer due to receive neo-adjuvant anthracycline and/or taxane-based chemotherapy were prospectively recruited following local research ethics committee approval and written informed consent. Breast MRI was performed prior to and after two cycles of NAC and pCR was assessed after surgery. The enhancement fraction (EF), tumour volume, initial area under the gadolinium curve (IAUGC), pharmacokinetic parameters (K(trans), kep and ve), the apparent diffusion coefficient (ADC) and R2* values, along with the percentage change in these parameters after two cycles were evaluated according to pCR status using an independent samples t-test. The area under the receiver operating characteristics curve (AUC) was calculated for each parameter. Linear discriminant analysis (LDA) determined the most important parameter in predicting pCR.. A reduction in the EF (-41% ± 38%) and tumour volume (-80% ± 25%) after 2 cycles of NAC were significantly greater in those achieving pCR (p=0.025, p=0.011 respectively). A reduction in the EF of 7% after 2 cycles of NAC identified those more likely to achieve pCR (AUC 0.76). AUC changes in other parameters were tumour volume (0.77), IAUGC (0.64), K(trans) (0.60), kep (0.68), ve (0.58), ADC (0.69) and R2* (0.41).. In a multi-parametric MRI model, the decrease in a non-model based vascular parameter the enhancement fraction as well as the tumour volume are the most important early predictors of pCR in breast cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Area Under Curve; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Forecasting; Humans; Image Enhancement; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Mastectomy; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Remission Induction; ROC Curve; Taxoids; Treatment Outcome; Tumor Burden; Young Adult

The purpose of the present study was to prospectively evaluate the efficacy and safety of endostar, a recombinant product of endostatin, combined with taxane-based regimens for HER-2 negative metastatic breast cancer (MBC) patients. Women with ages between 18-70 years with histologically confirmed MBC documented as HER-2-negative were included. Endostar was administered at 7.5 mg/m2, d1-14, q21d and was continued until progressive disease, unacceptable toxicity, consent withdrawal, or completion of 24 months of endostar, whichever came first. Taxane-based chemotherapy was continued until progressive disease, unacceptable toxicity, consent withdrawal, or up to 8 cycles. The primary endpoint was overall response rate (ORR). Fifty-seven patients were recruited. The ORRs for the whole population, first-, second-, and third-line therapy or beyond were 68.4%, 79.3%, 54.5%, and 16.7%, respectively. The median PFS was 10.8 (8.0-12.1) months, yet the median OS was still not attained. For the patients receiving first-, second-, and third-line therapy or beyond, median PFS was 11.9, 7.5, and 7.4 months, respectively (P=0.048). No significant difference in median PFS between hormonal receptor-positive and -negative patients was observed. The most common drug-related grade 3-4 hematologic toxicities were neutropenia (80.7%) and leukopenia (77.2%). Six (10.5%) patients experienced febrile neutropenia. The most frequent drug-related grade 3-4 non-hematologic toxicities were liver dysfunction (10.5%) and peripheral neurotoxicity (8.8%). No treatment-related deaths were reported. We conclude that Endostar combined with taxane-based regimens may be effective and safe for the treatment of HER-2-negative MBC. However, further investigations on its long-term efficacy and toxicity are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Drug Administration Schedule; Endostatins; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Nausea; Neoplasm Metastasis; Neutropenia; Prospective Studies; Receptor, ErbB-2; Recombinant Proteins; Taxoids; Treatment Outcome

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic chemotherapy resulting in pain, sensory loss, and decreased quality of life. Few studies have prospectively examined the relationship between sensory neuropathy symptoms, falls, and fall-related injuries for patients receiving neurotoxic chemotherapy.. To determine the association between the symptoms of CIPN and the risk of falls for patients receiving neurotoxic chemotherapy.. In this secondary analysis of a prospective study, 116 patients with breast, ovarian, or lung cancer who were beginning neurotoxic chemotherapy with a taxane or platinum agent were recruited from oncology clinics. These patients would call a novel automated telephone system daily for 1 full course of chemotherapy. The telephone system (SymptomCare@Home) used a series of relevant CIPN questions to track symptoms on a 0 to 10 ordinal scale and contained a questionnaire about falls. Those reporting a numbness and tingling severity score of 3 or greater for at least 10 days were considered to have significant CIPN symptoms and were compared with those patients who did not. Data analysis was performed in November 2015.. Chemotherapy with a neurotoxic taxane or platinum agent.. Patient-reported falls or near falls and fall-related injuries. The hypothesis was generated after data collection but prior to data analysis.. Of the 116 patients who started neurotoxic chemotherapy (mean [SD] age was 55.5 [11.9] years, and 109 [94.0%] were female), 32 met the predetermined criteria for CIPN symptoms. The mean duration of follow-up was 62 days, with 51 telephone calls completed per participant. Seventy-four falls or near falls were reported. The participants with CIPN symptoms were nearly 3 times more likely to report a fall or near fall than the participants without CIPN symptoms (hazard ratio, 2.67 [95% CI, 1.62-4.41]; P < .001). The participants with CIPN symptoms were more likely than the participants without CIPN symptoms to obtain medical care for falls (8 of 32 participants with CIPN symptoms [25.0%] vs 6 of 84 participants without CIPN symptoms [7.1%]; P = .01).. These findings suggest that the sensory symptoms of CIPN are an indicator of an increased risk of falling and an increased use of health care resources. This study demonstrates the utility of a novel telephone-based system to track neuropathy symptoms. Careful monitoring and coaching of patients receiving neurotoxic chemotherapy for new sensory symptoms may facilitate more effective fall prevention strategies.

Topics: Accidental Falls; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chi-Square Distribution; Female; Humans; Lung Neoplasms; Male; Middle Aged; Outcome Assessment, Health Care; Ovarian Neoplasms; Peripheral Nervous System Diseases; Platinum; Prospective Studies; Severity of Illness Index; Taxoids

A prospective study was conducted to identify women at increased risk for lymphoedema (LE) based on axillary surgery. Assessment occurred prior to surgery, within 4 weeks, and at 6, 12 and 18 months following surgery. Following post-surgery assessment, women were asked to complete weekly diaries regarding events that occurred in the previous week. Risk factors were grouped into demographic, lifestyle, breast cancer treatment-related, arm swelling-related, and post-surgical activities. Bioimpedance spectroscopy thresholds were used to determine presence of LE. At 18-months, 241 women with <5 nodes removed and 209 women with ≥5 nodes removed were assessed. For those with <5 nodes removed, LE was present in 3.3% compared with 18.2% for those with ≥5 nodes removed. There were insufficient events to identify risk factors for those with <5 nodes removed; for those with >5 nodes removed, independent risk factors included presence of arm swelling at 12-months (Odds Ratio (OR): 13.5, 95% CI 4.8, 38.1; P < 0.01), at 6-months (5.6 (2.0, 16.9); P < 0.01), and radiotherapy to the axilla (2.6 (0.7, 8.9); P = 0.14). Arm swelling at 6 and 12 months was associated with taxane-based chemotherapy, high body weight at diagnosis and arm swelling within 4 weeks post-surgery. Of the post-surgical events assessed in a sub-group of women with >5 nodes removed and who maintained weekly diaries, only blood drawn from the 'at-risk' arm was identified as a potential risk (OR 2.0; 0.8, 5.2). For women with ≥5 nodes removed, arm swelling in the first year poses a very strong risk for presence of LE at 18-months.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Axilla; Body Weight; Breast Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Humans; Lymph Node Excision; Lymphatic Metastasis; Lymphedema; Mastectomy; Middle Aged; Phlebotomy; Postoperative Complications; Prospective Studies; Radiotherapy; Risk Factors; Taxoids; Time Factors

Various prognostic indicators have been investigated in neoadjuvant chemotherapy (NAC)-treated invasive breast cancer (BC). Our study examines if lymphovascular invasion (LVI) is an independent predictor of survival in women receiving NAC. We performed a retrospective analysis in 166 women with operable invasive BC who underwent adriamycin- and taxane-based NAC between 2000 and 2013. The presence of LVI was noted in breast excisions following NAC. Associations between progression-free and overall survival and LVI and other clinicopathologic variables were assessed. Median follow-up was 31 months (range 1.4-153 months) with a total of 56 events and 24 deaths from any cause. LVI was found in 74 of 166 patients (45 %). In univariate analysis, the presence of LVI was associated with worse progression-free survival (HR 3.37, 95 % CI 1.87-6.06, p < 0.01) and overall survival (HR 4.35, 95 % CI 1.61-11.79, p < 0.01). In multivariate models adjusting for breast cancer subtype, LVI was significantly associated with a decrease in progression-free survival (HR 3.76, 95 % CI 2.07-6.83, p < 0.01) and overall survival (HR 5.70, 95 % CI 2.08-15.64, p < 0.01). When stratified by subtype, those with hormone receptor or HER2-positive BCs with no LVI had the most favorable progression-free and overall survival. Those with both LVI and triple-negative BC had the worst progression-free and overall survival. LVI is an important prognostic marker and is associated with worse clinical outcome in breast cancer patients receiving NAC.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Doxorubicin; Female; Humans; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoadjuvant Therapy; Prognosis; Retrospective Studies; Survival Analysis; Taxoids; Treatment Outcome

To quantify the prevalence of neurological complications among breast cancer patients at one and three years after diagnosis, and to identify factors associated with neuropathic pain (NP) and chemotherapy-induced peripheral neuropathy (CIPN).. Prospective cohort study including 475 patients with newly diagnosed breast cancer, recruited among those proposed for surgical treatment (Portuguese Institute of Oncology, Porto). Patients underwent a neurological evaluation and had their cognitive function assesses with the Montreal Cognitive Assessment, before treatment and at one and three years after enrollment. We estimated the prevalence of each neurological complication, and odds ratios (OR), adjusted for socio-demographic and clinical characteristics, to identify factors associated with NP and CIPN.. More than half of the patients [54.7%, 95% confidence interval (95%CI): 50.2-59.2] presented at least one neurological complication, at one or at three years after cancer diagnosis. Between the first and the third year of follow-up, there was an increase in the prevalence of NP (from 21.1% to 23.6%), cognitive impairment (from 7.2% to 8.2%), cerebrovascular disease (from 0.6% to 1.5%) and brain metastasis (from 0.0% to 0.6%). The prevalence of CIPN decreased from 14.1% to 12.6%. Axillary lymph node dissection was associated with NP at one year (OR = 2.75, 95%CI: 1.34-5.63) and chemotherapy with NP at three years (OR = 2.10, 95%CI: 1.20-3.67). Taxane-based chemotherapy was strongly associated with prevalence of CIPN at one and three years.. Neurological complications are frequent even three years after cancer diagnosis and NP remained the major contributor to the burden of these conditions among survivors.

Topics: Adult; Antineoplastic Agents; Axilla; Brain Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Intraductal, Noninfiltrating; Cerebrovascular Disorders; Cognitive Dysfunction; Female; Follow-Up Studies; Humans; Lymph Node Excision; Middle Aged; Neuralgia; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Prevalence; Prospective Studies; Risk Factors; Survivors; Taxoids

To evaluate toxicity in breast cancer patients treated with anthracycline and taxane based chemotherapy and whole breast hypofractionated radiotherapy, and to identify the risk factors for toxicity.. 537 early breast cancer patients receiving hypofractionated radiotherapy after conservative surgery were enrolled from April 2009 to December 2014, in an Italian cancer institute. The dose was 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction. The boost to the tumor bed was administered only in grade III breast cancer patients and in patients with close or positive margins. Acute and late toxicity were prospectively assessed during and after radiotherapy according to RTOG scale. The impact of patients clinical characteristics, performed treatments and dose inhomogeneities on the occurrence of an higher level of acute skin toxicity and late fibrosis has been evaluated by univariate and multivariate analysis.. The mean age was 74 (range 46-91 yrs). 27% of patients received boost. 22% of cases (n = 119) received also chemotherapy. The median follow-up was 32 months. G1 and G2/G3 acute skin toxicity were 61.3% and 20.5% and G1 and G2/G3 late fibrosis 12.6% and 4.3% respectively. Chemotherapy (p = 0.04), diabetes (p = 0.04) and boost administration (p < 0.01) were found to be statistically significant on the occurrence of late fibrosis, but a multivariate analysis did not show any factors connected. The boost administration (p < 0.01), the breast volume (p = 0.05), dose inhomogeneities (p < 0.01) and boost volume (p = 0.04) were found to be statistically significant as concerns the occurrence of acute skin reaction at the univariate analysis, but only the boost administration (p = 0.02), at multivariate analysis.. The results of our study, according to the large randomized trials, confirmed that hypofractionated whole breast irradiation is safe, and only the boost administration seems to be an important predictor for toxicity. Chemotherapy does not impact on acute and late skin toxicity.

Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast; Breast Neoplasms; Bridged-Ring Compounds; Chemoradiotherapy, Adjuvant; Dose-Response Relationship, Radiation; Female; Fibrosis; Follow-Up Studies; Humans; Middle Aged; Multivariate Analysis; Neoplasm Staging; Prospective Studies; Radiation Dose Hypofractionation; Radiation Injuries; Re-Irradiation; Risk Factors; Skin; Taxoids

To investigate the association between preoperative pathological Ki67 labeling index and serum tumor marker cancer antigen 153 (CA 153) with clinicpathological parameters and treatment outcomes in early breast cancer.. A retrospective study at 4 cancer centers in Saudi Arabia and Egypt was performed. Data were collected for female patients diagnosed with unilateral early breast cancer between March 2010 and October 2013. Cases treated with neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy were included. NACT included 68 cycles of anthracycline and taxane based regimens. Trastuzumab and hormonal treatments were added according to HER2 and hormone receptor status. Baseline serum CA15.3 and pathological Ki67 levels were evaluated and correlated with disease free survival (DFS) and overall survival (OS).. A total of 280 pts was included. The median age was 49 years (3866 y) and median overall survival was 35 (2038) months (mo). Estrogen receptors (ER), progesterone receptors (PR) and HER 2 receptors were positive in 233 (83.2%), 198 (70%) and 65 cases (23.2%), respectively. High preoperative Ki67 and CA15.3 were noted in 177 (63.2%) and 131 (46.8%). A total of 45 (16%) patients had distal or local recurrence and 24 (8.6%) died of their disease. Most of the relapsed cases had high preoperative Ki67 (n=41, 91%) and CA15.3 (n=28, 62%) values. All of the patients who died had a high Ki67 but CA15.3 was high in 9 (37%) only. Mean DFS/OS in patients with high preoperative Ki67 was 32 months /32 months as compared to 37 months/35 months in those with normal Ki67 (p<0.001). Correlation of preoperative CA15.3 and survival was statistically not significant.. Preoperative Ki67 can be a predictive and prognostic marker. Higher levels are associated with poor DFS and OS in patients with early BC.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Egypt; Female; Humans; Ki-67 Antigen; Mucin-1; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Saudi Arabia; Taxoids; Trastuzumab; Treatment Outcome

Topics: Animals; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Endothelium, Vascular; Female; Humans; MCF-7 Cells; Mice, Nude; Microvessels; Neoplasm Proteins; Neovascularization, Pathologic; Paclitaxel; Receptors, Notch; RNA Interference; Signal Transduction; Specific Pathogen-Free Organisms; Taxoids; Xenograft Model Antitumor Assays

TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.. 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.. Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).. Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Lapatinib; Middle Aged; Mutation; Neoadjuvant Therapy; Quinazolines; Receptor, ErbB-2; Taxoids; Trastuzumab; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53

This study aimed to explore the association of β-catenin expression pattern with pathological response after neoadjuvant chemotherapy in breast cancer (BC) patients.. In this retrospective exploratory study, data for 50 BC patients who received neoadjuvant chemotherapy were recorded. β-catenin expression in tumours was assessed using immunohistochemistry and classified as either membranous or cytoplasmic according to the pattern of staining. Distributions of different clinico-pathological parameters according to β-catenin expression were assessed using the Chi-square test. Logistic regression analysis was used to assess any relation of the pattern of β-catenin expression with the pathological response.. Cytoplasmic β-catenin expression was detected in 34% of BCs. Among our cases, 52% were hormonal receptor (HR)-positive, 24% were HER2-positive, 74% were clinical stage III and 74% received both anthracycline and taxane-based chemotherapy. Patients with cytoplasmic expression were more commonly younger than 40 years at diagnosis (cytoplasmic, 41.2% vs. no cytoplasmic expression, 12.1%, p=0.03). By doing t-test, cytoplasmic β-catenin expression was linked with a higher body mass index compared to membranous-only expression (mean± SD 33.0 ± 4.47 vs. 29.6 ±6.01, respectively, p=0.046). No significant associations were found between β-catenin expression and other parameters such as HR and HER2 status, or clinical stage. Complete pathological response (pCR) rate was twice as great in patients with membranous expression but without statistical signi cance (membranous- only, 33.3% vs. cytoplasmic, 17.6%, OR=2.3, 95% CI= 0.55-9.87, p=0.24).. This study suggests that cytoplasmic β-catenin expression may be linked with lower probability of achieving pCR after neoadjuvant chemotherapy. These data need to be validated in a larger cohort of patients.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cytoplasm; Female; Humans; Neoadjuvant Therapy; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Taxoids

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Topics: Anticoagulants; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Dicumarol; Drug Resistance, Neoplasm; Female; Humans; Pregnancy-Specific beta 1-Glycoproteins; Taxoids; Transforming Growth Factor beta

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Bridged-Ring Compounds; Humans; Neoadjuvant Therapy; Polymorphism, Single Nucleotide; Remission Induction; Taxoids

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Female; Hematuria; Humans; Middle Aged; Mitosis; Taxoids; Urinary Bladder; Urothelium

Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able to repopulate the tumor. The Hedgehog (HH) signaling pathway has been shown to regulate the proliferation and survival of breast cancer stem cells, and has been shown to promote resistance to chemotherapy through the activation of multi-drug resistance and pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4-24 h after DOC treatment. This activation had little effect on the bulk of the tumor cell population as inhibition of HH signaling failed to increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemness markers as well as mammosphere formation were observed after treatment with DOC suggesting an increase in the breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced by DOC treatment does not have a chemosensitizing effect on the heterogeneous tumor population, but may be required for survival and expansion of breast cancer stem cells after chemotherapy.

Topics: Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Cell Proliferation; Docetaxel; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; MCF-7 Cells; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Signal Transduction; Taxoids

FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression.. Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments.. FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome.. Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Cell Line, Tumor; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Docetaxel; Epirubicin; Female; Fluorouracil; Gene Expression; Gene Knockdown Techniques; Hepatocyte Nuclear Factor 3-alpha; Humans; Kaplan-Meier Estimate; Ki-67 Antigen; Middle Aged; Neoadjuvant Therapy; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Progesterone; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult

In a landmark article published in the May 1, 2001, issue of Clinical Cancer Research, Lee and colleagues reported the original preclinical studies demonstrating anticancer activity of BMS-247550 (ixabepilone) against taxane-sensitive and taxane-resistant cancers. Subsequent clinical trials established the clinical efficacy of ixabepilone, leading to its regulatory approval for the treatment of drug-resistant metastatic or locally advanced breast cancers.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Epothilones; Female; HCT116 Cells; Humans; Microtubules; Taxoids; Tubulin Modulators

During the past decade, neoadjuvant chemotherapy (NAC) has been increasingly used in patients to reduce large tumors to a size eligible for breast-conserving therapy (BCT). However, the association between NAC and Ki-67 has not yet been fully elucidated. The aim of this study was to evaluate the prognostic significance of Ki-67, specifically after NAC followed by BCT, particularly in terms of locoregional recurrence (LRR).. A total 217 patients who received BCT after NAC were retrospectively analyzed. In these patients, immunohistochemistry analyses defined four tumor subtypes, Luminal A, Luminal B, Triple negative, and HER2 type. Ki-67 was examined by immunohistochemistry in both pretreatment core needle samples and post-treatment surgical excision specimens. High Ki-67 expression was defined as >20%. The prognostic factors LRR, locoregional relapse-free survival (LRRFS), and overall survival (OS) were analyzed.. In total, LRR developed in 14 patients, and the 5 year-LRRFS was 94.2%. Post-treatment high Ki-67 expression, triple negative, the presence of lymphovascular invasion, and histological grade 3 were significantly high in LRR for prognostic factors (P < 0.05). There were significant differences in Kaplan-Meier method for LRRFS curves according to these three factors for patients receiving BCT following NAC (P < 0.05). There was a significant difference in the 5 year-OS for patients with and without LRR (41.7% vs. 93.9%, P < 0.001).. Post-treatment high Ki-67 expression could be one of the important prognostic factors of LRR, and require careful follow-up on LRR at the time of surveillance.

