er-086526 and Triple-Negative-Breast-Neoplasms

The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-βɣ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antineoplastic Agents; Camptothecin; Cyclin-Dependent Kinase Inhibitor Proteins; Drug Therapy, Combination; Female; Furans; High-Intensity Focused Ultrasound Ablation; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy; Ketones; Phosphoinositide-3 Kinase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Purinergic P1 Receptor Antagonists; Receptor, ErbB-2; Trastuzumab; Triple Negative Breast Neoplasms

Eribulin mesylate (eribulin) is indicated for patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapies in the US and for patients with locally advanced breast cancer (LABC) or MBC who have progressed after at least one chemotherapy in the European Union (EU). In both indications, prior therapy should include an anthracycline and a taxane in adjuvant or metastatic setting. Numerous studies evaluated eribulin in real-world (RW) breast cancer populations to reinforce its consistent effectiveness beyond registration randomized controlled trials (RCTs) that reported median overall survival (OS) of 13.1 and 15.9 months. In this systematic literature review (SLR), we summarize the cumulative evidence on eribulin's RW effectiveness in LABC/MBC.. We searched through Medline/PubMed and Embase databases between 2012 and 2019 for articles reporting RW eribulin use in the second- or third-line or later LABC/MBC setting. Because eribulin showed greatest OS benefits in triple negative breast cancer (TNBC) in RCTs, we also reviewed this tumor subtype. OS and progression-free survival (PFS) were the effectiveness outcomes of interest.. Overall, 34 journal articles or abstracts met the selection criteria. Median OS ranged between 6.9 and 28.0 months; median PFS varied from 2.3 to 14.7 months. Eight studies reported OS outcomes for TNBC patients, and median OS ranged between 3.0 and 23.0 months.. The SLR showed high variability in OS and to a lesser extent in PFS associated with eribulin use in RW setting. Despite heterogeneity in line of use and patient subtypes, this SLR supports effectiveness of eribulin for LABC/MBC in clinical practice.

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Furans; Humans; Ketones; Progression-Free Survival; Treatment Outcome; Triple Negative Breast Neoplasms

Eribulin mesylate (eribulin), an analogue of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with HER2-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule-targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling, and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients.

Topics: Clinical Trials as Topic; Epithelial-Mesenchymal Transition; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Molecular Targeted Therapy; Neovascularization, Pathologic; Triple Negative Breast Neoplasms

Topics: Breast Neoplasms; Disease-Free Survival; Evidence-Based Medicine; Female; Furans; Humans; Ketones; Molecular Targeted Therapy; Precision Medicine; Triple Negative Breast Neoplasms; Tubulin Modulators

Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.. The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.. Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m. Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients.. Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Neutropenia; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Triple Negative Breast Neoplasms

We evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations.. In this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m. Forty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31-71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3-7.4) and 3.0 (95% CI: 2.1-5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs.. Nivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC.. NCT04061863.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Breast Neoplasms; Female; Humans; Middle Aged; Nivolumab; Receptor, ErbB-2; Triple Negative Breast Neoplasms

A liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.. Patients received E7389-LF 2.0 mg/m. Of 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6-55.9) for all patients and 42.9% (95% CI: 21.8-66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9-8.3). The median overall survival was 18.3 months (95% CI: 13.2-not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point.. E7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia.. NCT03207672.

Topics: Breast Neoplasms; Cohort Studies; Drug Compounding; Febrile Neutropenia; Female; Furans; Humans; Ketones; Liposomes; Triple Negative Breast Neoplasms

Topics: Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Furans; Humans; Ketones; Pyridines; Triple Negative Breast Neoplasms

Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides information about the frequency and severity of AEs from the provider's perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug.. We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity.. 83 patients were enrolled: 45 into the HR+/HER2- cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24-39%) in the HR+/HER2- cohort and 13.2% (90% CI 5-26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2- disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy.. Eribulin is active in HER2- breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs. ClinicalTrials.gov Registration: NCT01827787.