Topics: Adult; Aged; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Female; Humans; Ki-67 Antigen; Lymph Node Excision; Mastectomy, Segmental; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Trastuzumab

Tau is a member of microtubule-associated proteins (MAPs) and expressed in normal breast epithelium and breast cancer cells. Tau expression levels in early breast cancer were correlated with the responsiveness of taxane-containing chemotherapy. However, it is unknown whether Tau contributes to breast cancer progression. Herein, Tau expression in recurrent and metastatic breast cancer (RMBC) and its predictive significance in taxane-containing palliative chemotherapy were investigated. Immunohistochemical (IHC) staining was conducted to detect Tau protein expression levels in biopsies from 285 patients with RMBC, and the correlation between Tau expression and sensitivity to taxane was evaluated. One hundred twenty-one (42.46 %, 121/285) patients were Tau positive in their tumor. One hundred ninety-four (68.07 %, 194/285) patients were effective clinical remission, which evaluated with response evaluation criteria in solid tumors (RECIST) criteria. In this group, 141 (85.98 %, 141/194) patients were Tau negative. We further analyzed the correlation between Tau expression and clinicopathological characteristics. Tau expression was positively correlated to estrogen receptor (ER) status. Multivariate logistic regression analysis showed that Tau expression significantly differentiated patients with effective response to treatment (95 % confidence interval (CI): 4.230-13.88, P < 0.01). Tau expression was identified as an independent factor to predict the sensitivity of tumors to taxane-containing palliative chemotherapy in RMBC, suggesting that Tau expression in RMBC may serve as a clinical predictor for taxane-containing palliative chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Palliative Care; Prognosis; tau Proteins; Taxoids

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Humans; Taxoids

Taxane-based chemotherapy for the treatment of breast cancer is associated with fluid retention in the extremities; however, its association with development of breast cancer-related lymphedema is unclear. We sought to determine if adjuvant taxane-based chemotherapy increased risk of lymphedema or mild swelling of the upper extremity. 1121 patients with unilateral breast cancer were prospectively screened for lymphedema with perometer measurements. Lymphedema was defined as a relative volume change (RVC) of ≥10 % from preoperative baseline. Mild swelling was defined as RVC 5- <10 %. Clinicopathologic characteristics were obtained via medical record review. Kaplan-Meier and Cox proportional hazard analyses were performed to determine lymphedema rates and risk factors. 29 % (324/1121) of patients were treated with adjuvant taxane-based chemotherapy. The 2-year cumulative incidence of lymphedema in the overall cohort was 5.27 %. By multivariate analysis, axillary lymph node dissection (ALND) (p < 0.0001), higher body mass index (p = 0.0007), and older age at surgery (p = 0.04) were significantly associated with increased risk of lymphedema; however, taxane chemotherapy was not significant when compared to no chemotherapy and non-taxane chemotherapy (HR 1.14, p = 0.62; HR 1.56, p = 0.40, respectively). Chemotherapy with docetaxel was significantly associated with mild swelling on multivariate analysis in comparison to both no chemotherapy and non-taxane chemotherapy groups (HR 1.63, p = 0.0098; HR 2.15, p = 0.02, respectively). Patients who receive taxane-based chemotherapy are not at an increased risk of lymphedema compared to patients receiving no chemotherapy or non-taxane adjuvant chemotherapy. Those treated with docetaxel may experience mild swelling, but this does not translate into subsequent lymphedema.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Incidence; Lymphedema; Mastectomy; Middle Aged; Taxoids; Time Factors; Young Adult

The purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC).. Between December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m(2) twice daily) was administered for 2 weeks followed by a 1-week rest period.. The response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P = .012), single-organ metastasis (51.5% vs. 32.0%; P = .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P = .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P < .001 and HR, 0.62; P = .004).. Our data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.

Topics: Administration, Oral; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Disease-Free Survival; Female; Follow-Up Studies; Humans; Neoplasm Metastasis; Receptor, ErbB-2; Taxoids; Treatment Outcome

The purpose of this study was to compare survival and risk of adverse events in women with early stage breast cancer (BC) treated with (1) doxorubicin (A), cyclophosphamide (C) + paclitaxel (P), (2) fluorouracil (F), epirubicin (E), cyclophosphamide (C) + docetaxel (D), or (3) dose-dense AC-P. Retrospective cohort study including 8462 women aged ≥18 years, with resected stage I-III BC, diagnosed between 2003 and 2009 in Ontario, identified through linkage of administrative databases. Primary outcome is overall survival (OS). Secondary outcomes are emergency room (ER) visits/hospitalizations, heart failure (HF), and leukemia. 4710 women were treated with FEC-D, 2065 with AC-P, and 1687 with dd AC-P. Adjusted 5-year OS was 92.1, 87.7, and 90.3 %, for each regimen, respectively (p = 0.0006). There was no difference in OS for FEC-D and dd AC-P in the propensity score-matched analyses (HR 1.24, 95 % CI 0.99-1.55). Five-year risk of HF was also similar (HR 1.09; 0.66-1.791.4 % for dd AC-P and 1.3 % for FEC-D and, p = 0.72). Treatment with FEC-D was significantly associated with ER visits and hospital admissions (p < 0.0001). The risks of leukemia were low and similar among the 3 groups (AC-P: 0.34 %, FEC-D: 0.08 %, dd AC-P: 0.12 %; p = 0.09). Although the efficacy of the three regimens was similar to that observed in randomized trials, we report higher toxicity with the use of these regimens in clinical practice. This was especially concerning for the docetaxel-containing regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Comorbidity; Databases, Factual; Emergency Medical Services; Female; Heart Failure; Hospitalization; Humans; Middle Aged; Mortality; Neoplasm Staging; Ontario; Population Surveillance; Registries; Risk Factors; Taxoids

Drug combinations are highly efficient in systemic treatment of complex multigene diseases such as cancer, diabetes, arthritis and hypertension. Most currently used combinations were found in empirical ways, which limits the speed of discovery for new and more effective combinations. Therefore, there is a substantial need for efficient and fast computational methods. Here, we present a principle that is based on the assumption that perturbations generated by multiple pharmaceutical agents propagate through an interaction network and can cause unexpected amplification at targets not immediately affected by the original drugs. In order to capture this phenomenon, we introduce a novel Target Overlap Score (TOS) that is defined for two pharmaceutical agents as the number of jointly perturbed targets divided by the number of all targets potentially affected by the two agents. We show that this measure is correlated with the known effects of beneficial and deleterious drug combinations taken from the DCDB, TTD and Drugs.com databases. We demonstrate the utility of TOS by correlating the score to the outcome of recent clinical trials evaluating trastuzumab, an effective anticancer agent utilized in combination with anthracycline- and taxane- based systemic chemotherapy in HER2-receptor (erb-b2 receptor tyrosine kinase 2) positive breast cancer.

Topics: Algorithms; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Databases, Pharmaceutical; Drug Interactions; Female; Humans; Outcome Assessment, Health Care; Protein Interaction Maps; Receptor, ErbB-2; Taxoids; Trastuzumab

Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN.. We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199.. When evaluating for grade 3-4 TIPN, 120 SNPs had a P value of <10(-4) from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3-4 TIPN (P = 1.7 × 10(-3); OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2-4 TIPN (HR, 2.1; P = 5.6 × 10(-16)) and grade 3-4 TIPN (HR, 2.6; P = 1.1 × 10(-11)) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10(-7)).. rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

Topics: Black People; Breast Neoplasms; Bridged-Ring Compounds; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; Receptors, Fc; Taxoids; White People

Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Moreover, many chemotherapeutic agents need to be interrupted due to toxicity. Here we report an extremely long duration of chemotherapy with eribulin (11 courses) in a taxane-pretreated metastatic breast cancer patient. Therapy was well tolerated with no worsening of pre-existing neuropathy, achieving excellent outcomes and a good quality of life. This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer chemotherapeutic agent.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Female; Furans; Humans; Ketones; Neoplasm Metastasis; Retreatment; Taxoids; Treatment Outcome

TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.. MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in ⩾1 core/tumour.. MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+; P<0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points.. Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Co-Repressor Proteins; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Taxoids

Several methods are used to assess the pathologic response of breast cancer after neoadjuvant chemotherapy (NAC) to predict clinical outcome. However, the clinical utility of these systems for each molecular subtype of breast cancer is unclear. Therefore, we applied six pathologic response assessment systems to specific subtypes of breast cancer and compared the results.. Five hundred and eighty eight breast cancer patients treated with anthracycline with/without taxane-based NAC were retrospectively analyzed, and the ypTNM stage, residual cancer burden (RCB), residual disease in breast and nodes (RDBN), tumor response ratio, Sataloff's classification, and Miller-Payne grading system were evaluated. The results obtained for each assessment system were analyzed in terms of patient survival.. In triple-negative tumors, all systems were significantly associated with disease-free survival and Kaplan-Meier survival curves for disease-free survival were clearly separated by all assessment methods. For HR+/HER2- tumors, systems assessing the residual tumor (ypTNM stage, RCB, and RDBN) had prognostic significance. However, for HER2+ tumors, the association between patient survival and the pathologic response assessment results varied according to the system used, and none resulted in distinct Kaplan-Meier curves.. Most of the currently available pathologic assessment systems used after anthracycline with/without taxane-based NAC effectively classified triple-negative breast cancers into groups showing different prognoses. The pathologic assessment systems evaluating residual tumors only also had prognostic significance in HR+/HER2- tumors. However, new assessment methods are required to effectively evaluate the pathologic response of HR+/HER2+ and HR-/HER2+ tumors to anthracycline with/without taxane-based NAC.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Neoplasm, Residual; Outcome Assessment, Health Care; Prognosis; Remission Induction; Reproducibility of Results; Retrospective Studies; Taxoids; Triple Negative Breast Neoplasms

Major advances in early detection and therapy have significantly increased the survival of breast cancer patients. Unfortunately, most cancer therapies are known to carry a substantial risk of adverse long-term treatment-related effects. Little is known about patient susceptibility to severe side effects after chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. On the other hand, recent advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discovery show great promise to provide clinically relevant protein biomarkers. In this study, we evaluated the association between protein content in serum exosomes and severity of CIPN. Women with early stage breast cancer receiving adjuvant taxane chemotherapy were assessed with the FACT-Ntx score and serum was collected before and after the taxane treatment. Based on the change in FACT-Ntx score from baseline to 12 month follow-up, we separated patients into two groups: those who had no change (Group 1, N = 9) and those who had a ≥20% worsening (Group 1, N = 8). MS-based proteomics technology was used to identify proteins present in serum exosomes to determine potential biomarkers. Mann-Whitney-Wilcoxon analysis was applied and maximum FDR was controlled at 20%. From the serum exosomes derived from this cohort, we identified over 700 proteins known to be in different subcellular locations and have different functions. Statistical analysis revealed a 12-protein signature that resulted in a distinct separation between baseline serum samples of both groups (q<0.2) suggesting that the baseline samples can predict subsequent neurotoxicity. These toxicity-associated biomarkers can be further validated in larger retrospective cohorts for their utility in identifying patients at high risk for CIPN.

Topics: Adult; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Case-Control Studies; Chemotherapy, Adjuvant; Cohort Studies; Exosomes; Female; Humans; Middle Aged; Neoplasm Proteins; Peripheral Nervous System Diseases; Prospective Studies; Proteomics; Risk Factors; Tandem Mass Spectrometry; Taxoids

The paper describes a case of irreversible dilated cardiomyopathy in a young female patient receiving polychemotherapy for breast cancer.. Представлен случай развития необратимой дилатационной кардиомиопатии у молодой пациентки, получавшей полихимиотерапию по поводу рака молочной железы.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cardiomyopathy, Dilated; Cardiotoxins; Doxorubicin; Female; Humans; Middle Aged; Taxoids; Trastuzumab

We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I-III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR > 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple-negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20-25 % of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Female; Gene Expression Profiling; Humans; Ki-67 Antigen; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; Survival Rate; Taxoids; Young Adult

The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC).. One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively.. Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ≤20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ≤20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS.. HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Middle Aged; Prognosis; PTEN Phosphohydrolase; Receptor, ErbB-2; Receptor, ErbB-3; Retrospective Studies; Taxoids; Trastuzumab

This study proposed a conception of individualized chemotherapy based on organ selectivity of drug distribution by retrospectively comparing the effect of vinorelbine and capecitabine in patients with metastatic breast cancer.. Between January 2002 and December 2009, 133 patients with lung metastasis and 87 patients with liver metastasis were analyzed and followed up until December 2012. The survival analysis was performed by Kaplan-Meier. Multivariate analysis was conducted to identify independent prognostic factors.. The median time to progression of the vinorelbine, capecitabine and anthracycline/taxane groups of patients with lung metastasis was 5.7, 2.9 and 2.1 months, respectively. Median overall survival of the vinorelbine group (27.4 months) was longer than the capecitabine (12.2 months, P = 0.027) and anthracycline/taxane groups (9.1 months, P < 0.001) in patients with lung metastasis. The median time to progression of the vinorelbine, capecitabine and anthracycline/taxane groups of patients with liver metastasis was 2.3, 7.3 and 2.6 months, respectively. Median overall survival of the capecitabine group (15.2 months) was longer than the vinorelbine (9.0 months, P = 0.029) and anthracycline/taxane groups (6.4 months, P = 0.004) in patients with liver metastasis.. Our results indicate that vinorelbine and capecitabine have different advantageous effects in breast cancer patients with lung/liver metastasis. Thus, we propose individualized chemotherapy based on organ specificity and pharmacokinetics.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Precision Medicine; Retrospective Studies; Taxoids; Vinblastine; Vinorelbine

Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer.. We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated.. The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28-0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20-2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05.. This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Genome-Wide Association Study; Humans; Middle Aged; Neoplasm Staging; Odds Ratio; Paclitaxel; Peripheral Nervous System Diseases; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Taxoids

To investigate the value of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET/CT) to predict a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.. Fifty-seven consecutive women with HER2-positive breast cancer, treated with trastuzumab plus taxane-based NAC, were prospectively included. Maximum Standardized Uptake Value of the primary tumor and axillary nodes were measured at baseline (PET₁.SUVmax) and after the first course of NAC (PET₂.SUVmax). Tumor metabolic volumes were assessed to determine Total Lesion Glycolysis (TLG). The tumor metabolic response (ΔSUVmax and ΔTLG) was calculated.. In univariate analysis, negative hormonal receptor status (p = 0.04), high tumor grade (p = 0.03), and low tumor PET₂.SUVmax (p = 0.001) were predictive of pCR. Tumor ΔSUVmax correlated with pCR (p = 0.03), provided that tumors with low metabolic activity at baseline were excluded. ΔTLG did not correlate with pCR. In multivariate analysis, tumor PET₂.SUVmax < 2.1 was the best independent predictive factor (Odds ratio =14.3; p = 0.004) with both negative and positive predictive values of 76 %. Although the metabolic features of the primary tumor did not depend on hormonal receptor status, both the baseline metabolism and early response of axillary nodes were higher if estrogen receptors were not expressed (p = 0.01 and p = 0.03, respectively).. In HER2-positive breast cancer, very low tumor residual metabolism after the first cycle of NAC (SUVmax < 2.1) was the main predictor of pCR. These results should be further explored in multicenter studies and incorporated into the design of clinical trials.

Topics: Adult; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Female; Fluorodeoxyglucose F18; Genes, erbB-2; Humans; Middle Aged; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Taxoids; Tomography, X-Ray Computed; Trastuzumab; Treatment Outcome

The aim of this study was to assess the response rates (clinical and pathological ) with docetaxel and epirubicin combination chemotherapy and its effect on outcome.. We retrospectively analysed locally advanced breast cancer (LABC) patients who received NACT from January 2008 to December 2012 in our tertiary care centre. LABC constituted 37% of all breast cancer cases and 120 patients fulfilled the eligibility criteria. The regimens used for NACT were, six cycles of DEC (docetaxel 75 mg/m2, epirubicin 75 mg/ m2, cyclophosphamide 500 mg/m2 on Day 1, 3 weekly) and a sequential regimen (4 cycles of FEC, 5-flurouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2 followed by 4 cycles of docetaxel 85 mg/m2).. The median age was 47 years (range 23-72). Ninety six ( 80 %) had T4 disease and 90% had clinically palpable lymph nodes at diagnosis. The median size of primary tumor at presentation was 5.9 cm. Hormone receptor positivity was seen in 55% and HER2/neu positivity, in 25%. Triple negative breast cancers constituted 25 % of the cases. The overall clinical response rate ( complete or partial ) was 85% and pathological complete responses were obtained in 15%. Four cases defaulted, 5 patients died of treatment related toxicity and 15% developed febrile neutropenia on DEC. The median duration of follow up was 22 months. The median time to relapse was 20 months and the 3 year relapse free and overall survival rates were 50% and 70% respectively.. LABC constituted 37% of all breast cancer cases at our institute. With NACT, pCR was seen in 15% of the cases. Sequential chemotherapy was better tolerated than concurrent anthracyline and taxane chemotherapy with a similar pCR.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Epirubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult

Neoadjuvant chemotherapy (NAC) is one of the standard care regimens for patients with resectable early-stage breast cancer. It would be advantageous to determine the chemosensitivity of tumors before initiating NAC. One of the parameters potentially compromising such chemosensitivity would be a hypoxic microenvironment of cancer cells. The aim of this study was thus to clarify the correlation between expression of the hypoxic marker carbonic anhydrase-9 (CA9) and chemosensitivity to NAC as well as prognosis of breast cancer patients.. A total of 102 patients with resectable early-stage breast cancer was treated with NAC consisting of FEC (5-fluorouracil, epirubicin, and cyclophosphamide) followed by weekly paclitaxel before surgery. Core needle biopsy (CNB) specimens and resected tumors were obtained from all patients before and after NAC, respectively. Chemosensitivity to NAC and the prognostic potential of CA9 expression were evaluated by immunohistochemistry.. CA9 positivity was detected in the CNB specimens from 47 (46%) of 102 patients. The CA9 expression in CNB specimens was significantly correlated with pathological response, lymph node metastasis, and lymph-vascular invasion. Multivariate analysis revealed that the CA9 expression in CNB specimens was an independent predictive factor for pathological response. The Kaplan-Meier survival curve revealed a significant negative correlation (p=0.013) between the disease-free survival (DFS) and the CA 9 expression in resected tissues after NAC. Multivariate regression analyses indicated that the CA9 expression in resected tissues was an independent prognostic factor for DFS.. CA9 expression in CNB specimens is a useful marker for predicting chemosensitivity, and CA9 expression in resected tissue is prognostic of DFS in patients with resectable early-stage breast cancer treated by sequential FEC and weekly paclitaxel prior to resection.

Topics: Adult; Aged; Anthracyclines; Antigens, Neoplasm; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Carbonic Anhydrase IX; Carbonic Anhydrases; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Taxoids

Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2).. Patients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated.. On average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0%) to $5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs.. Chemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Costs and Cost Analysis; Deoxycytidine; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Health Care Costs; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

To date, there is no effective marker to predict chemoresistance in cancers. In this study, we aimed to find a signature that can detect chemoresistance to taxane-based therapies in breast cancer. By studying the gene-expression profiling in discovery cohorts with 92 taxane-resistant and 68 taxane-sensitive patients, a 20-gene taxane-based chemotherapy signature (TAXSig) and a TAXSig equation were developed. The TAXSig and its equation were later validated in five further independent datasets with a total of 659 patients. In general, the TAXSig equation easily and effectively discriminated between chemoresistant and chemosensitive individuals. The TAXSig-identified groups showed significant differences in clinical outcomes both in estrogen-receptor-positive and -negative (ER(-)) breast cancer patients, while the TAXSig was especially powerful in identifying ER(-) patients who had a good prognosis and were chemosensitive. In conclusion, the TAXSig is a reliable, effective, and reproducible means of classifying chemoresistance to taxane-based therapies in breast cancer.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Markers; Humans; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Reproducibility of Results; Taxoids; Treatment Outcome

Adjuvant chemotherapy has changed dramatically in the last decades. Anthracycline-/Taxane-based and dose-dense chemotherapy regimens improved survival in node positive breast cancer. This study tries to answer the following questions:. This is a German multi-centre (17 participating hospitals all certified as breast cancer centres) retrospective cohort study. We included patients that received CMF-like (CMF) (n=1308), Anthracycline-based (A) (1046), Anthracycline-Taxane-based (AT) (1110) and dose-dense chemotherapy (DD) (213) into this analysis.. In case of N0 and 1-3 pos LN we did not observe statistically significant differences in overall (OS) and disease-free survival (DFS) between CMF/A/AT and (for 1-3 pos LN) DD. In the group of 4-10 pos LN we observe an improvement by the use of AT-based chemotherapy, which cannot further be improved by DD chemotherapy. However in the highest risk group, defined as ⩾11 pos LN, we observed a statistically significant improvement in survival by the use of DD chemotherapy. Also a statistically slightly non-significant trend towards improvement of survival parameters by the use of DD compared to AT chemotherapy could be observed. Only for G3 subtypes we could observe a survival benefit for DD. These results remain consistent after exclusion of non-guideline adherent patients (surgery, radiotherapy and endocrine therapy) in order to reduce the bias of guideline violations in other adjuvant treatment modalities.. DD chemotherapy is associated with improved survival parameters in patients with ⩾11 positive LN.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Guideline Adherence; Humans; Lymphatic Metastasis; Middle Aged; Neoplasms, Hormone-Dependent; Practice Guidelines as Topic; Receptor, ErbB-2; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult

This study was designed in an attempt to determine the influence of neoadjuvant chemotherapy on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her-2), and Ki-67 expressions in patients with breast cancer.. Pre- and post-neoadjuvant chemotherapy, paired-tumor specimens from 103 patients with breast cancer administrated with anthracycline or anthracycline combined taxane regimen were collected. Immunohistochemical staining for ER, PR, Her-2, and Ki-67 was performed by the DAKO EnVision method.. Among the 103 cases, five patients (4.9%) had a complete response (CR), 82 (79.6%) partial response (PR), 15 (14.6%) stable disease (SD), and one (0.9%) progressive disease (PD), yielding an overall response rate (CR + PR) of 84.5%. Nine patients achieved pathological CR. There was a significant decrease in the average index of Ki-67 postneoadjuvant chemotherapy, compared with that before chemotherapy (24.1% vs. 39.7%, P < 0.001). After neoadjuvant chemotherapy, the changes of Ki-67 in different subtypes of breast cancer were different (P < 0.001), and these changes correlated with response to neoadjuvant chemotherapy (P < 0.001). No significant changes in immunohistochemical expression were observed for ER, PR and Her-2.. Neoadjuvant chemotherapy apparently reduced Ki-67 index in primary breast carcinomas, but profiles for ER, PR and Her-2 were not significantly different before and after neoadjuvant chemotherapy. The change of Ki-67 correlated with molecular subtypes and response to neoadjuvant chemotherapy, suggesting that Ki-67 index was a surrogate marker to predict the treatment response of neoadjuvant chemotherapy.

Topics: Adult; Aged; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Immunohistochemistry; In Vitro Techniques; Ki-67 Antigen; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Taxoids; Young Adult

In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed.. Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel).. Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p≤0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p≤0.01).. Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

Topics: Aged; Breast Neoplasms; Bridged-Ring Compounds; Cytochrome P-450 CYP3A; DNA-Binding Proteins; Docetaxel; Drug-Related Side Effects and Adverse Reactions; Endonucleases; Female; Genetic Association Studies; Humans; Middle Aged; Mucositis; Paclitaxel; Polymorphism, Single Nucleotide; Taxoids

Clinical outcomes, including adverse events, in 52 advanced breast cancer patients treated with eribulin chemotherapy after taxane treatment (TX) were analyzed to confirm the effectiveness and safety of this treatment.The objective response rate (ORR) in patients was 34.6% (TX group 31.6%, non-TX group 36.4%). There were no significant differences in overall survival, time to treatment failure, or progression-free between three TX and non-TX groups. Further, adverse events did not differ between groups expression of neutropenia of Grade 3 or more. On the other hand, the number of patients with sensory peripheral neuropathy of Grade 1 or more was significantly more in the TX group than in the non-TX group. Eribulin chemotherapy was effective for the treatment of advanced breast cancer regardless of a history of taxane treatment.In addition, sensory peripheral neuropathy is a possible complication that can occur in advanced breast cancer patients treated with eribulin chemotherapy with taxane treatment history.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Peripheral Nervous System Diseases; Taxoids

The taxanes are a class of chemotherapeutic agents that are widely used in the treatment of various solid tumors. Although taxanes are highly effective in cancer treatment, their use is associated with serious complications attributable to large interindividual variability in pharmacokinetics and a narrow therapeutic window. Unpredictable toxicity occurrence necessitates close patient monitoring while on therapy and adverse effects frequently require decreasing, delaying or even discontinuing taxane treatment. Currently, taxane dosing is based primarily on body surface area, ignoring other factors that are known to dictate variability in pharmacokinetics or outcome. This article discusses three potential strategies for individualizing taxane treatment based on patient information that can be collected before or during care. The clinical implementation of pharmacogenetics, enzyme probes or therapeutic drug monitoring could enable clinicians to personalize taxane treatment to enhance efficacy and/or limit toxicity.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Drug Monitoring; Female; Humans; Neoplasms; Paclitaxel; Pharmacogenetics; Precision Medicine; Taxoids

The aim of this work was to compare a high-resolution diffusion-weighted imaging (HR-DWI) acquisition (voxel size = 4.8 mm(3)) to a standard diffusion-weighted imaging (STD-DWI) acquisition (voxel size = 29.3 mm(3)) for monitoring neoadjuvant therapy-induced changes in breast tumors.. Nine women with locally advanced breast cancer were imaged with both HR-DWI and STD-DWI before and after 3 weeks (early treatment) of neoadjuvant taxane-based treatment. Tumor apparent diffusion coefficient (ADC) metrics (mean and histogram percentiles) from both DWI methods were calculated, and their relationship to tumor volume change after 12 weeks of treatment (posttreatment) measured by dynamic contrast enhanced magnetic resonance imaging was evaluated with a Spearman's rank correlation.. The HR-DWI pretreatment 15th percentile tumor ADC (P = .03) and early treatment 15th, 25th, and 50th percentile tumor ADCs (P = .008, .010, .04, respectively) were significantly lower than the corresponding STD-DWI percentile ADCs. The mean tumor HR-ADC was significantly lower than STD-ADC at the early treatment time point (P = .02), but not at the pretreatment time point (P = .07). A significant early treatment increase in tumor ADC was found with both methods (P < .05). Correlations between HR-DWI tumor ADC and posttreatment tumor volume change were higher than the STD-DWI correlations at both time points and the lower percentile ADCs had the strongest correlations.. These initial results suggest that the HR-DWI technique has potential for improving characterization of low tumor ADC values over STD-DWI and that HR-DWI may be of value in evaluating tumor change with treatment.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Diffusion Magnetic Resonance Imaging; Female; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Taxoids; Treatment Outcome; Young Adult

To analyze the factors affecting pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients.. A retrospective cohort study was carried out to analyze the clinical data of 141 breast cancer patients treated with neoadjuvant chemotherapy. The factors affecting pCR and the changes of tumor receptor status before and after treatment were analyzed.. Among all the 141 patients, 21 patients (14.9%) achieved pCR. The rate of pCR achieved by regimens of anthracycline combined with taxane was higher (16.8%, 19/113) than that by anthracycline-containing regimens (7.1%, 1/14). The dose intensity of anthracycline had a significant correlation with pCR rate (P < 0.05). The pCR rate in the relative dose intensity of taxane ≥ 0.85 arm was higher than that of < 0.85 arm (P = 0.02). Eighty patients (56.7%) had completed more than 4 cycles of chemotherapy and the median time to achieve pCR was 6 (3 to 10) cycles. The pCR rate had a significant difference between patients < 6 and ≥ 6 cycles (7.1% vs. 22.5%,P = 0.01). Multivariate analysis showed that tumor size measured by palpation ≤ 5 cm and ≥ 6 chemotherapy cycles were significantly related with pCR rate (P < 0.05). In all the 21 pCR patients, the pre-treatment ER(-), PR(-), HER-2(-) statuses were in 14, 14 and 17 patients, respectively. The status of ER, PR, HER-2 of most patients (74.2%, 69.7% and 87.7%, respectively) was not changed after treatment. Among the patients with changes in receptor status, ER changed from negative to positive was in the majority (37.1%, 13/35 vs. 12.9%, 4/31, P < 0.05), and the percentage of changes in PR and HER-2 status had no significant differences.. The regimens of anthracycline combined with taxane can achieve a higher pCR rate. The lymph node and receptor status before therapy have no significant correlation with pCR. Patients who have primary tumor size ≤ 5 cm, ≥ 6 chemotherapy cycles and enough dose intensity are easier to achieve pCR. The receptor status before and after therapy should be determined, and according to any positive results, physicians can chose HER-2 targeted therapy and/or endocrine therapy after surgery to benefit the patients.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Female; Humans; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Proportional Hazards Models; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Remission Induction; Retrospective Studies; Taxoids; Tumor Burden

This study aimed to elucidate the clinical implication of human epidermal growth factor receptor 2/centromeric probe for chromosome 17 (HER2/CEP17) ratio and HER2 immunohistochemistry (IHC) results in patients with HER2 fluorescence in situ hybridization (FISH)-positive metastatic breast cancer (MBC) who received first-line trastuzumab plus taxane chemotherapy.. Using clinical data of patients with HER2 FISH-positive MBC who received first-line trastuzumab plus taxane chemotherapy, we analyzed the clinical outcome according to the HER2/CEP17 ratio and HER2 IHC analysis.. Fifty-two women were analyzed. The median age was 50 years (range 27-69 years). Patients with a HER2/CEP17 ratio ≥3.0 had significantly longer progression-free survival (PFS) (17.2 vs. 7.4 months; p = 0.002) with a tendency toward higher response rate (RR) (p = 0.325) and longer overall survival (OS) (p = 0.129). Patients with HER2 IHC 1+ had significantly shorter OS (14.0 vs. 42.4 months; p = 0.013) along with a tendency toward lower RR (p = 0.068) and shorter PFS (p = 0.220). In the multivariate analysis, HER2/CEP17 ratio <3.0 (p = 0.004) and Eastern Cooperative Oncology Group (ECOG) PS 2 (p = 0.015) were significant factors for shorter PFS, and HER2 IHC 1+ (p = 0.015) and ECOG PS 2 (p = 0.036) were significant factors for poor OS.. Our data support that HER2/CEP17 ratios and HER2 IHC scores may predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 FISH-positive MBC.

Topics: Adult; Aged; Algorithms; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Female; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Mammary Glands, Human; Middle Aged; Neoplasm Proteins; Prognosis; Receptor, ErbB-2; Retrospective Studies; Survival Analysis; Taxoids; Trastuzumab

Tau is a microtubule-associated protein and expressed in normal breast epithelial cells and breast cancer. Tau expression in breast cancer may be important for chemotherapy optimization. This study is to investigate the expression of Tau in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy. Levels of Tau protein in advanced breast cancer were detected immunohistochemically. The chemotherapeutic efficacy indexes in Tau(-) group, which includes the remission rate, Miller-Payne pathological reactive grade, and pathologic complete response rate, were improved compared with that in Tau(+) group. There was difference in the efficacy indexes among ER+ subgroups but not among ER- patients. In addition, Tau expression was positively correlated (r = 0.32, P < 0.00). In multivariate analysis, when age, clinical stage, postoperative lymph node metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status were included, postoperative lymph node metastasis and Tau-negative status were identified as independent predictors of pathologic complete response. In conclusion, negative Tau protein expression may be an effective predictor for taxane-containing neoadjuvant chemotherapy, especially in ER+ subgroups. Further study on the molecular mechanism and utility of Tau for individualizing adjuvant chemotherapy is warranted.

Topics: Adult; Aged; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Ki-67 Antigen; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; tau Proteins; Taxoids; Tumor Suppressor Protein p53; Young Adult

For neoadjuvant taxane and anthracycline-based chemotherapy for breast cancer, patients with pathological complete response (pCR) have a favorable prognosis compared with patients with residual disease (RD). Although a number of pCR predictors based on microarray profiles have been proposed to guide neoadjuvant chemotherapy, most of these have not been independently validated in inter-laboratory datasets, possibly owing to the fact that microarray measurements are sensitive to experimental batch effects and inter-array data normalizations. In this study, we developed a rank-based method to tackle this difficulty. First, we extracted from two datasets a combination of gene pairs, each of which had opposing relative expression orders in patients with pCR and those with RD, and used these to build a pCR predictor. This pCR predictor was found to have sensitivities of 74 and 86 % and specificities of 71 and 68 % in another two independent datasets from multiple laboratories, and these results were better than the performances of three previously reported predictors. Considering that patients with minimal RD also tend to have a good prognosis, we then developed a prognosis predictor for RD as a complement to the pCR predictor, in order to identify a group of patients likely to have a good prognosis, taking into account both the RD level and the intrinsic risk factors. In the independent validation, there was a significant difference (P = 0.001) in distant relapse-free survival between the patients likely to and those not likely to have a good prognosis according to our prognosis predictor. In conclusion, the rank-based predictors for response and prognosis can accurately and robustly predict patients with improved prognosis who might benefit from neoadjuvant taxane and anthracycline-based chemotherapy.

Topics: Algorithms; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Computational Biology; Female; Gene Expression Profiling; Humans; Medical Informatics; Neoadjuvant Therapy; Prognosis; Reproducibility of Results; Taxoids; Treatment Outcome

To determine the relationship between obesity, diabetes, and survival in a large cohort of breast cancer patients receiving modern chemotherapy and endocrine therapy.. We identified 6342 patients with stage I-III breast cancer treated between 1996 and 2005. Patients were evaluated according to body mass index (BMI) category and diabetes status.. In a multivariate model adjusted for body mass index, diabetes, medical comorbidities, patient- and tumor-related variables, and adjuvant therapies, relative to the normal weight, hazard ratios (HRs) for recurrence-free survival (RFS), overall survival (OS), and breast cancer-specific survival (BCSS) for the overweight were 1.18 [95% confidence interval (CI) 1.02-1.36], 1.20 (95% CI 1.00-1.42), and 1.21 (95% CI 0.98-1.48), respectively. HRs for RFS, OS, and BCSS for the obese were 1.13 (95% CI 0.98-1.31), 1.24 (95% CI 1.04-1.48), and 1.23 (95% CI 1.00-1.52), respectively. Subset analyses showed these differences were significant for the ER-positive, but not ER-negative or HER2-positive, groups. Relative to nondiabetics, HRs for diabetics for RFS, OS, and BCSS were 1.21 (95% CI 0.98-1.49), 1.39 (95% CI 1.10-1.77), and 1.04 (95% CI 0.75-1.45), respectively.. In patients receiving modern adjuvant therapies, obesity has a negative impact on RFS, OS, and BCSS; and diabetes has a negative impact on RFS and OS. Control of both may be important to improving survival in obese and diabetic breast cancer patients.

Topics: Anthracyclines; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Body Composition; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Diabetes Mellitus; Disease-Free Survival; Female; Humans; Middle Aged; Obesity; Paclitaxel; Receptor, ErbB-2; Receptors, Estrogen; Survival; Tamoxifen; Taxoids; Treatment Outcome

While clinical and pathologic responses are important prognostic parameters, biological markers from core needle biopsy (CNB) are needed to predict neoadjuvant chemotherapy (NAC) response, to individualize treatment, and to achieve maximal efficacy. We retrospectively evaluated the cases of 183 patients with primary breast cancer who underwent surgery after NAC (anthracycline and taxane) at the National Cancer Center Hospital (NCCH). We analyzed EGFR, HER2, and p53 expression and common clinicopathological features from the CNB and surgical specimens of these patients. These biological markers were compared between sensitive patients (pathological complete response;pCR) and insensitive patients (clinical no change;cNC and clinical progressinve disease;cPD). In a comparison between the 9 (5%) sensitive patients and 30 (16%) insensitive patients, overexpression of p53 but not overexpression of either HER2 or EGFR was associated with a good response to NAC. p53 (p＝0.045) and histological grade 3 (p＝0.011) were important and significant predictors of the response to NAC. The correspondence rates for histological type, histological grade 3, ER, PgR, HER2, p53, and EGFR in insensitive patients between CNB and surgical specimens were 70%, 73%, 67%, 70%, 80%, 93%, and 73%. The pathologic response was significantly associated with p53 expression and histological grade 3. The correspondence rate of p53 expression between CNB and surgical specimens was higher than that of other factors. We conclude that the level of p53 expression in the CNB was an effective and reliable predictor of treatment response to NAC.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Biopsy, Large-Core Needle; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Predictive Value of Tests; Receptor, ErbB-2; Taxoids; Tumor Suppressor Protein p53

A 32-year-old woman was seen in our hospital for complaints of bulge and pain in the sternum, and upon examination showed a lump in the left breast and enlarged left axillary lymph nodes. The patient was diagnosed with invasive ductal carcinoma with metastasis to the sternum that was T2N1M1(OSS), Stage IV, hormone-receptor-positive, and HER2-negative. Four courses each of EC and taxane therapy were performed as primary systemic chemotherapy in combination with zoledronic acid, which resulted in calcification of the osteolytic lesion in the sternum and reduced tumor mass in the breast. The patient was judged to have a partial response(PR)to the treatment. Eight months later, breast-conserving surgery and axillary lymph node dissection were performed, followed by radiation therapy to the left breast and sternum. Treatment with zoledronicac id is ongoing and postoperative hormonal therapy has been started. Four years and 4 months after the initial diagnosis, the lesion in the sternum has calcified and hardened and the patient has not had a recurrence in the same breast or elsewhere in the body.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Chemoradiotherapy; Cyclophosphamide; Epirubicin; Female; Humans; Mastectomy, Segmental; Neoplasm Staging; Sternum; Taxoids

Women with breast cancer treated with aromatase inhibitors (AIs) may experience musculoskeletal symptoms that lead to discontinuation of effective therapy. The purpose of the current study is to evaluate the clinical and genetic predictors for AIs-related musculoskeletal adverse events(MS-AEs).. We recruited 436 postmenopausal Chinese Han women receiving adjuvant AIs therapy for early-stage hormone-sensitive breast cancer. Patients completed a self-administered questionnaire assessing the presence of musculoskeletal symptoms that started or worsened after initiating AIs. 27 single nucleotide polymorphisms (SNP) of ESR1, ESR2 and PGR were analyzed by Sequenom MassARRAY assays and /or PCR-based TaqMan assays.Of the 436 enrolled women, 206 cases experienced musculoskeletal symptoms.Patients who received taxane chemotherapy were more than two times more likely than other patients to have AIs-related MS-AEs. Genetic assay had showed that only two ESR1 SNPs, rs2234693 and rs9340799 were associated with AIs-related MS-AEs.TT genotype and the T allele in rs2234693 was statistically significantly lower in AIs-Related MS-AEs group than controls (P = 0.001; P = 9.49E-7). The frequency of AA genotype and the A allele in rs9340799 was higher (P = 2.20E-5; P = 3.09E-4).. Our results suggested that prior taxane-based chemotherapy was the clinical predictor, while rs2234693 and rs9340799 were the genetic predictors for AIs-related MS-AEs.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents; Aromatase Inhibitors; Asian People; Breast Neoplasms; Bridged-Ring Compounds; Case-Control Studies; China; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Musculoskeletal Diseases; Neoplasm Staging; Odds Ratio; Polymorphism, Single Nucleotide; Postmenopause; Receptors, Progesterone; Taxoids

The aim of this study was to evaluate the change of breast density in the normal breast of patients receiving neoadjuvant chemotherapy (NAC). Forty-four breast cancer patients were studied. MRI acquisition was performed before treatment (baseline), and 4 and 12 weeks after treatment. A computer-algorithm-based program was used to segment breast tissue and calculate breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) (the ratio of FV over BV × 100%). The reduction of FV and PD after treatment was compared with baseline using paired t-tests with a Bonferroni-Holm correction. The association of density reduction with age was analyzed. FV and PD after NAC showed significant decreases compared with the baseline. FV was 110.0 ml (67.2, 189.8) (geometric mean (interquartile range)) at baseline, 104.3 ml (66.6, 164.4) after 4 weeks (p < 0.0001), and 94.7 ml (60.2, 144.4) after 12 weeks (comparison with baseline, p < 0.0001; comparison with 4 weeks, p = 0.016). PD was 11.2% (6.4, 22.4) at baseline, 10.6% (6.6, 20.3) after 4 weeks (p < 0.0001), and 9.7% (6.2, 17.9) after 12 weeks (comparison with baseline, p = 0.0001; comparison with 4 weeks, p = 0.018). Younger patients tended to show a higher density reduction, but overall correlation with age was only moderate (r = 0.28 for FV, p = 0.07, and r = 0.52 for PD, p = 0.0003). Our study showed that breast density measured from MR images acquired at 3T MR can be accurately quantified using a robust computer-aided algorithm based on non-parametric non-uniformity normalization (N3) and an adaptive fuzzy C-means algorithm. Similar to doxorubicin and cyclophosphamide regimens, the taxane-based NAC regimen also caused density atrophy in the normal breast and showed reduction in FV and PD. The effect of breast density reduction was age related and duration related.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Organ Size; Taxoids

Epidermal growth factor (EGF) is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the clinical and pathologic implications of serum EGF levels in patients with HER2-positive metastatic breast cancer (MBC).. We analyzed serum EGF levels from baseline serum samples of consecutive patients with HER2-positive MBC who received first-line trastuzumab plus taxane chemotherapy and correlated them with treatment outcomes and pathologic features.. A total of 50 women were analyzed. The median age was 47 years (range 27-72 years). Patients with high serum EGF levels (≥10.0 pg/mL) had significantly longer overall survival (47.0 months (95 % confidence interval (CI) 28.3-65.7 months) vs. 23.3 months (95 % CI 13.5-33.1 months); p = 0.009) with a tendency toward longer progression-free survival (p = 0.123). Serum EGF levels were not associated with hematologic or cardiac adverse events. Progesterone receptor-positive patients had significantly higher serum EGF levels than progesterone receptor-negative patients (24.3 pg/mL (range 9.5-69.0 pg/mL) vs. 12.3 pg/mL (range 0.0-59.5 pg/mL); p = 0.006).. Our data suggest that high serum EGF levels may be associated with good prognosis in patients with HER2-positive MBC receiving trastuzumab plus taxane chemotherapy. In addition, serum EGF levels were associated with progesterone receptor positivity.