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Furans; Humans; Ketones; Receptor, ErbB-2; Triple Negative Breast Neoplasms

As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.. In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1-2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m. The study included 167 patients (phase Ib,. Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Female; Furans; Gene Expression; Humans; Infusions, Intravenous; Ketones; Middle Aged; Safety; Treatment Outcome; Triple Negative Breast Neoplasms

To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients.. Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety.. The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively.. In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen.. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Female; Furans; Homologous Recombination; Humans; Japan; Ketones; Neoadjuvant Therapy; Paclitaxel; Treatment Outcome; Triple Negative Breast Neoplasms

A PARP inhibitor is effective in breast cancer patients with BRCA1/2 germline mutations, and in cell lines with BRCA1 promoter methylation. However, its efficacy in breast cancer patients with BRCA1 promoter methylation is still unknown.. Biopsy samples were obtained from 32 triple-negative breast cancer (TNBC) patients treated with eribulin/olaparib combination therapy in a clinical trial (UMINID: 000009498) and analyzed for their mutations by FoundationOne CDx. DNA methylation was evaluated by quantitative methylation-specific PCR and bisulfite sequencing, and its level was adjusted for tumor cell fraction.. Among 20 TNBC patients evaluable for both methylation and mutations, one (5%) and five (25%) patients had a high (> 80%) and low (30-80%) BRCA1 promoter methylation levels, respectively. One patient with a high methylation level, also having a BRCA2 mutation of unknown significance, displayed complete response. Among the 5 patients with low methylation levels, only one patient with a BRCA2 mutation of unknown significance displayed long-lasting disease control (24 weeks). Patients with a BRCA1 or BRCA2 mutation, or high BRCA1 promoter methylation showed better 6-month progression-free survival (PFS) compared with the other patients (P = 0.009).. Quantitative methylation analysis suggested that addition of homozygous BRCA1 promoter methylation to mutations may more accurately identify TNBC patients who would benefit from olaparib/eribulin combination therapy. (209 words).

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; BRCA1 Protein; DNA Methylation; Female; Follow-Up Studies; Furans; Gene Expression Regulation, Neoplastic; Humans; Ketones; Mutation; Phthalazines; Piperazines; Prognosis; Promoter Regions, Genetic; Survival Rate; Triple Negative Breast Neoplasms

Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy.. Patients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.. In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.. Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation.. EU Clinical Trial Register, EudraCT number 2012-004956-12.

Topics: Adult; Anthracyclines; Bridged-Ring Compounds; Female; Furans; Humans; Ketones; Neoadjuvant Therapy; Taxoids; Treatment Outcome; Triple Negative Breast Neoplasms

The VERITAS (A Phase 1B open-label study to assess the safety and tolerability of everolimus in combination with eribulin in triple-negative breast cancers) trial (EudraCT number: 2014-000135-17) is a phase Ib, open label, multicenter, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study based on the combination of everolimus with eribulin in sequential cohorts of metastatic triple negative breast cancer (TNBC) patients.. The primary objective of the study is to identify the recommended dose of everolimus in combination with eribulin. Secondary endpoints include the assessment of pharmacokinetics and antitumor activity of the experimental treatment. The sample size is based on the Bayesisan approach with regards to the maximum tolerated dose (MTD) and maximum tolerated dose (MTD) observed. An average sample size of approximately 12 patients is deemed reasonable based on simulations.. The VERITAS trial is expected to determine the recommended dose of everolimus in combination with eribulin in TBNC. This study may open the way for further analysis of this combination in phase II studies in this orphan disease of active drug combination such as the TNBC subset.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Everolimus; Female; Furans; Humans; Ketones; Maximum Tolerated Dose; Middle Aged; Research Design; Triple Negative Breast Neoplasms

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carboplatin; Female; Furans; Genes, BRCA1; Genes, BRCA2; Humans; Kaplan-Meier Estimate; Ketones; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Odds Ratio; Treatment Outcome; Triple Negative Breast Neoplasms

Eribulin is a novel antimicrotubule drug, which is approved in the second line treatment of advanced breast cancer in patients who received anthracyclines and taxanes. The article presents the results of two huge phase III clinical trials (301, 305) and their pooled analysis. Eribulin monotherapy demonstates staistically significant improved overall survival compared to standart treatments (15.2 mnths vs 12.8 mnths, p = 0.03 in pooled analysis). Certain subgroups of patients--Her2-negative and triple-negative have the most survival benefit. According to own experience with Eribulin inside the clinical trials, presented in the article, the drug is effective and well tolerated even by older patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Female; Furans; Humans; Kaplan-Meier Estimate; Ketones; Leukopenia; Meta-Analysis as Topic; Microtubules; Neutropenia; Severity of Illness Index; Treatment Outcome; Triple Negative Breast Neoplasms