Topics: Adult; Aged; Anemia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Proteins; Prognosis; Receptor, ErbB-2; Receptors, Progesterone; Retrospective Studies; Survival Analysis; Taxoids; Trastuzumab; Up-Regulation

Forkhead Box Protein 3 (FOXP3) is a marker for immunosuppressive CD4+CD25+ regulatory T cells (Tregs). We investigated whether there were significant numbers of FOXP3-positive Tregs in triple-negative breast cancer (TNBC) using immunohistochemistry, and whether the presence of FOXP3-positive Tregs was associated with other prognostic factors, such as stage or histologic grade. We investigated the number of tumor-infiltrating FOXP3-positive Tregs in formalin-fixed TNBC specimens obtained from patients who received palliative treatment between 1999 and 2007.. Immunohistochemistry was used to assess the number of CD4+, CD25+, and FOXP3+ Tregs in tumor tissue and normal breast tissue from 86 TNBC patients. Univariate and multivariate analyses evaluated outcomes according to the number of FOXP3-positive Tregs.. Of the 86 tumor specimens, 22 (25.6%) expressed more than 15 FOXP3-positive Tregs per 10 high power fields in the peritumoral area. On multivariate analysis, staining showing ≥ 15 FOXP3-positive Tregs was an independent prognostic factor for overall survival and progression free survival with hazard ratios of 2.4 (95% CI 1.0-5.6; p = 0.049) and 2.0 (95% CI 1.1-3.6; p = 0.032), respectively. In TNBC, FOXP3-positive Tregs had stronger prognostic significance than did FOXP3-negative Tregs. The finding of improved survival associated with highly infiltrating FOXP3-positive Tregs in TNBC contrasted with several other types of solid cancer.. TNBC may be differently driven by FOXP3 via an immune mechanism. The inclusion of FOXP3+ Tregs may help to improve prognostication for TNBC.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; CD4-Positive T-Lymphocytes; Disease-Free Survival; Drug Utilization; Female; Forkhead Transcription Factors; Humans; Immunohistochemistry; Interleukin-2 Receptor alpha Subunit; Lymphatic Metastasis; Multivariate Analysis; Neoplasm Invasiveness; Pleural Neoplasms; Prognosis; T-Lymphocytes, Regulatory; Taxoids

Expression of class ΙΙΙ β-tubulin (βΙΙΙ-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies including breast cancer. However its predictive value in a neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether βΙΙΙ-tubulin expression in breast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy.. We determined βΙΙΙ-tubulin expression in 85 breast cancers, including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery. βΙΙΙ-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using residual cancer burden (RCB) score.. High βΙΙΙ-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers (P = .003) but not with tumor size, estrogen receptor (ER) status, or human epidermal growth factor receptor 2 (HER2)/neu overexpression. In ER(-) tumors treated with neoadjuvant chemotherapy, high βΙΙΙ-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores (P = .021).. This study reveals differential βΙΙΙ-tubulin expression in breast cancers of different histologic grades, hormone receptors, and HER2/neu status. It also suggests a potential role for βΙΙΙ-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER(-) breast cancer, which has not been previously reported. These data provide a strong rationale for considering βΙΙΙ-tubulin status and further validation of this marker in a large study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Retrospective Studies; Taxoids; Tubulin

Distant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients' life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor.. To identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response), established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test). Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method).. These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Signal Transduction; Taxoids

A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Aurora Kinases; Benzazepines; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle Proteins; Cell Line, Tumor; Co-Repressor Proteins; Cyclin B; Drug Resistance, Neoplasm; Female; Humans; Mitosis; Molecular Chaperones; Neoplasm Proteins; Nuclear Proteins; Poly-ADP-Ribose Binding Proteins; Protein Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; Taxoids; Tumor Suppressor Protein p53; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases; Ubiquitin-Specific Peptidase 7

Whether the presence of steroid receptors in luminal breast cancers renders them resistant to taxanes remains uncertain. Here we assess the role of progesterone receptors (PR) on taxane-induced cell death. We previously showed that estrogen receptor (ER)-positive human breast cancer cells that inducibly express PR-A or PR-B isoforms were protected from taxane-stimulated apoptosis when compared to the identical cells lacking PR. Surprisingly, PR-dependent protection occurred in the absence of progesterone, demonstrating that the unliganded receptors were biologically active. The present studies demonstrate that unliganded PR, focused on PR-A, protect breast cancer cells from taxane-stimulated apoptosis. The studies identify genes regulated by taxanes in isogenic ER-positive cells that either lack or express PR-A. We show that unliganded PR-A alters the gene expression pattern controlled by taxanes, especially multiple genes involved in the spindle assembly checkpoint, a group of proteins that insure proper attachment of microtubules to kinetochores during mitosis. Importantly, taxanes and unliganded PR regulate many of these genes in opposite directions. As a result, mitotic slippage is exacerbated by the presence of PR, leading to an increase in the number of multinucleated cells both in vitro and in xenograft tumors. We describe a simple new assay for assessing multinucleation in paraffin sections. We speculate that rather than inducing cell death, unliganded PR exploits multinucleation to promote cell survival from taxane therapy. This can be prevented with antiprogestin.

Topics: Animals; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle Checkpoints; Cell Line, Tumor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; M Phase Cell Cycle Checkpoints; Mice; Mice, Nude; Microtubules; Mitosis; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Taxoids; Xenograft Model Antitumor Assays

Breast cancer is a genetically heterogenous disease with subtypes differing in prognosis and chemosensitivity. The basal-like breast cancer (BLBC) molecular subtype is associated with poorer outcomes, but is more responsive to taxane-based chemotherapy. Kinesins are intracellular transport proteins that interact with microtubules, which are also the mechanistic target for taxanes. We investigated the relationship between taxane resistance in BLBC and kinesins using both expression and functional studies. Kinesin (KIF) expression was evaluated in three settings in relation to taxane resistance: (i) the NCI-60 cancer cell lines, (ii) pre-treatment samples from four BLBC patient cohorts receiving neoadjuvant chemotherapy regimens with and without taxanes, and (iii) post-treatment samples from residual breast cancer following neoadjuvant taxane-containing chemotherapy. We used a novel functional approach to gene modification, validation-based insertional mutagenesis, to select kinesin-overexpressing clones of BLBC cells for evaluation of related mechanisms of taxane resistance. In the NCI-60 cell line dataset, overexpression of the kinesin KIFC3 is significantly correlated with resistance to both docetaxel (P < 0.001) and paclitaxel (P < 0.001), but not to platinum-based chemotherapy, including carboplatin (P = 0.49) and cisplatin (P = 0.10). Overexpression of KIFC3 and KIF5A in pre-chemotherapy samples similarly predicted resistance to paclitaxel in the MDACC cohorts (P = 0.01); no KIF predicted resistance to fluorouracil-epirubicin-cyclophosphamide or cisplatin in BLBC patient cohorts treated without taxanes. KIF12 is the most overexpressed KIF gene in post-chemotherapy taxane-resistant residual breast cancers (2.8-fold-change). Functional studies established that overexpression of KIFC3, KIF5A, and KIF12 were specific in mediating resistance to docetaxel and not vincristine or doxorubicin. Mutation of the ATP-binding domain of a kinesin abolished its ability to mediate docetaxel resistance. Overall, kinesin overexpression correlates with specific taxane resistance in BLBC cell lines and tissues. Our results suggest a novel approach for drug development to overcome taxane resistance in breast cancer through concurrent or sequential use of kinesin inhibitors.

Topics: Adenosine Triphosphate; Adult; Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Cluster Analysis; Docetaxel; Drug Resistance, Neoplasm; Female; Gene Expression; Gene Expression Profiling; HEK293 Cells; Humans; Kinesins; Middle Aged; Neoplasm Staging; Paclitaxel; Protein Binding; Taxoids; Vincristine

Patients suffering from triple-negative breast cancer (TNBC) have poor prognosis mainly because no standard treatment is currently available. Our objectives were to explore the prognostic factors for first relapse of patients with TNBC. A cohort of 687 patients with TNBC, diagnosed and treated between January 1995 and December 2008 at Sun Yat-sen University Cancer Center, were retrospectively analyzed. Cox proportional hazards models were fitted to explore factors that predict relapse development. Survival rate was computed using the Kaplan-Meier product limit method. The median age of the 687 patients was 46 (range 16-76 years), and 64.8% of the patients were pre-menopausal. The median follow-up time was 56 months (range 14-156 months), in which 194 patients had recurrence, and 115 died. The median recurrence-free time was 25 months (range 4-143 months), with 118 (60.8%) of the cases first relapsing at a single site. The three- and five-year disease-free survival rates were 79.7 and 72.6%, respectively. Primary tumor size at diagnosis, lymph node status, and type of regimen used in the (neo)adjuvant chemotherapy were considered independent predictors of first relapse. CMF-containing adjuvant chemotherapy significantly decreased recurrence compared with the anthracycline- or taxane-based regimens (RR = 0.66, 95%; CI 0.45-0.96; P = 0.030). The median time from first relapse to death was 26 months (range 2-121 months). The two- and five-year survival rates were 60.6 and 36.6%, respectively. Liver metastasis at first recurrence and progression-free survival over 12 months after first-line therapy were two important factors that affected survival rate after recurrence. The median relapse time of TNBC was about 2 years after diagnosis. CMF regimens for TNBC patients may be more effective than anthracycline- or taxane-based regimens. Liver metastasis at first recurrence signifies unfavorable prognosis.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Immunoenzyme Techniques; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Taxoids; Young Adult

Several studies have suggested that bisphosphonates have an antitumor effect. In the current study, the authors sought to evaluate whether the use of bisphosphonates increased the rate of pathological complete response (pCR) in patients with breast cancer.. The authors identified 1449 patients with breast cancer who were receiving taxane- and anthracycline-based neoadjuvant chemotherapy between 1995 and 2007 at The University of Texas MD Anderson Cancer Center. Patients who received bisphosphonates for osteopenia or osteoporosis while receiving chemotherapy were also identified. The primary outcome was the percentage of patients achieving a pCR. Groups were compared using the chi-square test. A multivariable logistic regression model was fit to examine the relation between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan-Meier method was performed; groups were compared using the log-rank test.. Of the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (P < .001) and less likely to be obese (P = .04). The pCR rate was 25.4% in the bisphosphonate group and 16% in the nonbisphosphonate group (P = .11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (odds ratio, 2.18; 95% confidence interval, 0.90-5.24); however, the difference was not found to be statistically significant. With a median follow-up of 55 months (range, 3 months-145 months), no differences in disease recurrence or survival were observed.. The use of bisphosphonates at the time of neoadjuvant chemotherapy was not found to be associated with a statistically significant increase in the rates of pCR. The observed estimates suggest a positive effect; however, the small percentage of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Diseases, Metabolic; Breast Neoplasms; Bridged-Ring Compounds; Diphosphonates; Disease-Free Survival; Female; Humans; Middle Aged; Neoadjuvant Therapy; Osteoporosis; Taxoids; Treatment Outcome

We assessed the efficacy of taxane chemotherapy in BRCA1- and BRCA2-associated patients compared with sporadic metastatic breast cancer patients.. Response rates (RRs) to and progression-free survival (PFS) after taxane chemotherapy of 35 BRCA1-associated and 13 BRCA2-associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third).. Among BRCA1-associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)-negative patients, BRCA1-associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec-positive patients were similar in BRCA1-associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2-associated patients, who were mainly HRec-positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively).. BRCA1-associated, HRec-negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec-negative patients. HRec-positive BRCA1- and BRCA2-associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients.

Topics: Adult; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Bridged-Ring Compounds; Case-Control Studies; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genetic Testing; Humans; Middle Aged; Mutation; Pharmacogenetics; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Taxoids; Treatment Outcome

To assess the usefulness of positron emission tomography combined with computed tomography using (18)F-fluorodeoxyglucose (FDG PET/CT) for optimizing chemotherapy during neoadjuvant chemotherapy for primary breast cancer.. One hundred and eight patients (110 tumors) with breast cancer (≥2 cm, stages II and III) received neoadjuvant chemotherapy consisting of an anthracycline-based regimen and taxane. The maximal value of the baseline standardized uptake value (SUV) and the change in SUV after four cycles of an anthracycline-based regimen relative to baseline SUV were assessed for predicting pathological complete response (pCR) after sequential taxane.. Tumors with pCR had significantly higher baseline SUV (9.3 ± 3.7 SD) compared to those with non-pCR (7.2 ± 3.8 SD) (p = 0.02), but there was a considerable overlap between two groups. On PET scan after four cycles of chemotherapy, thirty-three patients (33.7%) with a 72.1% or greater reduction in SUV were considered as responders and the performance in predicting pCR had a sensitivity of 88.9% and specificity of 78.7%.. The baseline SUV could not be a useful indicator for predicting pCR due to the wide range in sensitivity. On the other hand, a relative change in SUV after completion of an anthracycline-based regimen could be useful for predicting pCR.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Female; Fluorodeoxyglucose F18; Humans; Middle Aged; Neoadjuvant Therapy; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Taxoids; Tomography, X-Ray Computed

The safety and efficacy of skin-sparing mastectomy (SSM) with immediate reconstruction (IR) in patients with locally advanced breast cancer are unclear. The purpose of this study is to compare the outcomes of women with noninflammatory Stage III SSM with IR vs. non-SSM-treated women who underwent neoadjuvant chemotherapy and adjuvant radiation therapy (XRT).. Between October 1997 and March 2010, 100 consecutive patients (40 SSM with IR vs. 60 non-SSM) with Stage III breast cancer received anthracycline- and/or taxane-based neoadjuvant chemotherapy, mastectomy, and adjuvant XRT. Clinical stage (SSM with IR vs. for non-SSM) was IIIA (75% vs. 67%), IIIB (8% vs. 18%), and IIIC (8% vs. 8%). Tumors greater than 5 cm were found in 74% vs. 69%; 97% of patients in both groups were clinically node positive; and 8% vs. 18% had T4b disease.. The time from initial biopsy to XRT was prolonged for SSM-IR patients (274 vs. 254 days, p = 0.04), and there was a trend toward XRT delay of more than 8 weeks (52% vs. 31%, p = 0.07) after surgery. The rate of complications requiring surgical intervention was higher in the SSM-IR group (37.5% vs. 5%, p < 0.001). The 2-year actuarial locoregional control, breast cancer-specific survival, and overall survival rates for SSM with IR vs. non-SSM were 94.7% vs. 97.4%, 91.5% vs. 86.3%, and 87.4% vs. 84.8%, respectively (p = not significant).. In our small study with limited follow-up, SSM with IR prolonged overall cancer treatment time and trended toward delaying XRT but did not impair oncologic outcomes. Complication rates were significantly higher in this group. Longer follow-up is needed.

Topics: Adult; Aged; Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Doxorubicin; Female; Humans; Mammaplasty; Mastectomy; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Radiotherapy Dosage; Survival Rate; Taxoids; Time Factors; Treatment Outcome; Tumor Burden

The aim of this retrospective study was to assess the efficacy and safety of the relatively old lowcost CMFVP regimen (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisolone) as compared to newer and more costly chemotherapeutic agents.. An analysis of the medical records of female patients with metastatic breast cancers treated with a CMFVP combination at the Shaare Zedek Medical Center (SZMC) was performed. 32 patients with measurable metastatic disease were included in the analysis. The median age was 59.9 years (range 36-102 years). 20 of the patients had previously been treated with both anthracyclines and taxanes.. Therapy was generally well tolerated and toxicity manageable. Median time to disease progression was 20.97 weeks (range 2-103 weeks). 6 patients (19%) demonstrated a partial response, and 7 patients (22%) had stable disease lasting 3 or more months for an overall clinical benefit of 41%. 4 of the 20 patients previously treated with both anthracyclines and taxanes had a partial response, and 4 patients had stable disease lasting 3 or more months for a clinical benefit of 40%.. On the basis of this small retrospective survey, we conclude that CMFVP combination chemotherapy is both effective and safe in patients with metastatic breast cancer previously treated with both taxanes and anthracyclines.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Cyclophosphamide; Female; Fluorouracil; Humans; Male; Methotrexate; Middle Aged; Prednisone; Taxoids; Treatment Outcome; Vincristine

Despite the growing number of clinical trials assessing preoperative systemic chemotherapy (PST) for locally advanced breast cancer, the optimal regimen has still to be defined.. This was to evaluate the toxicity, operability rate, pathological response rate and disease-free and overall survival associated with a PST regimen consisting of the sequential administration of single agents according to the individual tumor response.. Medical files were reviewed of 102 consecutive patients with breast cancer treated in 2000-2007 with a neoadjuvant sequential regimen of doxorubicin followed by taxane. The number of cycles and the addition of taxane were based on tumor response.. Seventy percent of the patients had inoperable disease at diagnosis and 29% were given preoperative therapy for breast conservation. All patients underwent surgery, 65% achieved breast conservation. An overall pathological complete response (breast and nodes) was achieved in 14% of the patients, and a complete nodal pathologic response in 34%. At a median follow-up of 54 months, the overall survival rate was 82% and the disease-free survival rate was 70%. There was no treatment-related mortality. Febrile neutropenia occurred in 19% of the patients.. A neoadjuvant regimen of doxorubicin with or without a sequential taxane, in which the number of cycles and the sequential administration of taxane are determined according to clinical response, appears to be safe and effective for patients with locally advanced breast cancer and yields a high rate of breast conservation. Tailored PST can spare patients receiving unnecessary chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prospective Studies; Receptor, ErbB-2; Taxoids

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoplasm Metastasis; Research; Taxoids

Early markers of response to chemotherapy, measured by blood markers and imaging, may ultimately lead to tailored therapies that avoid cumulative toxicity.. We performed a small pilot study to compare early changes in levels of circulatory tumor cells (CTCs) with changes in tumor proliferation, using metabolic imaging with [(18)F] 3´-deoxy-3´-fluorothymidine PET (FLT-PET) in women with advanced breast cancer, before and during docetaxel therapy.. In those individuals in whom we could detect CTCs, a decrease in CTC count correlated with a decrease in FLT-PET signal, within 2 weeks.. Combined, these two technologies are likely to provide a powerful, albeit expensive, tool to assess immediate responses to therapy.

Topics: Breast Neoplasms; Bridged-Ring Compounds; Cell Proliferation; Dideoxynucleosides; Drug Monitoring; Female; Humans; Neoplastic Cells, Circulating; Pilot Projects; Positron-Emission Tomography; Taxoids

There is considerable heterogeneity in the use of chemotherapy in early breast cancer (BC), despite international recommendations issued from the NCCN, NIH and the St.Gallen bi-annual conference.. We included 1,535 patients from seven Swiss cancer registries between 2003 and 2005 receiving chemotherapy for stage I to III BC. Chemotherapy was categorised into (a) FAC/FEC, anthracyclines followed by CMF or anthracycline-taxane combinations (FAC-T) (781 patients) and (b) other chemotherapy regimens such as CMF/AC (EC) (754 patients). Predictors for choosing FAC-T over non-FAC-T chemotherapy were separately determined in all patients and in ER-negative patients (n = 496) by multivariate logistic regression analysis.. The use of FAC-T increased significantly over time, from 44% in 2003 to 55% in 2005. BC stage III (versus stage I-II) and nodal positivity were the predominant predictors for using FAC-T chemotherapy in the adjusted model (odds ratio (OR) 4.1, 95%-confidence intervals (CI) 2.6-6.3 and OR 3.0, 95%-CI 2.0-4.4, respectively). In high-risk ER-negative BC patients, poor histological differentiation was more important to choose FAC-T chemotherapy (OR 3.8, 95%-CI 1.9-7.5) than tumour stage or nodal status. The use of FAC-T chemotherapy varied substantially among the seven geographic regions, from 20% in rural Grisons-Glarus to 73% in Zurich.. Tumour biology is a predominant factor for choosing FAC-T over older chemotherapy regimens in patients with ER-negative early BC, but improvements should be made to reduce the substantial regional heterogeneity. Further epidemiological studies should assess how the use of FAC-T chemotherapy is affecting clinical outcome in patients with early BC and different risk profiles.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Carboplatin; Confidence Intervals; Cyclophosphamide; Deoxycytidine; Doxorubicin; Epirubicin; Female; Fluorouracil; Gemcitabine; Health Services Accessibility; Humans; Logistic Models; Lymphatic Metastasis; Medication Adherence; Methotrexate; Middle Aged; Multivariate Analysis; Neoplasm Staging; Odds Ratio; Paclitaxel; Receptors, Estrogen; Switzerland; Taxoids; Vinblastine; Vinorelbine

Aneusomy 17 causes inconsistency in fluorescence in situ hybridization (FISH)-based human epidermal growth factor receptor (HER)-2 status assessment using different algorithms (copy number or the HER-2/centromere enumerator probe 17 [CEP-17] ratio). We investigated the effects of FISH-based HER-2 status assessment and aneusomy 17 on responsiveness to neoadjuvant chemotherapy (NAC).. This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab.. The pathologic complete remission (pCR) rate in the breast and axilla was 24.3% (95% confidence interval [CI], 17.7%-32.0%). Although HER-2 status, assessed by either HER-2/CEP-17 ratio-based FISH or copy number-based FISH, was a predictor of NAC sensitivity, ratio-assessed HER-2 status had a poorer performance in determining patients' responsiveness to NAC (p = .029). Patients who were not HER-2 amplified when assessed using the HER-2/CEP-17 ratio but were HER-2 amplified when assessed using copy number (~5%) were eventually proven to be responsive to NAC, with a pCR rate of 57% (95% CI, 18.4%-90.1%). In contrast, patients who were HER-2 amplified when assessed by the ratio but not HER-2 amplified when assessed using copy number (~3%) were completely irresponsive. Higher HER-2 copy numbers represented increasing chances of a pCR (adjusted odds ratio, 3.09; 95% CI, 1.35-7.08), with an apparent gene-dose effect (p for trend < .001).. It is likely that HER-2 copy number but not the HER-2/CEP-17 ratio determines NAC sensitivity. Additional studies to validate our findings are warranted.

Topics: Adolescent; Adult; Aged; Algorithms; Antineoplastic Agents; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Chromosomes, Human, Pair 17; Female; Gene Dosage; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Logistic Models; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Prospective Studies; Receptor, ErbB-2; Taxoids; Young Adult

The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available.. We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents.. Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol.. Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients.

Topics: Anthracyclines; Antigens, Neoplasm; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Proliferation; DNA Topoisomerases, Type II; DNA-Binding Proteins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; Humans; Middle Aged; Molecular Targeted Therapy; RNA, Messenger; Taxoids; Treatment Outcome; Tubulin

To determine the patterns of use of anthracycline- and taxane-based chemotherapy for breast cancer treatment.. Claims from a 5% national Medicare sample and from a nationally representative claims database (Marketscan) from 1998 to 2009 were used. Patients with International Classification of Diseases (ICD), ninth revision, codes indicating breast cancer, ICD and Common Procedural Terminology codes indicating breast surgery, and claims for chemotherapy between 3 months before and 12 months after surgery comprised the study cohort. Chemotherapy was classified as anthracycline-based or taxane-based, and the percentages of use were calculated. Piecewise regression models were used to identify the inflection points in the rates of chemotherapy use. The effect of patient characteristics on receiving different types of chemotherapy was estimated by multivariable logistic regression models.. A total of 4,458 patients were included in the Medicare cohort and 30,422 in the private insurance cohort. After 2005, a sharp increase in the use of taxane-based chemotherapy and a decline in anthracycline-based chemotherapy was seen. By 2008 in the Medicare cohort, 51% of patients received taxane-based and 32% received anthracycline-based chemotherapy. By the end of 2008, the majority of patients younger than 65 years were also receiving taxane-based chemotherapy. Patients younger than 35 years were less likely to be treated with a taxane-based regimen, whereas patients who underwent 21-gene recurrence score testing and those treated with trastuzumab were more likely to receive taxane-based chemotherapy.. The use of anthracycline-based chemotherapy has declined, and the majority of patients with breast cancer are instead receiving taxane-based chemotherapy. The potential impact on patient outcomes is unknown.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Utilization; Female; Humans; Middle Aged; Taxoids

To carry out a cost minimisation analysis including a comparison of the costs arising from first-line treatment by bevacizumab plus docetaxel (BD) versus bevacizumab plus paclitaxel (BP) of patients with metastatic breast cancer (mBC).. All consecutive patients with human epidermal growth receptor 2-negative mBC and treated at Besançon University hospital between 2006 and 2010 by a first-line therapy containing bevacizumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization and healthcare travel.. Progression-free survival difference between the two treatments was insignificant (p-value=0.31). BP treatment was associated with a higher mean total cost than that of BD treatment, €53,093 ± 34,395 versus €60,196 ± 48,766, respectively.. Whereas bevacizumab is recommended for first-line treatment of mBC with paclitaxel-based chemotherapy, our study has shown that BD treatment is the most cost-efficient regimen. It could be an attractive option in France, with a potential cost saving of €24,000,000 per year.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Female; Humans; Middle Aged; Neoplasm Metastasis; Taxoids

We determined the success rate of new drug approval by the US FDA in two breast cancer indications, one of which used a biomarker. This allowed us to assess if biomarkers improved clinical trial risk in breast cancer. We performed a retrospective screening of industry-sponsored drug development programs registered on clinicaltrials.gov from 1998 to 2012 for HER2-positive patients compared to patients that had either failed or had been exposed to anthracycline or taxane, whose first phase I in this indication occurred no earlier than 1998. Compounds not registered on clinicaltrials.gov and studied exclusively outside the US were excluded. Twenty-nine drugs for HER2-positive patients and 28 drugs for anthracycline/taxane-exposed patients met our screening criteria. The overall success rate of new drug development in anthracycline/taxane patients was only 15 %, while in HER2-positive patients it was 23 %. However, HER2-targeted therapies underperformed compared to broad acting agents. The cost for clinical trial testing alone, when adjusted for the risk of failure, for HER2-positive breast cancer patients was $199 million, significantly lower than the cost of $274 million for anthracycline/taxane-experienced patients. The use of a validated biomarker, such as HER2, reduced clinical trial risk by as much as 50 % resulting in cost savings of 27 % in advanced and metastatic breast cancer. However, these data have to be evaluated in a context in which studies combining a novel drug with a novel biomarker not yet recognized by the FDA may actually increase clinical trial risk.

Topics: Anthracyclines; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Approval; Female; Humans; Receptor, ErbB-2; Retrospective Studies; Taxoids; United States; United States Food and Drug Administration

Full oral chemotherapy (CT) is an active and convenient therapeutic option for patients with advanced breast cancer (ABC). In this retrospective analysis, we reviewed the characteristics and the outcome of patients treated by oral vinorelbine either as a single-agent or in combination with capecitabine as first- or second-line CT in the metastatic setting.. We analysed 216 patients with ABC who started treatment with a full oral CT at 13 centers and seven countries between 2006 and 2008. To be eligible, patients must have received either as a first-(56%) or second-line (44%) therapy oral vinorelbine as a single-agent (54%) or in combination with capecitabine (46%).. Main patients' characteristics in the full population (n=216): median age (range): 61 (32-87) years; categories of age: <50 years: 18%, 50-65 years: 44%, ≥ 65 years: 38%; hormone receptor-positive: 63%; ≥ 2 metastatic sites: 58%; visceral metastases: 49%; prior CT: 86%; prior CT for ABC: 44%; prior anthracycline treatment: 69%; prior taxane treatment: 43%, prior anthracycline plus taxane: 38%; prior endocrine therapy: 63%. Median number of cycles: 6 (range=1-54); 48% of patients received more than 6 cycles. G3/4 toxicities: neutropenia 8%, anaemia 2%, thrombocytopenia 1%, febrile neutropenia/neutropenic infection 2%, nausea 6%, vomiting 4%, diarrhea 6%, fatigue 6%, hand-foot syndrome 14% (combination with capecitabine), neuropathy 1%, alopecia (grade 2) 1%.. disease control was achieved in 77% of patients [95% confidence interval=71-83%], 74% as single-agent, 81% in combination, 82% in first-line, 71% in second-line. Median progression-free survival was 9.7 months [95% confidence interval=8.2-12.6 months] in first-line and 6.6 months [95% confidence interval=5.5-8.5 months] in second-line therapy. Caregivers described these oral regimens as convenient (81%), well-tolerated (84%) and with a good compliance by patients (76%).. These data from everyday practice confirm, as shown in different clinical trials, that oral vinorelbine is an active and well-tolerated CT for ABC, either as a first- or second-line in patients pre-treated with anthracyclines or taxanes. The convenience of its oral administration in association with its good tolerance profile, allows for continuation of treatment until disease progression without a pre-planned maximum of cycles.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Carcinoma; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Hematologic Diseases; Humans; Middle Aged; Patient Compliance; Retrospective Studies; Severity of Illness Index; Taxoids; Vinblastine; Vinorelbine

The risk of treatment-related death (TRD) and febrile neutropaenia (FN) with adjuvant taxane- based chemotherapy for early breast cancer is unknown in Malaysia despite its widespread usage in recent years. This study aims to determine these rates in patients treated in University Malaya Medical Centre (UMMC).. Patients who were treated with adjuvant taxane-based chemotherapy for early breast cancer stages I, II or III from 2007-2011 in UMMC were identified from our UMMC Breast Cancer Registry. The TRD and FN rates were then determined retrospectively from medical records. TRD was defined as death occurring during or within 30 days of completing chemotherapy as a consequence of the chemotherapy treatment. FN was defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L.. A total of 622 patients received adjuvant chemotherapy during this period. Of these patients 209 (33.6%) received taxane-based chemotherapy. 4 taxane-based regimens were used namely the FEC-D, TC, TAC and AC-PCX regimens. The commonest regimen employed was the FEC-D regimen accounting for 79.9% of the patients. The FN rate was 10% and there was no TRD.. Adjuvant taxane-based chemotherapy in UMMC for early breast cancer has a FN rate of 10%. Primary prophylactic G-CSF should be considered for patients with any additional risk factor for FN.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Cause of Death; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Doxorubicin; Epirubicin; Female; Fever; Fluorouracil; Humans; Malaysia; Middle Aged; Neutropenia; Paclitaxel; Retrospective Studies; Risk Factors; Taxoids

A suggestive case of metastatic disease from breast cancer is reported. The HER-2-positive tumor was refractory to several agents, including anti-HER-2 therapy, trastuzumab, and lapatinib. After re-induction of trastuzumab in combination with activated natural killer (NK) cell injection therapy, tumor markers decreased, and finally a synergistic effect of taxane and capecitabine led to treatment response. This case suggests that multidisciplinary therapy including an immunological approach might be a breakthrough in the treatment of refractory disease.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Carcinoma, Ductal, Breast; Combined Modality Therapy; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Killer Cells, Natural; Lapatinib; Lung Neoplasms; Middle Aged; Prognosis; Quinazolines; Receptor, ErbB-2; Salvage Therapy; Taxoids; Trastuzumab

Reducing primary tumor volume is the main role of neoadjuvant chemotherapy for breast cancer. We evaluated the benefit of adding docetaxel to anthracyclin as neoadjuvant therapy. This study is a retrospective cohort analysis comparing the efficacy of neoadjuvant chemotherapy in patients subjected to docetaxel and epirubicin or 5-fluoruracil, epirubicin and cyclophosphamide combinations (DE and FEC group, respectively). The mean number of chemotherapy delivered was similar in both groups (P = 0.8). A total of 316 patients were treated (151 in FEC group and 165 in DE group). Primary endpoint was the clinical and pathological response to therapy. Breast conserving surgery rate was compared. In T1/2 staged patients, the complete clinical response rate was 7.5% in FEC group and 32% in DE group (P = 0.002), and the breast conserving surgery rate was 72 and 73% in FEC and DE groups, respectively (P = 0.9). In the subset of patients staged as T3 and T4a-c, objective response was higher in DE group (P < 0.0001 and P = 0.008, respectively). Breast conserving surgery rate was 38 and 63% in FEC and DE groups, respectively, in T3 staged patients and, 20.5 and 37% in T4a-c staged patients (P = 0.003 and 0.08). Despite the similar number of chemotherapy cycles delivered in both groups, the presence of microscopic axillary lymph node involvement after chemotherapy was less frequent in DE group. Neoadjuvant chemotherapy with DE combination is more effective in terms of clinical and pathological response propitiating higher breast conserving surgery rate than FEC combination in stage II and III breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Cyclophosphamide; Docetaxel; Epirubicin; Female; Fluorouracil; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Retrospective Studies; Taxoids

The objective of our study was to show the impact of different chemotherapy regimens on the incidence of amenorrhea (chemotherapy-induced amenorrhea [CIA]) in premenopausal women of various ages with breast cancer.. This is a follow-up study of 226 premenopausal women with breast cancer who had received one of three chemotherapy regimens: conventional (cyclophosphamide/methotrexate/5-fluorouracil), anthracycline based, and anthracycline-taxane based. They were evaluated for the incidence of CIA in the follow-up clinic of the Iranian Center for Breast Cancer. A statistical analysis using SPSS software was performed, and logistic regression and Cox regression model were used to determine the risk factors for CIA.. Of the 226 women with a median age of 40 years (range, 26-56 y) who participated in this study, 154 (68.1%) developed CIA. In 101 (65.6%) of these women, CIA was established. CIA was present in 52.5% of the women who had been treated with conventional regimens (cyclophosphamide/methotrexate/5-fluorouracil), 66.7% of the women who had been treated with anthracycline, and 78.7% of the women who had been treated with anthracycline-taxane. Therefore, the frequency of CIA was significantly higher in the taxane-based chemotherapy group than in the other groups (P = 0.015). Although a slightly higher incidence of CIA in women with hormone-insensitive tumors (estrogen receptor negative and progesterone receptor negative) versus hormone-sensitive tumors (estrogen receptor positive and progesterone receptor positive) who had been treated with combination regimens was observed, no statistically significant difference was found (P = 0.629). Of all of the risk factors that were evaluated in the study, anthracycline-taxane-based regimens (odds ratio, 4.059; 95% CI, 1.6-9.8) and age older than 40 years (odds ratio, 3.5; 95% CI, 1.9-6.6) were the most important factors in the development of CIA.. The type of chemotherapy and the age of the woman at the onset of breast cancer are the most important risk factors in CIA. Taxane-based regimens induced more CIA than did other regimens.

Topics: Adult; Amenorrhea; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Methotrexate; Middle Aged; Neoplasm Staging; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Risk Factors; Taxoids; Treatment Outcome

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Endothelial Cells; Female; Fibroblasts; Humans; Immunohistochemistry; Microfilament Proteins; Middle Aged; Receptors, Cytoplasmic and Nuclear; Scleroderma, Systemic; Skin; Taxoids; Trans-Activators

The purpose of this study was to determine the incidence of amenorrhea among breast cancer patients aged 40 years and younger following adjuvant chemotherapy.. A follow-up questionnaire survey was conducted with premenopausal women with breast cancer who were treated with adjuvant anthracycline and taxane-based chemotherapy.. In total, 66 women were retrospectively reviewed. Forty-nine patients were treated with a regimen containing anthracycline followed by taxane and 17 patients with anthracycline alone. Fifty-eight patients (87.9%) experienced amenorrhea during chemotherapy; 14 patients (21.2%) had persistent amenorrhea after chemotherapy. The incidence of amenorrhea during chemotherapy and persistent amenorrhea was higher in patients older than 36 than in younger patients (97.9 vs. 63.2%, 27.7 vs. 5.3%). Additional taxane resulted in a higher incidence of amenorrhea compared with anthracycline-containing regimen alone (93.9 vs. 70.6%). Multivariate analysis showed that age (≥36 years) was independently associated with the incidences of amenorrhea during chemotherapy (p = 0.007).. Age was the strongest predictor of the incidence of amenorrhea during chemotherapy. It is unclear whether additional taxane may contribute to amenorrhea. This information could be useful in deciding whether to use adjuvant chemotherapy.

Topics: Adult; Amenorrhea; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Multivariate Analysis; Retrospective Studies; Taxoids

Capecitabine is a widely accepted option in pre-treated metastatic breast cancer (MBC) patients. However, little is known about specific activity in molecularly defined subgroups of patients. Here, response, survival and prognostic factors were examined in a prospectively characterized cohort of human epidermal growth factor receptor 2 (HER2) negative MBC patients receiving capecitabine following anthracycline and taxane failure.. Medical records from 75 HER2-negative MBC pre-treated with anthracycline and/or taxane and receiving capecitabine monotherapy at the Institut Paoli-Calmettes between 2002 and 2009 were reviewed. Univariate and multivariate analysis according the Cox regression model were employed to identify factors predictive for response, progression-free survival (PFS) and overall survival (OS).. Overall, the objective response rate (ORR) was 29.3% (95% CI: 20-40). The ORR in HER2-negative/hormonal receptor (HRe) positive and HER2-negative/HRe-negative patients were 37% (95% CI: 26-50) and 0% (95% CI: 0-19), respectively, (p=0.003, Fisher's test). With a median follow-up of 35.2 months after capecitabine initiation, median PFS was 6.6 months (95% CI: 4.7-10.4) and median OS was 18.4 months (95% CI:14.1-24.9). In univariate analysis, HRe-negative status was the strongest prognostic factor for PFS (hazard ratio (HR)=2.09; p-value=0.015, log-rank test). In multivariate analysis, only three variables (HRe-negative status, initial disease-free interval <24 months and extra-regional lymph node involvement) were considered independently associated with poor PFS, while five variables (grade 2/3, initial disease-free interval <24 months, central nervous system metastases, interval between diagnosis of metastases and capecitabine initiation <24 months, and number of metastatic sites on capecitabine initiation) were associated with poor OS.. The median OS of pretreated patients with HER2-negative MBC receiving capecitabine is approximately 18 months, but HER2-negative/HRe-negative patients have a low probablility of response/disease control to capecitabine and require innovative therapies.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Receptor, ErbB-2; Taxoids; Treatment Outcome

Taxane drugs block cell-cycle progression via centrosomal impairment, induction of abnormal spindles, and suppression of spindle microtubule dynamics. Affected cells experience aberrant mitosis or mitotic slippage, which may trigger apoptosis.. The aim was to characterize the histopathologic changes due to taxane therapy in skin biopsy specimens.. Three examples were identified of benign skin biopsy specimens of patients receiving paclitaxel or docetaxel therapy for breast carcinoma or leiomyosarcoma. All specimens were studied by light microscopy after routine histopathologic processing.. All cases exhibited numerous apoptotic and mitotic figures including atypical forms, changes consistent with cytotoxic effects of taxane. The first case had been provisionally considered by the referring pathologist to be a malignant melanoma; however, when reviewed in consultation, it was ultimately diagnosed as an atypical nevus; the second and third cases were diagnosed as reactive epidermal hyperplasia and ecthyma, respectively, in addition to showing background taxane effects.. This study is limited by the relatively small number of cases examined.. Taxane therapy has profound cytopathic effects in skin biopsy specimens, and in difficult cases these changes may raise consideration of possible malignancy. Dermatopathologists should use caution when interpreting biopsy specimens of patients receiving taxane therapy.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Biopsy; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle; Docetaxel; Female; Humans; Leiomyosarcoma; Male; Mitosis; Paclitaxel; Skin; Skin Diseases; Taxoids

Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.. To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.. Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.. Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).. Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.. A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Topics: Adult; Algorithms; Anthracyclines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Forecasting; Gene Expression Profiling; Genes, erbB-2; Genes, Neoplasm; Genomics; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Prognosis; Prospective Studies; Receptors, Estrogen; Risk; Taxoids

This study aimed to determine the changes in the expression of genes for selected specific transcriptional factors that have both activating and repressing functions in in vitro ductal breast cancer cells, under the influence of paclitaxel, applying the microarray technique. The cells are treated with 60 ng/ml and 300 ng/ml doses of paclitaxel that correspond to those applied in breast cancer therapy. About 60 ng/ml doses of paclitaxel cause a statistically significant increase in expression of all the 16 analysed genes coding transcriptional factors, ranging from 1.84-fold (for PO4F2) to 4.65-fold (for LMO4) (p < 0.05) in comparison with the control cells, and enhanced the taxane mechanism of action. The 300 ng/ml doses of paclitaxel cause a cytotoxic effect in the cells. In this article, we argue that these changes in gene expression values may constitute prognostic and predictive factors in ductal breast cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Pharmacological; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Oligonucleotide Array Sequence Analysis; Paclitaxel; Primary Cell Culture; Prognosis; Taxoids; Transcription Factors; Tumor Cells, Cultured

Trastuzumab is an established treatment for HER2-positive breast cancer (BC). We analyzed Swiss patterns of care in patients with HER2-positive BC after disease progression on trastuzumab-containing therapy for metastatic BC (MBC).. A retrospective analysis was performed in six Swiss BC centers. Patients with HER2-positive MBC treated with at least one infusion of trastuzumab for advanced disease between January 2006 and December 2007 were identified. Treatment patterns in first and further lines were analyzed.. All of the 72 identified patients received trastuzumab as their first palliative anti-HER2 therapy, either as monotherapy (n = 23) or in combination with chemotherapy (typically taxane or vinorelbine; n = 49). Median time to progression was 8.1, 8.0 and 7.9 months in the monotherapy, trastuzumab-taxane and trastuzumab-vinorelbine cohorts, respectively. After progression on first-line anti-HER2 therapy, trastuzumab was continued in 67 of 68 patients who received further therapy. One patient received second-line lapatinib plus capecitabine. The median duration of anti-HER2 therapy was 20 months. Patients received a median of 4 lines of anti-HER2 therapy.. Durable responses were achieved with repeated exposure to anti-HER2 therapy. In a selected patient population, trastuzumab monotherapy appears to be a reasonable first-line treatment option.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Disease Progression; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Retrospective Studies; Switzerland; Taxoids; Trastuzumab; Vinblastine; Vinorelbine

In flat-rate reimbursement systems, the hospital's own costs should not exceed its revenues. In a cohort of primary breast cancer (pBC) patients, costs and reimbursement for febrile neutropenia (FN) were compared to verify cost coverage.. A prospective, observational study in pBC patients receiving adjuvant anthracycline ± taxane-based chemotherapy calculated the costs per in-patient FN episode. The correlating revenues were retrospectively analyzed from diagnosis-related group (DRG) invoices. The actual costs of the therapies were compared to the individual DRG revenues, and the results are presented from the provider's perspective.. In 50 patients, n = 11 patients were treated for FN as in-patients. The hospital's overall treatment costs were € 18,288, on average (Ø) € 1663 per case (range € 1139-2344); the overall DRG revenues were € 23,593, Ø € 2145 per case (range € 1266-2660). In n = 8 cases, the DRGs were cost covering, and in n = 3 cases, a loss was observed, but overall resulting in a gain of Ø € 482 per case and thus being cost covering for the provider. Inadequate DRG coding (n = 4/11; 36.4%) resulted in a preventable loss of Ø € 1069/case.. The costs of FN treatment vary substantially and DRG reimbursements do not necessarily reflect the provider's costs. Surprisingly, the in-patient treatment of FN here is overall more than cost covering if adequately coded. The main reasons are asymmetrical costs for this FN low-risk pBC group. These results emphasize the importance of correct medical coding to avoid potential losses.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Comorbidity; Diagnosis-Related Groups; Female; Fever; Germany; Health Care Costs; Hospitalization; Humans; Income; Insurance, Health, Reimbursement; Male; Middle Aged; Neutropenia; Prevalence; Taxoids

Neoadjuvant chemotherapy (NAC) is increasingly being used in breast cancer treatment. Research has revealed an elevated expression of miR-221 in adriamycinresistant MCF-7/ADR cells. This study aimed to explore the potential role of miR-221 as a biomarker for chemosensitivity in breast cancer patients who previously received NAC.. The expression levels of circulating miR-221 in the plasma of 93 breast cancer patients who previously received NAC and in 32 healthy individuals were assessed. The correlations between miR-221 and clinicopathological features and chemosensitivity were also analysed.. The expression level of miR-221 was significantly associated with hormone receptor (HR) status (p = 0.008). Patients with higher plasma miR-221 levels tended to be HR-negative. Patients with different miR-221 levels had significant differences in the overall response rate (p = 0.044) but not in the pathologic complete response rate (p = 0.477).. Our results indicate that plasma miR-221 may be a predictive biomarker for sensitivity to NAC in breast cancer patients.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; China; Drug Resistance, Neoplasm; Female; Humans; MicroRNAs; Neoadjuvant Therapy; Prevalence; Prognosis; Reproducibility of Results; Risk Assessment; Risk Factors; Sensitivity and Specificity; Taxoids; Treatment Outcome

Topics: Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Cyclophosphamide; Disease Progression; Docetaxel; Female; Genes, erbB-2; Humans; Taxoids; Time Factors; Trastuzumab

Many drugs can be used for adjuvant therapy of breast cancer, including anthracyclines, cyclophosphamide, 5-fluorouracil (5-fU) and, recently, taxanes (TXT) have shown promising results. 5-FU blocks thymidylate synthase (TS) which cross-links p53 mRNA, inhibiting its synthesis. TS overexpression is one of the main mechanisms involved in 5-FU drug resistance. Enough p53 mutations can confer resistance to chemotherapy using anthracyclines and 5-FU, while are associated with improved responses to TXT. The aim of this study was to examine the TS and p53 levels in tumor samples and to compare the efficacy of FEC (5-FU, epirubicin, cyclophosphamide) and TXT chemotherapy in a group of patients with differing TS and p53 status. We examined 84 breast tumor samples using immunohistochemistry. TS and p53 levels were inversely related, and TS and p53 positivity was significantly associated with the failure of FEC treatment and with a good response to TXT therapy (p <0.001). This confirms the predictive role of these two markers, which should be considered when choosing the appropriate adjuvant therapy for breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Epirubicin; Female; Fluorouracil; Humans; Immunohistochemistry; Neoplasm Staging; Prognosis; Taxoids; Thymidylate Synthase; Tumor Suppressor Protein p53

Topics: Anthracyclines; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Humans; Neoadjuvant Therapy; Taxoids

Capecitabine may have a higher acquisition cost compared with other select chemotherapy agents; however, its use is not associated with many of the costs typically encountered with intravenous chemotherapy, such as costs incurred through administration procedures and the management of subsequent tolerability issues. This study compared the cost of capecitabine- and taxane-based regimens in the treatment of breast cancer.. Thomson Reuters MarketScan, a US employer claims database, was used to identify patients with a breast cancer diagnosis between 2000 and 2005 and at least one chemotherapy claim or hormone treatment in 2004 or 2005.. Cost data for treatment administration and management of selected chemotherapy-related adverse events were collected. Multivariate analyses were performed to adjust for differences in patient demographic and clinical factors.. A total of 3630 patients were included in this analysis; 4216 treatment episodes were recorded. Mean unadjusted total monthly expenditures were lowest for capecitabine regimens compared with taxane plus anthracycline or other taxane regimens ($8445 vs. $13,295 and $12,323, respectively; P < 0.0001). The adjusted total monthly cost for capecitabine regimens was lower than the cost for taxane plus anthracycline regimen ($10,895 vs. $13,115) and other taxane regimens ($9253 vs. $12,116). Adjusted complication costs for taxane treatment episodes were almost double than those seen with capecitabine ($5509 for anthracycline plus taxane vs. $2940, and $3829 for other taxane regimens vs. $1750).. Lower complication-related expenditures with capecitabine therapy accounted for majority of the cost differential seen in comparison with taxane-based therapy.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Cost of Illness; Cost Savings; Cost-Benefit Analysis; Databases, Factual; Deoxycytidine; Drug Costs; Female; Fluorouracil; Humans; Middle Aged; Retrospective Studies; Taxoids; United States

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Taxoids; Trastuzumab

Four major clinical trials have established that trastuzumab added to adjuvant systemic chemotherapy for women with HER2+ breast cancer significantly improves disease-free and overall survival compared with chemotherapy alone. We evaluated pathologic complete response (pCR) rate and cardiac safety of preoperative doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab.. We reviewed pCR rate and change in left ventricular ejection fraction in women with operable HER2+ breast cancer (defined as immunohistochemical 3+ or fluorescence in situ hybridization ratio > or = 2.2) who were treated between 2002 and 2008 with doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab before definitive breast surgery.. We identified 33 patients, of whom 42.4% received preoperative chemotherapy without trastuzumab and 57.6% of whom received trastuzumab with chemotherapy. The pCR rates were 28.6% and 52.6% in the group that received chemotherapy alone or with trastuzumab, respectively (odds ratio, 2.78; 95% CI, 0.64-12.1; P = .173). Severe cardiac events or treatment delays as a result of cardiac toxicity were not observed. With a median follow-up time of 14 months, 21.4% of patients in the non-trastuzumab group and 10.5% in the trastuzumab group had disease recurrence.. Sequential administration of preoperative doxorubicin and cyclophosphamide followed by a taxane and trastuzumab combination is safe in women with primary operable HER2+ breast cancer and is associated with a high pCR rate. Large randomized phase III clinical trials are evaluating the role of preoperative trastuzumab when added to anthracycline- and/or taxane-based regimens.

Topics: Adult; Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Receptor, ErbB-2; Retrospective Studies; Stroke Volume; Taxoids; Trastuzumab; Treatment Outcome

Glutathione-S-transferase-pi (GST-pi) is a detoxification enzyme expressed in breast cancer; however its involvement in chemotherapy sensitivity and prognosis is not well understood. We evaluated the expression of GSTpi and its predictive role of chemotherapy response. Breast tumor samples from 166 patients at stage I/II of the disease were immunostained for GST-pi, and the expression was 96 %. There was a trend toward improved disease-free survival with high GST-pi expression (p =.09). There was a statistically non-significant association between high GST-pi expression and improved outcome with adjuvant chemotherapy (p =.055). Further studies should evaluate the role of GST-pi expression in relation to response to different chemotherapies.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Female; Glutathione S-Transferase pi; Humans; Middle Aged; Neoplasms, Hormone-Dependent; Prognosis; Taxoids

PURPOSE Although most breast cancer patients who receive neoadjuvant chemotherapy (NCT) have a tumor response, a small proportion experience progressive disease (PD). Predictors of response have been reported, but predictors for progression have not been identified. We sought to identify predictors of tumor progression during NCT with the ultimate aim of identifying patients who might benefit from a first-line surgical approach or from novel targeted therapies. PATIENTS AND METHODS Data were obtained from reviewing medical records of patients with stage I to III breast cancer who received NCT (anthracycline and/or taxane based). Statistical analysis was performed to compare patients with any response or stable disease with patients with PD. RESULTS One thousand nine hundred twenty-eight patients received NCT; 1,762 patients (91%) had some response, 107 (6%) had stable disease, and 59 (3%) had PD at some point during NCT. Factors predictive of PD included African American race (P = .002), tumor (T) status (P = .002), and American Joint Committee on Cancer clinical stage (P = .02). Histopathologic features of PD were high tumor grade (P = .005), high Ki-67 score (P = .002), and negative estrogen receptor (ER)/progesterone receptor (PR) status (P < .001/P < .001). Pre-NCT T status, race, and ER status were independent predictors of progression in multivariate analysis. Disease progression was a negative predictor of distant disease-free survival and overall survival in multivariate analysis (P < .001). CONCLUSION Factors predictive of PD include race, advanced tumor stage, high nuclear grade, high Ki-67 score, and ER/PR negativity. Because many of these variables are also associated with response to NCT, novel molecular predictors are needed to identify patients at risk for progression on standard NCT.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Disease Progression; Female; Humans; Middle Aged; Neoadjuvant Therapy; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Taxoids; Treatment Outcome; Young Adult

To investigate the change of breast density with quantitative magnetic resonance (MR) imaging in the contralateral normal breast of patients receiving neoadjuvant chemotherapy.. This study was approved by the institutional review board and was HIPAA compliant. Informed consent was obtained. Fifty-four patients with breast cancer (mean age, 47 years; age range, 30-74 years) treated with NAC protocol and enrolled in a breast MR imaging research study were studied. The density in the contralateral normal breast was analyzed by using an MR imaging-based segmentation method. The effect of chemotherapy on the change of density following the doxorubicin and cyclophosphamide (AC) and the AC and taxane regimen was evaluated. The dependence on age was investigated by using a multivariate regression model.. In patients who underwent both AC and taxane follow-up, the mean percentage of change from the individual's baseline density was -10% (95% confidence interval: -12.8%, -7.2%) after AC and -12.7% (95% confidence interval: -16%, -9.4%) after AC and taxane. In patients who underwent both follow-up studies after one to two and four cycles of AC, the mean percentage of change was -9.4% (95% confidence interval: -13.5%, -5.3%) after one to two cycles of AC and -14.7% (95% confidence interval: -20.6%, -8.7%) after four cycles of AC. The percentage reduction of density was significantly dependent on age. Patients younger than 40 years had a greater reduction after chemotherapy than patients older than 55 years (P = .01).. By using three-dimensional MR imaging, patients receiving chemotherapy showed reduction of breast density, and the effects were significant after initial treatment with one to two cycles of the AC regimen.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Contrast Media; Cyclophosphamide; Doxorubicin; Female; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Linear Models; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Regression Analysis; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Taxoids; Treatment Outcome

Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered.. Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS.. The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation.. Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Inflammation; Neoplasm Metastasis; Prognosis; Retrospective Studies; Taxoids; Time Factors

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Humans; Taxoids

The current study was conducted to evaluate the influence of race/ethnicity and tumor subtype in pathologic complete response (pCR) following treatment with neoadjuvant chemotherapy.. A total of 2074 patients diagnosed with breast cancer between 1994 and 2008 who were treated with neoadjuvant anthracycline- and taxane-based chemotherapy were included. pCR was defined as no residual invasive cancer in the breast and axilla. The Kaplan-Meier product-limit was used to calculate survival outcomes. Cox proportional hazards models were fitted to determine the relationship of patient and tumor variables with outcome.. The median patient age was 50 years; 14.6% of patients were black, were 15.2% Hispanic, 64.3% were white, and 5.9% were of other race. There were no differences in pCR rates among race/ethnicity (12.3% in black, 14.2% in Hispanics, 12.3% in whites, and 11.5% in others, P = .788). Lack of pCR, breast cancer subtype, grade 3 tumors, and lymphovascular invasion were associated with worse recurrence-free survival (RFS) and overall survival (OS) (P

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Middle Aged; Neoadjuvant Therapy; Taxoids; Treatment Outcome

The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers.. Patients with breast cancer were enrolled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays.. Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and controls for any of the inflammatory markers tested.. AIMSS is probably not associated with a systemic inflammatory response. Pre-treatment cytokine levels may predict for development of AIMSS.

Topics: Aged; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Case-Control Studies; Cytokines; Estrogens; Female; Humans; Inflammation; Middle Aged; Musculoskeletal Diseases; Postmenopause; Syndrome; Tamoxifen; Taxoids

Cancer chemotherapeutic treatment is a complex scientific task. The ChemoFx Drug Response Marker (DRM) assists physicians in identifying treatment protocols likely to be effective for specific patients.. The ChemoFx DRM was used to study drug response in vitro. Established human cancer cell lines and primary cultures of patient tumor specimens were challenged with chemotherapeutic agents to observe response of multiple tumor samples and determine whether drugs with similar mechanisms of action elicit similar response.. These studies demonstrated heterogeneous response among patient tumor samples and clustering of drug response with similar mechanisms of action. Also highlighted was the reproducibility of ChemoFx DRM and its utility in characterizing tumor response to chemotherapy.. Heterogeneous drug responses observed in vitro were similar to those observed clinically. Response characteristics were similar for drugs with similar mechanisms of action, suggesting response heterogeneity is determined at a cellular and molecular level.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Neoplasms; Ovarian Neoplasms; Platinum Compounds; Reproducibility of Results; Taxoids

The main objective of the present study was to compare the effects of three common chemotherapy regimes in terms of disease-free survival (DFS) of breast cancer (BC) patients; the three explored regimes were taxane-based, anthracycline-based and CMF (cyclophosphamide methotrexate and 5-fluorouracil).. In this historical-cohort study, we obtained the information of 62 patients with confirmed BC in non-metastatic stage and followed them for 8 years. All the patients had undergone modified radical mastectomy surgery and had received adjuvant chemotherapy in three medical centers in Tehran, Iran. DFS was considered as the end-point. Afterwards, an extended log-logistic regression model was used to compare these regimes.. The mean (SD) age of patients was 49.0 (10.3) years. The median time of follow-up was 20.0 months and the probability of 5-years DFS was 0.48. Survival analysis indicated that the type of chemotherapy (OR(CMF vs. taxane) = 0.33, OR(anthracycline vs. taxane) = 0.74), grade (OR(III vs. I or II) = 0.35), tumor size (OR(>5 cm vs. <5 cm)= 0.179) and nodal involvements (OR(Yes vs. No)= 0.36) affected DFS.. The current study revealed that the efficacy of taxane-based, in terms of DFS, was more than CMF (p = 0.05). Moreover, taxane-based chemotherapy prolonged DFS more than anthracycline-based one although the difference was not significant (p= 0.63). Finally, considering the importance of tumor size, histological grade and number of involved lymph nodes in lengthening DFS, it is crucial to highlight the role of public education and screening programs in order to detect tumor in its early stages.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Iran; Lymphatic Metastasis; Methotrexate; Middle Aged; Models, Statistical; Neoplasm Staging; Prognosis; Survival Rate; Taxoids

To summarize the clinical experience of trastuzumab treatment in neoadjuvant, adjuvant, metastatic setting of Chinese patients with Her-2 positive breast cancer and evaluate the efficacy of trastuzumab in combination with chemotherapy.. From January 2004 to December 2008, 141 outpatients with breast cancer treated with trastuzumab were investigated retrospectively. The follow-up time ranged from 3 to 319 months. The disease free survival time (DFS) of metastatic setting was calculated. The overall survival time (OS), time to treatment failure (TTF) and clinical response rate (CRR, including complete response, partial response and stable disease) of adjuvant, first-line, second-line therapy were analyzed statistically.. In the neoadjuvant regimen, paclitaxel plus carboplatin in combination with trastuzumab accounted for 66.7%, which achieved pathological complete response in 10 of 16 patients. In the adjuvant regimen, anthracycline or anthracycline followed by taxane accounted for 53.9%. The median DFS of 57 cases with metastatic diseases was 17 months. The CRR of first-line trastuzumab use in metastatic setting was 84.5%, compared with 44.4% of second-line use. The median TTF of first-line treatment was 24 months compared with 5 months of second-line treatment. Statistically significant differences were observed.. The regimen of paclitaxel plus carboplatin in combination with trastuzumab deserves wide clinical use. In metastatic setting, first-line treatment of trastuzumab plus chemotherapy can achieve a higher response rate than second-line treatment. Continued trastuzumab therapy combined with different chemotherapy treatment after disease progression may obtain additive clinical advantage.

Topics: Adult; Anthracyclines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carboplatin; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paclitaxel; Receptor, ErbB-2; Retrospective Studies; Survival Rate; Taxoids; Trastuzumab; Treatment Failure

It is not clear what the optimal treatment of chemotherapy is for patients with heavily treated metastatic breast cancer (MBC). We have retrospectively examined the efficacy and safety of S-1 in patients with MBC who had been previously treated with anthracycline, taxane, and capecitabine.. Patients with MBC who had been administered S-1, an oral modulated compound containing a fluoropyrimidine derivative, between November 2001 and June 2003 at the Cancer Institute Hospital were retrospectively reviewed. S-1 at a standard dose of 50 mg/body was administered twice daily for four weeks, followed by a two-week rest period. This was repeated every six weeks until disease progression or unacceptable toxicity.. Thirty-five patients were assessed. The patients were heavily pretreated with anthracycline (100%), taxane (paclitaxel or docetaxel) (100%), capecitabine (100%), vinorelbine (71%), and mitomycin (69%). Median follow-up time of patients was 9.6 months (range, 1.2-26.6). ORR was 3% (95% confidence interval: 0-9%), and CBR was 20% (95% confidence interval: 6-33%). Time to treatment failure was 2.8 months. Overall survival was 21.4 months. Grade 1 or 2 adverse events were observed in 17% and 13%, respectively. Grade 3 events occurred as anorexia (9%), nausea (9%), vomiting (9%), diarrhea (14%), fatigue (3%), and elevation of AST/ALT (3%). No grade 3 was seen as hand-foot syndrome. Neither grade 3 nor 4 was observed in bone marrow suppression.. S-1 was fairly well tolerated, but demonstrated very limited activity in capecitabine-pretreated patients who had already been exposed to anthracycline and taxane. It was suggested that S-1 clinically exhibited cross-resistance to capecitabine.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antimetabolites, Antineoplastic; Bone Neoplasms; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Combinations; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Pleural Neoplasms; Prognosis; Retrospective Studies; Survival Rate; Taxoids; Tegafur; Treatment Outcome

The aim of this study was to evaluate the role of platinum-containing chemotherapy for metastatic triple-negative breast cancer (TNBC) patients in terms of the response rate (RR) and progression-free survival. A second aim was to characterize the clinical behavior at the time of relapse of TNBC. We retrospectively analyzed the clinical outcomes of patients with metastatic breast cancer who received taxane-platinum chemotherapy as the first- or second-line treatment, focusing on the TN phenotype. In total, 257 patients with metastatic breast cancer received platinum-containing chemotherapy at Samsung Medical Center from 1999 to 2006. Of these patients, 106 patients with available data on estrogen (ER), progesterone (PgR) and human epidermal growth factor receptor-2 (HER2) receptor status received taxane-platinum regimen as the first- or second-line treatment. The overall RR of patients with TNBC was 39%. This rate did not differ significantly from those of patients with other phenotypes. The time to death after chemotherapy (19 vs. 50 months, p = 0.037) and overall survival (OS) (21 vs. 56 months, p = 0.030) differed significantly between patients with TNBC and non-TNBC. TNBC showed a unique locoregional infiltration pattern at relapse, which might reflect its aggressive clinical behavior. Despite the similar response to platinum-containing chemotherapy, patients with TNBC had a shorter OS than patients with non-TNBC. The implication of TN phenotype as poor prognostic factor is uncertain, because it needs to be defined whether poor outcome is related to the rapid growing characteristics of tumor itself or the resistance to drug therapy. Further prospective studies are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Phenotype; Platinum Compounds; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Recurrence; Retrospective Studies; Taxoids; Treatment Outcome; Young Adult

It is accepted that preoperative chemotherapy can result in increased breast preservation for breast cancers greater than 4 cm. The benefits of preoperative chemotherapy are less clear, however, for patients who present with smaller tumors and are already candidates for breast-preserving surgery. The goal of this study is to assess the effect of preoperative chemotherapy on breast cancers between 2 and 4 cm diameter.. A retrospective chart review was conducted of patients diagnosed with new breast cancer at the Yale-New Haven Breast Center for the years 2002-2007. Patients were included in the study if their breast cancer was between 2 and 4 cm and their initial surgical treatment had been completed. Patients with distant metastases were excluded.. There were 156 new cancers that met study requirements. Forty-seven patients underwent preoperative chemotherapy, and 109 patients had their surgery first, usually followed by chemotherapy. Initial surgery was lumpectomy for 31 out of 47 patients (66%) in the preoperative chemotherapy group compared with 62 out of 109 patients (57%) in the surgery group. For patients with lumpectomies, 2 out of 31 patients (6%) in the preoperative group had positive margins and required re-excision compared with 20 out of 62 patients (37%) in the surgery-first group (P<0.01).. We conclude that, for tumors between 2 and 4 cm, preoperative chemotherapy is associated with a significantly decreased rate of re-excision following lumpectomy. This not only results in fewer mastectomies, but also avoids the morbidity and inferior cosmetic results associated with a re-excision lumpectomy.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Lymph Nodes; Lymphatic Metastasis; Mastectomy; Mastectomy, Segmental; Middle Aged; Neoplasm Staging; Preoperative Care; Prognosis; Prospective Studies; Retrospective Studies; Risk Factors; Survival Rate; Taxoids; Treatment Outcome

The objectives of this study were to examine the patterns of use for adjuvant therapy and the changes in surgical practice for patients with early stage breast cancer and to describe how recent large clinical trial results impacted the patterns of care at The University of Texas M. D. Anderson Cancer Center (MDACC).. The study included 5486 women who were diagnosed with stage I through IIIA breast cancer between 1997 and 2004 and received their treatment at MDACC. A chi-square trend test and multivariate logistic regression model were used to assess changes in treatment patterns over time.. Among lymph node-positive patients, the use of anthracycline plus taxane chemotherapy increased from 17% in 1997 to 81% in 2004 (P < .001). Meanwhile, the use of anthracyclines without taxanes dropped from 76% to 20% (P < .001) between 1997 and 2000. For postmenopausal patients who received endocrine therapy, the use of tamoxifen was replaced increasingly by the use of aromatase inhibitors (from 100% on tamoxifen in 1997 to 14% in 2004; P < .001). The percentage of women who underwent initial sentinel lymph node biopsy increased significantly during the period from 1997 to 2004 (from 1.8% to 69.7%, respectively, among patients who underwent mastectomy; and from 18.1% to 87.1%, respectively, among patients who underwent breast-conserving surgery; P < .001).. The results from this study suggested that key findings from adjuvant therapy and surgical procedures from large clinical trials often prompt immediate changes in the patient care practices of research hospitals like MDACC.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Early Detection of Cancer; Estrogen Antagonists; Female; Humans; Lymphatic Metastasis; Tamoxifen; Taxoids; Time Factors

Chemotherapy-induced amenorrhea occurs in about 20-70% of premenopausal breast cancer patients. Chemotherapy-induced amenorrhea can affect choice of hormonal therapy, fertility, and quality of life of breast cancer survivors. We retrospectively analyzed the incidence of amenorrhea after adjuvant chemotherapy and the subsequent recovery of the menses in 145 breast cancer patients. Age, smoking, alcohol consumption, body mass index, chemotherapy regimen, previous hormonal therapies, and previous childbearing were analyzed as potential predictive factors of ovarian function recovery. Median age was 42 years at the beginning of adjuvant chemotherapy with 30.3% of patients below 40 years of age. The majority (87.6%) of patients received anthracycline-based chemotherapy, 35.2% of patients received a cyclophosphamide-methotrexate-5-fluorouracil regimen and 42.8% received a taxane. The incidence of chemotherapy-induced amenorrhea was 80, and 35.3% of these patients resumed menses after a median of 8 months. In multivariate analysis, younger age (<40 years, P=0.01) and taxane-based chemotherapy (P=0.03) were associated with increased probability of recovery of menses after chemotherapy-induced amenorrhea. In contrast, cyclophosphamide-methotrexate-5-fluorouracil-based chemotherapy (P=0.07) and previous childbearing (P=0.04) were associated with an increased probability of permanent chemotherapy-induced amenorrhea. Recovery of menses after chemotherapy-induced amenorrhea occurs more probably in younger women, with no pregnancies and receiving taxanes.

Topics: Adult; Age Factors; Amenorrhea; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Logistic Models; Menstruation; Middle Aged; Multivariate Analysis; Parity; Pregnancy; Premenopause; Proportional Hazards Models; Recovery of Function; Retrospective Studies; Taxoids; Time Factors; Young Adult

The most commonly used chemotherapeutic regimens in the treatment of metastatic breast cancer (MBC) include anthracyclines and taxanes. In our study, we investigated the efficacy and tolerability of cisplatin plus gemcitabine combination chemotherapy regimen in patients with MBC, who exhibited disease progression after anthracycline- and taxane-based chemotherapy.. Thirty-three patients with taxane/anthracycline-resistant MBC have been treated with gemcitabine 1,000 mg/m(2) intravenously and cisplatin 30 mg/m(2) intravenously on days 1 and 8 of a 3-week treatment cycle.. Thirty-one patients were assessable for response. One of the 31 patients (3.2%) showed complete response, while 7 patients (22.6%) showed partial response; the objective response rate was 25.8%. Stable and progressive disease was observed in 6 (19.4%) and 17 patients (54.8%), respectively. The median time to progression was 4 months (95% CI 2.15-5.85). The median survival time of all patients was 9.5 months (95% CI 7.86-11.14).. Gemcitabine and cisplatin combination therapy is moderately active and safe in patients with MBC previously treated with anthracycline and taxanes.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Gemcitabine; Humans; Middle Aged; Neoplasm Metastasis; Survival Rate; Taxoids

Anthracycline, taxane or trastuzumab play a central role in systemic chemotherapy for breast cancer. The standard of subsequent treatment is capecitabine, S-1, vinorelbine, irinotecan or gemcitabine. Ixabepilone or nanoparticle paclitaxel is effective for taxane-resistant breast cancer. Lapatinib proves effective for trastuzumab-resistant HER2-overexpressing breast cancer and also for brain metastasis. Trastuzumab-DM1, pertuzumab and neratinib are promising drugs. In terms of antiangiogenic agents, bevacizumab in combination with taxane demonstrates efficacy. Axitinib, sunitinib or pazopanib is under investigation. It is necessary to study the best manner of sequence and combination in these drugs.

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Immunotherapy; Taxoids

Topics: Adult; Age Factors; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Breast Neoplasms; Bridged-Ring Compounds; Cohort Studies; Disease-Free Survival; Female; Humans; Mastectomy, Segmental; Middle Aged; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Registries; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome; White People

Resistance to chemotherapy is a complex and very frequent problem in the treatment of breast cancer. It is associated with a poor prognosis and short overall survival. We report a patient with advanced breast cancer without response to anthracyclines or taxanes but who controlled the disease for 15 months with the combination of ixabepilone and capecitabine.

Topics: Adult; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Taxoids; Treatment Outcome

Topics: Aged; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Female; Humans; Lymphopenia; Taxoids; Treatment Outcome

Topics: Adult; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Taxoids; Urinary Bladder Diseases

Topics: Anthracyclines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Drug Therapy, Combination; Humans; Patient Selection; Receptor, ErbB-2; Taxoids; Trastuzumab

Treatment efficiency of adjuvant therapy in breast cancer is only revealed after several years by statistical evaluation and gives no answer for the individual patient. We here present a method to analyze the response to adjuvant chemotherapy online in individual patients.. In 25 consecutive non-metastatic primary breast cancer patients adjuvant fluorouracil/epirubicin/cyclophosphamid (FEC) or EC followed by taxane (EC-T) or cyclophosphamid/methotrexate/fluorouracil (CMF) therapy were given. Circulating epithelial tumor cells (CETC) were quantified before and after each second cycle of the therapy regimen, between the anthracycline and the taxane block of the regimen and in some cases repeatedly during CMF treatment. Independent of the initial cell number CETC numbers showed a decline, no change or a minor increase in 15 patients of which 14 remained in complete remission and 1 suffered local relapse. Ten patients showed an increase at the end of therapy of which 4 have relapsed during the observation time of between 2 months and up to 54 months. This patient group was compared to a previously published group of 25 patients who have all reached a follow-up of 4.5 years or until relapse.. As in the previous report, Kaplan-Meier analysis revealed a high correlation between the response of CETC to therapy and relapse (p < 0.0001) and curves of both patient groups were super imposable. Multivariate analysis revealed the response of CETC to therapy to be an independent predictive marker for relapse.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cell Count; Chemotherapy, Adjuvant; Cohort Studies; Cyclophosphamide; Epirubicin; Epithelial Cells; Female; Fluorouracil; Humans; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Prognosis; Remission Induction; Survival Rate; Tamoxifen; Taxoids

Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR- and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an invitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Breast Neoplasms; Bridged-Ring Compounds; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; ErbB Receptors; Female; G2 Phase; Gefitinib; Humans; Immunoprecipitation; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-akt; Quinazolines; Survival Rate; Taxoids; Transplantation, Heterologous; Tumor Cells, Cultured

Of 231 patients with recurrent or metastatic breast cancer treated in Hiei Hospital between January 2001 and March 2005, for whom data on hormone receptor (HR) and HER 2/neu were available, we retrospectively analyzed the association of the response rate with HR and HER 2 in 172 patients treated with taxane in whom the treatment response could be evaluated. Among the patients treated with taxane alone,the response rates were 37.5% (n=67) in the HR (+) patients and 14.6% (n=41) in the HR (-) patients (p=0.0131). In particular, taxane resistance was suggested in the HR (-)/HER 2 (-) patients (response rate: 4.2%, n=24). Concerning combination therapy with trastuzumab and taxane, the response rate were 52.8% in the HR (+)/HER 2 (+) patients and 60.4% in the HR (-)/HER 2 (+) patients. In 27 of these patients, single therapy with taxane was switched to combination therapy with taxane and trastuzumab after they became resistant to taxane, and 8.3% of the HR (+)/HER 2 (+) patients and 53.3% of the HR (-)/HER 2 (+) patients responded to this combination therapy (p=0.0192), suggesting the synergistic effects of the two agents in HR (-)/HER 2 (+) patients. Therefore, HR and HER 2 were associated with the sensitivity to a chemotherapeutic agent, taxane. Stratification with respect to HR and HER 2 is important in the treatment of metastatic breast cancer. In particular, therapeutic strategies for HR (-)/HER 2 (-) patients with a poor prognosis must be established in the future.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Liver Neoplasms; Pleural Effusion, Malignant; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Taxoids; Trastuzumab

The optimal treatment of metastatic breast cancer patients previously treated with anthracycline and taxane is unknown. Common therapeutic alternatives include capecitabine and vinorelbine. This retrospective chart review compares overall survival following treatment with capecitabine, vinorelbine, or both agents sequentially in this group of women.. Electronic patient records and charts of patients who received anthracycline and taxane-based chemotherapy and subsequently received capecitabine and/or vinorelbine at 3 Canadian cancer centers, between November 1994 and June 2003, were retrospectively reviewed.. A total of 140 patients met the study eligibility criteria: 45 patients received vinorelbine as a single agent and 68 received capecitabine as a single agent. The median duration of therapy was 64 days with vinorelbine and 129 days with capecitabine (P = 0.0012). Median overall survival was 102 days for the vinorelbine group and 188 days for the capecitabine group (P < 0.0001). Survival at 1 year was 15.6% for the vinorelbine group and 28.4% for the capecitabine group (P = 0.017). Twenty-seven patients received both agents sequentially; and in this group, the median duration of therapy was 110 days (87 days with vinorelbine and 138 days with capecitabine), and the median overall survival was 390 days.. This exploratory analysis suggests that patients with tumors previously treated with both anthracycline and taxane can still obtain significant survival benefit from further chemotherapy. The results indicate that capecitabine may be superior to vinorelbine in this setting.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Retrospective Studies; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

Taxanes (TX) were administered to 246 of 292 patients with recurrent/metastatic breast cancer (MBC) who were treated in Hiei Hospital between January 2001 and May 2006. Recently, TX has been increasingly prescribed for preoperative treatment and postoperative adjuvant therapy. To improve the prognosis of MBC, regimens effective for TX-resistant cancer patients should be developed. In this study, with respect to hormone receptor (HR) and Her 2/neu (HER 2), we retrospectively investigated whether our series responded to the regimens used after TX resistance was acquired. As post TX-resistance therapy (trastuzumab was combined in HER2-positive patients), 387 treatment regimens were administered to 166 patients. The following regimens achieved a response rate (patients achieving PR or CR/patients who could be evaluated) of 10% or more: combination therapy with TX and capecitabine (11/61, 18%), CPT-11 (10/57, 17.5%), vinorelbine (5/46, 10.9%), MFL-P (continuous treatment with MTX, 5-FU, LV, and CDDP) (12/47, 25.5%), and DMpC (5'-DFUR, MPA, CPA p.o.) (5/16, 31.2%). The latter 2 regimens achieved a high response rate,and some HR (-) and HER 2 (-) patients also responded to these regimens. In HR (+) or HER 2 (+) patients who responded to TX, survival was longer than that of non-responders. However, there was no difference in the treatment responsiveness of post-TX regimens between TX-responders and non-responders, suggesting the survival-prolonging effect of TX.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Receptor, ErbB-2; Retrospective Studies; Survival Rate; Taxoids; Trastuzumab

To describe the postural control of women who received taxane chemotherapy for treatment of breast cancer using quantitative and clinically feasible measures.. Prospective descriptive study.. University-based comprehensive cancer center.. Twenty women who completed taxane treatment for breast cancer and 20 healthy controls participated in this study.. Not applicable.. Two quantitative measures of postural control were used, Sensory Organization Test (SOT) and center of pressure (COP) velocities. Two clinically feasible measures of postural control were used, the Fullerton Advanced Balance Scale (FABS) and Timed Up & Go (TUG) test.. Compared with healthy controls, women with breast cancer had poorer postural control on all of the outcome measures. FABS and TUG scores correlated moderately with SOT and COP scores.. After taxane chemotherapy, women with breast cancer show significantly increased postural instability compared with matched controls. Clinically feasible measures of postural control correlated with quantitative tests. These results suggest that these clinical measures may be useful to screen patients to determine who may benefit from rehabilitation.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Feasibility Studies; Female; Follow-Up Studies; Humans; Middle Aged; Postural Balance; Posture; Prognosis; Prospective Studies; Sensation Disorders; Task Performance and Analysis; Taxoids

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Humans; Neoadjuvant Therapy; Taxoids; Treatment Outcome

We experienced a case of recurrent breast cancer resistant to prior medications, which was treated with oral S-1, a fluoropyrimidine-class anticancer drug, and exhibited the marked shrinkage of liver metastasis. The prior treatments including anthracycline and taxane were judged not effective because of the progressive disease. Then the oral treatment with S-1 was started at 120 mg/day bid. targeting metastatic lesions of the liver. At the end of the second cycle,a significant improvement was noted with a decrease rate of 82.5%. The S-1 monotherapy was thus considered to be an effective treatment for advanced or recurrent breast cancer resistant to anthracyclines and taxanes.

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Mastectomy, Segmental; Middle Aged; Oxonic Acid; Pyridines; Taxoids; Tegafur

We had 2 patients with marked shrinkage of liver metastasis by administration of the oral fluorinated pyrimidine anticancer drug S-1 for advanced/recurrent breast cancer that was resistant to taxane and another antitumor drugs. Both patients almost completed the full dose through the whole course of treatment,and the drug showed good tolerability. S-1 was considered to possess beneficial antitumor efficacy and tolerability and to be promising as home chemotherapy for advanced/recurrent breast cancer.

Topics: Administration, Oral; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Middle Aged; Oxonic Acid; Pyridines; Taxoids; Tegafur

We had 3 patients with recurrent/advanced breast cancer in whom a notable reduction in the size of the targeted tumors was seen following administration of S-1 (TS-1), a new oral pyrimidine fluoride anticancer drug. All of the patients had received taxane and/or anthracycline anticancer drugs as prior therapy; however, they were judged to be non-responsive to the drugs. The size of the targeted tumor decreased to 55.7% after 3 courses of the therapy in Patient 1. The tumor disappeared at completion of the third course in Patient 2, although the therapy was temporarily suspended during the second course due to adverse drug reactions, and the therapy was then resumed after 2-week drug withdrawal. Patient 3 was able to undergo long-term therapy, consisting of 8 courses for 11 months, and the size of the tumor reduced to 58.1%. No serious adverse drug reactions to S-1 occurred in our 3 patients. It is thought that less toxicity enabled Patient 3 to undergo long-term therapy. We consider S-1 to be a useful anticancer drug for treatment of taxane and/or anthracycline resistant recurrent breast cancer.

Topics: Aged; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Lymph Node Excision; Lymph Nodes; Mastectomy, Segmental; Middle Aged; Oxonic Acid; Pyridines; Taxoids; Tegafur

A 35-year-old woman with taxane and anthracycline-resistant recurrent breast cancer with multiple lung metastasis and carcinomatous lymphangitis was treated with CMF as third-line chemotherapy. A complete response was achieved,and the toxicities were tolerable. We thought that CMF could be a useful regimen as third-line chemotherapy for metastatic breast cancer.

Topics: Adult; Anthracyclines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cyclophosphamide; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Lung Neoplasms; Lymphangitis; Methotrexate; Quality of Life; Remission Induction; Tamoxifen; Taxoids

In clinical studies of both heavily and minimally pretreated patients with advanced breast cancer, the combination of Gemcitabine plus cisplatin (GC), given in a variety of schedules and doses, has demonstrated moderate safety and efficacy in both heavily and minimally pretreated advanced breast cancer with response rate from 29-63% (median 46%).. We evaluated the activity and toxicity of another GC regimen (gemcitabine 1,000 mg/m(2) days 1, 8 plus cisplatin 75 mg/m(2) day 1 every 3 weeks) in 30 breast cancer patients who failed chemotherapy with anthracycline and/or taxanes as adjuvant or neoadjuvant, or primary therapy.. We obtained overall response in 15 of 29 evaluable patients (52%), with responses occurring in all subgroups of disease (unresectable locally advanced, locoregional recurrence, and distant metastasis). Toxicity was primarily hematologic, with grade 3/4 neutropenia and thrombocytopenia in 37% and 17% of patients, respectively. The only grade 3/4 non-hematologic toxicity was grade 3 nausea/vomiting in 12% of patients.. Our data suggest that gemcitabine plus cisplatin appears to be effective and has an acceptable toxicity profile in anthracycline and/or taxane pretreated patients with advanced breast cancer.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Breast Neoplasms, Male; Bridged-Ring Compounds; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Remission Induction; Salvage Therapy; Survival Rate; Taxoids; Treatment Failure

To analyze the clinical characteristics, efficiency of treatment and potential prognostic factors of breast cancer patients with liver metastases (BCLM).. The data of clinical characteristics, response to treatment and survival were retrospectively analyzed in 152 breast cancer patients with liver metastasis using SPSS 11.5.. The median disease free survival (DFS), the median survival of recurrence (MSR) and median time to progress (TTP) of this series was 21 months, 16 months and 7.4 months, respectively. The response rate in chemotherapy group was higher than that in the transcatheter arterial chemoembolization (TACE) group (37.7% vs. 53%, P = 0. 039). The TTP was longer (7 m vs. 10 m, P = 0.048) and the response rate (63.3% vs. 40.0%, P = 0.04) in taxanes-based chemotherapy group was significantly higher than that in non-taxanes-containing regimen. The MSR in patients with single liver metastases treated by TACE was longer than that by chemotherapy (16 m vs. 30 m, P = 0.0052), but it was not observed in the patients with multiple metastases. Pathological tumor size (PT) and axillary lymph node status at diagnosis, negative estrogen receptor (ER) status, abnormal ALT level induced by liver metastases, metastastic tumor size were significantly correlated with shorter survival.. The effective chemotherapy especially the taxane-containing regimen and TACE may improve outcome for breast cancer patient with liver metastasis.

Topics: Alanine Transaminase; Antineoplastic Agents; Breast; Breast Neoplasms; Bridged-Ring Compounds; Chemoembolization, Therapeutic; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Liver Neoplasms; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Receptors, Estrogen; Retrospective Studies; Taxoids

Tumour anaemia is a common symptom in cancer patients, particularly in those receiving chemotherapy. The aim of the current study was to analyse the impact of haemoglobin levels on the prognosis of patients with primary breast cancer receiving adjuvant chemotherapy. A total of 129 patients were available for analysis. The estimated median five-year overall survival rate was 76.6%. Mean Hb prior to primary surgery was 13.8 g/dl (SD 1.09), pre-chemotherapy Hb 12.8 g/dl (SD 1.2), and nadir Hb during chemotherapy 11.0 g/dl (SD1.1), respectively. Hb values were analysed as continuous variables in the Cox model. Survival analyses did not show a correlation between preoperative and pre-chemotherapy Hb levels with patient outcome. However, univariate analysis identified low nadir Hb (p=0.008), larger tumours (p=0.042), and hormone-receptor-negative tumours (p=0.022) to be significantly associated with poor patient survival. This result was persistent when analysis was adjusted for relevant prognostic factors in a multivariate Cox proportional hazards model. Nadir Hb, 1.54-fold increased risk for death (95% CI 1.03-2.32), and tumour size, 3.2-fold increased risk (95% CI 1.17-8.77) remained as independent variables, whereas hormone-receptor status failed to retain significance. The present data showed anaemia during adjuvant chemotherapy to be associated with poor survival in patients with primary breast cancer. Prospective randomized trials are warranted to examine the value of correcting anaemia with regard to improve disease control and survival.

Topics: Aged; Anemia; Antineoplastic Agents; Austria; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Hemoglobins; Humans; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Survival Analysis; Tamoxifen; Taxoids; Time Factors

Taxanes are used for the treatment of many human cancers, as first- and second-line chemotherapeutics. In the course of treatment many patients develop resistance or hypersensitivity to one form of taxane and require a different taxane to rescue the therapeutic benefit of the drug. There is currently no method to reliably predict tumor responses to taxanes prior to therapy or when resistance or hypersensitivity develops. We adapted the quartz crystal microbalance (QCM) biosensor technique to study responses of human mammary epithelial tumor cells to taxanes. Studies indicate that stable frequency and resistance levels are reached at 24 h. Cells in the QCM can then be treated with taxanes and responses monitored in real time via frequency and resistance changes reflecting alterations of cell mass distribution and viscoelastic properties. Distinct shifts in frequency and resistance accurately predicted apoptosis or resistance to treatment, as determined in parallel convention assays. QCM analysis accurately predicted docetaxel was more effective than paclitaxel and MCF-7 cells were more resistant to taxanes compared to MDA-MB-231 cells. These studies suggest "signature" patterns for taxane responsivity could be compared to those of patient biopsy samples to predict therapy outcome prior to treatment for initial therapy or to rescue therapy efficacy.

Topics: Antineoplastic Agents; Apoptosis; Biological Assay; Biosensing Techniques; Breast Neoplasms; Bridged-Ring Compounds; Cell Count; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Equipment Design; Equipment Failure Analysis; Feasibility Studies; Humans; Miniaturization; Taxoids; Transducers

The purpose of this study was to assess the value of MRI measurements of breast tumor size for predicting recurrence-free survival (RFS) in patients undergoing neoadjuvant (preoperative) chemotherapy and to compare the predictive value of MRI with that of established prognostic indicators.. The study included 62 patients undergoing neoadjuvant chemotherapy. The longest diameter and volume of each tumor were measured on MRI before and after one and four cycles of treatment. Change in diameter on clinical examination, tumor size at pathology, and the number of positive nodes were determined. Each measure of tumor extent was assessed for the ability to predict RFS.. Univariate Cox analysis showed initial MRI volume was the strongest predictor of RFS (p = 0.002). Final change in MRI volume (p = 0.015) was more predictive than change in diameter on MRI (p = 0.077) or clinical examination (p = 0.27). Initial diameter on MRI (p = 0.003) and clinical examination (p = 0.033), tumor size at pathology (p = 0.016), and number of positive nodes (p = 0.045) were also significantly predictive of RFS. Early change in MRI volume (p = 0.071) and diameter (p = 0.081) after one chemotherapy cycle showed trends of association with RFS. Multivariate analysis showed initial MRI volume (p = 0.005) and final change in MRI volume (p = 0.003) were significant independent predictors.. MRI tumor volume was more predictive of RFS than tumor diameter, suggesting that volumetric changes measured using MRI may provide a more sensitive assessment of treatment efficacy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Doxorubicin; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Predictive Value of Tests; Proportional Hazards Models; Survival Analysis; Taxoids

A 53-year-old woman presented with an advanced right breast cancer together with skin manifestations and massive axillary lymph node metastases, as well as distant metastases in the lung and the liver. The patient received surgery after 6 courses of chemotherapy with epirubicine and intravenous cyclophosphamide (80/600 mg/m2). A weekly paclitaxel regimen (80 mg/m2) was started because the tumor markers increased soon after surgery. Despite chemotherapy, no response was confirmed, then weekly docetaxel (35 mg/m2) was started. Although the tumor markers decreased after administration of docetaxel, severe liver disfunction appeared and did not improve after cessation of docetaxel. Computed tomography (CT) revealed numerous metastatic nodules in the bilateral lobes of the liver. UFT (400 mg/day) and cyclophosphamide (100 mg/day) were administered for 4 weeks followed by 2 weeks cessation and then combined with continuous medroxyprogesterone acetate (800 mg/day). Liver function tests were normalized 3 months after, and the massive metastatic liver tumors disappeared completely. Lung metastasis also subsided. In spite of these good responses, tumor markers did not normalize and skin nodules appeared around the surgical site. Administration was stopped 36 weeks after initiation of the treatment.

Topics: Adenocarcinoma, Scirrhous; Administration, Oral; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Medroxyprogesterone Acetate; Middle Aged; Taxoids; Tegafur; Uracil

Twenty-five percent of all women with breast carcinoma are premenopausal and are at risk for chemotherapy-induced menopause with long-term side effects. Although there is considerable documentation of the rates of chemotherapy-induced amenorrhea with classic adjuvant regimens, there are inadequate data that address the impact of taxanes on menstrual function in this setting. The objective of this analysis was to determine the incidence of long-term amenorrhea (> or = 12 mos) in women with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane-based chemotherapy, with or without subsequent tamoxifen.. The authors identified 235 premenopausal women with breast carcinoma age 40 years or younger who were treated with adjuvant anthracycline and taxane-based chemotherapy at Memorial Sloan-Kettering Cancer Center from January 1997 to June 2003.. One hundred sixty-six patients met all eligibility criteria and had sufficient follow-up for evaluation. The median age of patients at diagnosis was 36 years (range, 27-40 yrs). All patients had regular pretreatment menses, 25 patients (15%) developed long-term amenorrhea, and 141 patients (85%) resumed menstruation. Eighty-two patients (49%) also received tamoxifen: The incidence of amenorrhea among them was 17%. There was a statistically significant association between age and the development of amenorrhea, with older women at higher risk (P < 0.01).. The sequential addition of a taxane to standard adjuvant anthracycline-based chemotherapy did not appear to produce a high rate of chemotherapy-related amenorrhea compared with historic controls. To increase the information available to assist young patients who are considering adjuvant therapy, prospective studies should incorporate menstrual function ascertainment by patient-reported history and assays of ovarian function.

Topics: Adult; Age Distribution; Amenorrhea; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Female; Humans; Incidence; Neoplasm Staging; Premenopause; Prognosis; Retrospective Studies; Tamoxifen; Taxoids; Time Factors

Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Neoplasm Metastasis; Phosphorylation; Receptor, ErbB-2; Retrospective Studies; Taxoids; Treatment Outcome

A patient with lung metastasis of breast cancer was reported. The patient underwent surgery in December, 1999. Her breast cancer then recurred in December, 2000. After treatment failure with anthracycline and taxane antitumor drugs,she participated in a phase II study of S-1, a fluorinated pyrimidine anticancer drug, which was given orally at 80 mg/m2/day (2 doses). After completion of 4 courses of treatment,the target lesions of the lung metastasis markedly shrunk by 47.5% as compared with the pretreatment. Because salvage therapy with S-1 alone showed good antitumor efficacy and beneficial tolerability when the standard dosage was maintained, it was considered that this home therapy was effective for advanced/recurrent breast cancer that was resistant to anthracycline and taxane antitumor drugs.

Topics: Administration, Oral; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma, Ductal, Breast; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Oxonic Acid; Pyridines; Quality of Life; Salvage Therapy; Taxoids; Tegafur

99mTc-Labeled annexin V has been used for the imaging of tumor apoptosis induced by chemotherapy. However, owing to the short half-life of annexin V, multiple injections of the radiotracer are necessary to capture the peak apoptotic activity. In this study, we evaluated the imaging properties of an (111)In-labeled, long-circulating annexin V.. Both polyethylene glycol (PEG) and the metal chelator diethylenetriaminepentaacetic acid (DTPA) were simultaneously introduced to annexin V or ovalbumin through the use of a heterofunctional PEG precursor. Imaging studies were performed in mice bearing subcutaneously inoculated human mammary MDA-MB-468 tumors. The mice were treated with poly(L-glutamic acid)-paclitaxel, monoclonal antibody C225, or a combination of poly(L-glutamic acid)-paclitaxel and C225, followed by intravenous injection of (111)In-DTPA-PEG-annexin V. Images were acquired 48 h after the injection of the radiotracer. Autoradiography and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining were performed on adjacent tumor slices for the localization of apoptotic cells. The imaging properties of unPEGylated annexin V and PEGylated ovalbumin were also determined to permit assessment of the specificity of (111)In-DTPA-PEG-annexin V.. Tumor apoptotic index increased from 1.67% +/- 0.31% at baseline to 7.60% +/- 0.72% and 11.07% +/- 1.81%, respectively, 4 d after treatment with poly(L-glutamic acid)-paclitaxel or combined poly(L-glutamic acid)-paclitaxel and C225. Tumor uptake (percentage of injected dose per gram of tumor [%ID/g]) of PEGylated (111)In-DTPA-PEG-annexin 4 d after treatment was significantly higher in tumors treated with poly(L-glutamic acid)-paclitaxel (10.76 +/- 1.38 %ID/g; P = 0.001) and with combined poly(L-glutamic acid)-paclitaxel and C225 (9.84 +/- 2.51 %ID/g; P = 0.029) than in nontreated tumors (6.14 +/- 0.67 %ID/g), resulting in enhanced visualization of treated tumors. (111)In-DTPA-PEG-annexin V distributed into the central zone of tumors, whereas (111)In-DTPA-annexin V was largely confined to the tumor periphery. Furthermore, uptake of (111)In-DTPA-PEG-annexin V by tumors correlated with apoptotic index (r = 0.87, P = 0.02). Increase in tumor uptake of the nonspecific PEGylated protein (111)In-DTPA-PEG-ovalbumin was also observed after poly(L-glutamic acid)-paclitaxel treatment (55.6%), although this increase was less than that observed for (111)In-DTPA-PEG-annexin V (96.7%).. Increased uptake of and improved visualization with (111)In-DTPA-PEG-annexin V in solid tumors after chemotherapy are mediated through both specific binding to apoptotic cells and nonspecific retention of macromolecular contrast agents in the tumors. (111)In-Labeled, PEGylated annexin V may be used to assess tumor response to chemotherapy.

Topics: Animals; Annexin A5; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Bridged-Ring Compounds; Female; Mice; Mice, Nude; Neoplasm Transplantation; Organometallic Compounds; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Taxoids; Treatment Outcome

Sentinel node biopsy (SNB) is used for evaluation of axillary lymph node status of patients with breast cancer. The usefulness of SNB after neoadjuvant chemotherapy is not established. In addition, SNB after endocrine therapy has rarely been evaluated. We assessed the feasibility of dye guided SNB after neoadjuvant endocrine therapy in comparison with those of SNB after chemotherapy.. A total of 36 patients subjected to SNB after endocrine therapy alone (n = 16) (tamoxifen, anastrozole or combination of goserelin and tamoxifen) or after chemotherapy (n = 20) (anthracycline and/or taxane) were included. SNB was performed with indigocarmine dye prior to the wide resection of the tumor or mastectomy.. Sentinel nodes were successfully identified in 100% (16/16) of patients after endocrine therapy and in 85% (17/20) of patients after chemotherapy. The mean number of harvested sentinel nodes was 2.2 after endocrine therapy and 1.8 after chemotherapy. There was no false negative case after endocrine therapy and there was one false negative case after chemotherapy (8% of overall false negative rate).. SNB seemed feasible and accurate after neoadjuvant endocrine therapy in patients with breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Anthracyclines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Bridged-Ring Compounds; Feasibility Studies; Female; Goserelin; Humans; Lymph Nodes; Middle Aged; Neoadjuvant Therapy; Nitriles; Pilot Projects; Sentinel Lymph Node Biopsy; Tamoxifen; Taxoids; Triazoles

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer.. Thirty patients with breast cancer, clinical diameter > 3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR).. Univariate analysis showed that a > 65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438-464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263-23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5).. DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Contrast Media; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Predictive Value of Tests; Taxoids

We describe a 57-year-old woman who underwent modified mastectomy for right breast cancer (T2N0M0) with overexpression of HER2, in whom lung metastasis developed 3 years after operation. She received sequential chemotherapy, including epirubicin plus cyclophosphamide, docetaxel, paclitaxel and trastuzumab, but the lung lesion progressed after transiently showing a partial response. Oral treatment with UFT and cyclophosphamide was begun as fifth-line treatment. The lung tumor shrank after 2 months, and a partial response has been maintained during continued treatment with UFT and cyclophosphamide. No adverse effects have occurred. We regard combination therapy with oral UFT and cyclophosphamide to be useful for the management of metastatic breast cancer, even in heavily pretreated cases with overexpression of HER2.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cyclophosphamide; Drug Combinations; Epirubicin; Female; Humans; Lung Neoplasms; Mastectomy, Segmental; Middle Aged; Receptor, ErbB-2; Taxoids; Tegafur; Trastuzumab; Uracil

Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Camptothecin; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Middle Aged; Retrospective Studies; Survival Rate; Taxoids

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Female; Humans; Meta-Analysis as Topic; Taxoids

The goal of adjuvant chemotherapy in the treatment of breast cancer is to reduce recurrence and mortality. With respect to quality of life and morbidity, however, such treatments come at a cost. Decreased cognitive functioning, development of fatigue, and mood alterations are common during chemotherapy and persist after its conclusion as evidenced by subjective self-reports and objective neurocognitive performance records. Few efforts, however, have used standardized neuropsychological measures, and no study has empirically selected those measures that best distinguish women in active chemotherapy from those who have previously completed it. Perhaps the most glaring deficit in the literature is that no study has used baseline data to track individual neurocognitive changes across treatment phases and after completion. This article provides an overview of the field of neuropsychology and the cognitive domains theorized to be affected by chemotherapy and the measures typically used, including validated computerized tests, which are tools for future studies; briefly summarizes existing research on the cognitive effects that chemotherapy has on breast cancer patients; compares data resulting from an ongoing pilot study of the cognitive performance of women actively undergoing anthracycline-containing chemotherapy with that of women 6-12 months post chemotherapy completion; and provides a preliminary analysis of the relationship between cognitive and emotional functioning. Future uses of these data to refine the ideal tools that efficiently, accurately, and validly detect short-term and persistent chemotherapy effects are proposed.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Cognition Disorders; Diagnosis, Computer-Assisted; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Humans; Mastectomy; Middle Aged; Neoplasm Staging; Neuropsychological Tests; Pilot Projects; Quality of Life; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Taxoids

To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.

Topics: Aminoacridines; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Disease Models, Animal; Drug Combinations; Female; Floxuridine; Humans; Lung Neoplasms; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Taxoids; Tegafur; Uracil

We have compared the nature of interaction of certain taxanes with microtubular protein, and the mechanism of action underlying cytotoxic activity. Taxanes induced tubulin assembly in vitro, but only taxanes bearing side chain were capable of inducing the formation of stable tubulin polymers. Electron microscopy detections showed that taxane-induced polymers are structurally similar to microtubules formed by paclitaxel, with differences in length. Otherwise, light microscopy views have shown that intracellular microtubule network is deeply reorganized by taxanes into short fibers, unlike paclitaxel-bundled microtubules. Taxanes inhibited the growth of various human tumor cell lines, but cell cycle analysis did not always indicate a block in the G2/M phase. These agents alter some apoptotic signal transduction pathways, probably by a mechanism distinct from microtubule interaction. Briefly, the effectiveness of taxanes is closely related to their chemical structure, and depends on their interaction with microtubular protein. By virtue of this mechanism, some of these taxanes may provide usefulness for therapeutic improvements.

Topics: 3T3 Cells; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle; Cell Survival; Colonic Neoplasms; Female; G2 Phase; Humans; Mice; Microtubules; Mitosis; Structure-Activity Relationship; Taxoids; Tubulin; Tumor Cells, Cultured

Constitutive bcl-2 overexpression increases the tumorigenic and metastatic potential of doxorubicin-resistant, estrogen-independent, MCF-7 ADR human breast cancer cells. We evaluated the sensitivity to taxanes (paclitaxel, docetaxel and IDN 5109) of 2 bcl-2-overexpressing MCF-7 ADR clones and control neomycin-transfected MCF-7 ADR neo cells. The 2 bcl-2-overexpressing MCF-7 ADR clones were relatively resistant to all 3 taxanes, whereas the MCF-7 ADR neo cells were relatively resistant to paclitaxel and docetaxel, but sensitive to IDN 5109. We found that both MCF-7 ADR neo and bcl-2-overexpressing MCF-7 ADR clones express high levels of the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor-alpha (TGF-alpha). Therefore, we tested the growth inhibitory effect of ZD1839 (Iressa, AstraZeneca, Macclesfield, UK), an orally active, selective EGFR tyrosine kinase inhibitor (EGFR-TKI) that is in clinical development. ZD1839 inhibited the growth in soft agar of all 3 clones in a dose-dependent manner (IC(50) of approximately 0.1 microm). This effect was accompanied by a dose-dependent inhibition of EGFR tyrosine autophosphorylation and of the production of TGF-alpha, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). To determine whether the blockade of EGFR signaling might affect the sensitivity of bcl-2-overexpressing MCF-7 ADR cells to taxanes, cells were treated with ZD1839 in combination with paclitaxel, docetaxel or IDN 5109, and dose-dependent cooperative growth inhibition as well as apoptosis potentiation were observed. Combined treatment with IDN 5109 and ZD1839 also resulted in a significant inhibition of bcl-2 expression in bcl-2-overexpressing MCF-7 ADR cells. These results demonstrate the ability of ZD1839 to overcome taxane resistance in a model of hormone-independent, multidrug-resistant, human breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Bridged-Ring Compounds; Cell Division; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; ErbB Receptors; Female; Fibroblast Growth Factor 2; Gefitinib; Humans; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Quinazolines; Taxoids; Transfection; Transforming Growth Factor alpha; Tumor Cells, Cultured

To determine the incidence of leptomeningeal carcinomatosis (LMC), as the first manifestation of systemic progression, in breast cancer patients after obtaining a major response (complete response, CR or >80% partial response, PR) to first-line taxane-based chemotherapy treated between 1996 and 2000 in our Medical Oncology Unit.. Patients with histologically proven breast cancer having either metastatic disease, or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155).. Seven patients with a median age of 54 (range: 40-70) years developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range: 2-18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while one patient received i.t. methotrexate and RT to lumbar spine. Two patients responded to treatment for LMC, while two achieved stable disease and three progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range: 1-31+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, P = 0.019). Seven out of 86 responders (8.1%; 95% confidence interval, 2.4-13.9) developed LMC as the first sign of progression after a major response to first-line chemotherapy.. LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared in retrospect to non-taxane-treated patients. Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multiinstitutional trials is warranted and identification of potential prognostic factors might help identify patients requiring appropriate prophylactic therapy.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Disease Progression; Female; Humans; Injections, Spinal; Meningeal Neoplasms; Methotrexate; Middle Aged; Retrospective Studies; Spinal Cord Neoplasms; Taxoids; Time Factors; Treatment Outcome

Significance of Technetium 99m ((99m)Tc)-MIBI scintigraphy in the prediction of response to anthracylines and taxanes (both are substrates for P-glycoprotein [P-gp]) as well as relation between (99m)Tc-MIBI uptake and P-gp or MDR1 mRNA expression in tumors were studied in patients with breast carcinoma.. Forty-six female patients with locally advanced (n = 15) or metastatic (n = 31) breast carcinoma were recruited in this study. Before chemotherapy (epirubicin and cyclophosphamide [n = 20] or decetaxel [n = 26]), (99m)Tc-MIBI scintigraphy was performed to obtain the T/N (tumor to normal tissue) ratios of (99m)Tc-MIBI uptake at 10 minutes (T/N[e]) and at 180 minutes (T/N[d]) after the (99m)Tc-MIBI injection. Expression of MDR1 mRNA and P-gp in tumors (n = 32) were determined by a quantitative real-time polymerase chain reaction and immunohistochemistry, respectively.. Clinical significance of T/N(e) and T/N(d) ratios in the prediction of chemotherapeutic response was evaluated using the arbitrary cutoff values of 3.0 for T/N(e) ratios and 2.0 for T/N(d) ratios. Positive predictive value, negative predictive value, and diagnostic accuracy of T/N(d) ratios (81.0%, 96.0%, and 89.1%, respectively) were higher, although statistically not significant, than those of T/N(e) ratios (73.3%, 77.4%, and 76.1%, respectively), and these values were not affected by type of chemotherapy. MDR1 mRNA levels were not significantly different between the lesions with high (> or = 2.0) and low (< 2.0) T/N(d) ratios, but P-gp expression was significantly (P < 0.01) higher in the lesions with low T/N(d) ratios than in those with high T/N(d) ratios.. T/N(d) ratios determined by (99m)Tc-MIBI scintigraphy are useful in the prediction of response to chemotherapy with epirubicin and cyclophosphamide or docetaxel as well as in the in vivo evaluation of P-gp expression status in tumors in patients with locally advanced or recurrent breast carcinoma.

Topics: Adult; Aged; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Female; Genes, MDR; Humans; Middle Aged; Polymerase Chain Reaction; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; RNA, Messenger; Taxoids; Technetium Tc 99m Sestamibi; Treatment Outcome

Xeloda (capecetabine) has been tested for efficacy and toxicity in treating disseminated breast cancer after the potential of anthracycline (group 1) chemotherapy, anthracyclines plus taxanes (group 2) was exhausted. The patients included into the study (54) were divided into groups 1 (33) and 2 (21). Apparent response was in 24 and 21%, respectively. The drug may be used both in out-patients and those refractory to anthracycline chemotherapy and anthracyclines plus taxanes due to moderate toxicity, slight myelodepression and absence of alopecia which seldom makes treatment useless.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Deoxycytidine; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Staging; Taxoids; Treatment Failure; Treatment Outcome

Metastatic breast cancer is a common clinical entity, and its treatment is still a major clinical problem in modern oncology. Both cisplatin (CDDP) and 5-fluorouracil (5-FU) are effective agents.. In this retrospective study, the therapeutic efficacy and tolerability of CDDP and continuous infusion of 5-FU were evaluated in patients with pretreated metastatic breast cancer. 16 patients were surveyed. All of them were pretreated with anthracyclines in an adjuvant and/or therapeutic setting. Eight of them also received taxanes after the failure of anthracyclines. CDDP at 80 mg/m(2) for 1 day and 5-FU at 1,000 mg/m(2) as a continuous 24-hour infusion for 5 consecutive days were administrated every 3 weeks.. 13 patients were included in response analysis. Because of severe toxicity, chemotherapy protocols of 3 patients were stopped after the first cycle. The objective response rate (partial response) was 46%. No complete response was observed. The median response duration was 5 (3.5-7) months in the response group. Favorable objective responses were observed more frequently in cases with skin metastasis. Five out of 6 patients who attained partial remission had skin metastasis. Response rates were similar in patients pretreated with taxanes and in those not pretreated with taxanes (75 vs. 80%). The most serious toxicity was myelosuppression (25%).. Although this study is based on only a limited number of patients, the combination of CDDP and 5-FU can be recommended in patients refractory to both anthracyclines and taxanes and especially in cases of skin metastasis with a good performance status.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Premedication; Skin Neoplasms; Taxoids; Treatment Outcome

High-dose chemotherapy with autologous stem cell support (HDC-ASCS) can produce high complete remission rates in patients with metastatic breast cancer (MBC). However, the majority of those so treated will relapse within 3 years. The ability of such patients to tolerate further myelosuppressive chemotherapy may be limited and the best therapy is undefined. In this retrospective study we assessed the role of capecitabine as initial therapy after relapse. Ten patients (median age = 47 years; oestrogen receptor-positive, n = 4; visceral disease, n = 6; prior anthracycline, n = 8, prior taxanes, n = 10), whose disease progressed at a median of 246 days (range 69-480) after HDC-ASCS and who were treated with capecitabine (2500 mg/m2 per day for 2 weeks of a 3-week cycle) as initial therapy for relapse, were assessed retrospectively for response and toxicity. They received a median of eight cycles (range 4-24) of capecitabine. The toxicities encountered while receiving capecitabine were: hand-foot syndrome (grade 1, n = 3; grade 2, n = 4; grade 3, n = 1); diarrhoea (grade 1, n = 1; grade 2, n = 3); nausea (n = 2) and fatigue (n = 5). Haematological toxicity was seen in only one patient. No patient required hospitalization for toxicity. Three achieved a complete remission, four a partial remission and three disease stabilization. After a median follow-up of 183 days from commencing capecitabine (range 97-540), all patients were alive and five were in remission. Five progressed after remissions that lasted between 63 and 252 days. Oral capecitabine is an active and well-tolerated agent when used alone as first-line therapy in patients who have relapsed after HDC-ASCS for MBC.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Retrospective Studies; Survival Rate; Taxoids; Transplantation, Autologous; Treatment Outcome

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pemetrexed; Survival Rate; Taxoids; Thymidylate Synthase; Treatment Outcome

Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Docetaxel; Drug Carriers; Female; Humans; Liposomes; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Taxoids