The aim of this study was to identify factors associated with progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC) treated with eribulin in a real-world setting, to improve information provision in those considering treatment.. Patients treated with eribulin for MBC at The Christie NHS Foundation Trust, Manchester, UK, between August 2011 and December 2018 were included (n = 439). Data were collected by retrospective review of medical records and electronic prescribing systems. Factors such as biological subtype, distant recurrence-free interval, previous lines of chemotherapy and the 'average duration of previous treatment lines' (ADPT) (calculated as: (date of initiation of eribulin-date of MBC) / the number of previous treatment lines in the metastatic setting) were evaluated for prognostic impact using Cox proportional hazards regression.. Our results indicate that the ADPT lines is an important factor when predicting the outcome with eribulin chemotherapy in a palliative setting and that quantitative guidance on the likely PFS and OS with treatment can be provided using ADPT. Validation in additional cohorts is warranted.

Topics: Breast Neoplasms; Female; Furans; Humans; Ketones; Retrospective Studies; Triple Negative Breast Neoplasms

Improved prognosis for triple-negative breast cancer (TNBC) has plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC.. The effect of eribulin in combination with an HDAC inhibitor was tested in three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by Western blotting for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin.. The simultaneous administration of low concentrations (0.2 μM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5 μM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5 μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Immunohistochemical analyses revealed that the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC.. HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.

Topics: Acetylation; Cell Line, Tumor; Cell Proliferation; Furans; Histone Deacetylase 6; Humans; Ketones; Triple Negative Breast Neoplasms; Tubulin

Eribulin mesylate (EM) is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin. EM has been reported to be active in metastatic breast cancer. In this paper, we report efficacy and safety of data of EM in a retrospective, real-world series of patients with poor prognosis, hormone-refractory, or triple-negative metastatic breast cancer.. The analysis was carried out at 4 interrelated oncology centers. EM was delivered at the dose of 1.4 mg/m2 in 100 mL of normal saline over 2 to 5 minutes on days 1 and 8 every 21 days. EM was continued until disease progression or unacceptable toxicity. Side effects were reported every cycle as per standard clinical practice and graded according to NCI-CTCAE, version 4.0. Time-to-progression and overall survival were reported.. In this series of 90 patients the overall response rate was 22%, and 21% and 23% in the hormonal-resistant group and the triple-negative one, respectively. Stable disease was recorded in 24%, 21%, and 27%, respectively, in the whole series, the hormonal-resistant group, and the triple-negative one, respectively. Time-to-progression was 3.5 months (range, 1 to 22 mo) in the whole series and 3.0 months (range, 1 to 14.7 mo) and 3.4 months (range, 2.2 to 16.2 mo) in the hormonal-resistant group and the triple-negative one, respectively. Overall survival reached a median of 11.4 months.. This multicenter study, albeit retrospective, demonstrates the activity of this combination as third-line chemotherapy option in a challenging clinical setting such as triple-negative or hormone-resistant patients with breast cancer progressing after several lines of hormonal manipulations.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Furans; Humans; Ketones; Middle Aged; Neoplasms, Hormone-Dependent; Retrospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms

Eribulin was approved in the United States (US) in 2010 for patients with metastatic breast cancer (MBC) who previously received at least two chemotherapeutic regimens, including anthracycline and taxane in the adjuvant or metastatic setting. With significant changes to the treatment landscape over the past decade, assessment of the real-world effectiveness of eribulin in clinical practice when used according to the approved US indication is valuable.. Patients with MBC were identified by community oncologists through a retrospective, multi-site patient chart review; de-identified data were abstracted into electronic case report forms. Eligible patients initiated eribulin consistent with approved US indication between 1 January 2011 and 31 December 2017. Clinical outcomes assessed included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in all patients and those with triple negative breast cancer (TNBC).. The analysis included 513 patients (median 59.0 years; 38.8% with Eastern Cooperative Oncology Group status ≥ 2). Eribulin was third-line therapy for 78.0% of patients, and fourth-line or later for the remainder. ORR was 54.4%, median PFS was 6.1 months (95% CI: 5.8, 6.6), and median OS was 10.6 months (95% CI 9.9, 11.7) in all patients. Among the 49.9% of patients with TNBC, ORR was 55.1%, median PFS was 5.8 months (95% CI 5.1, 6.4), and median OS was 9.8 months (95% CI 8.6, 11.0).. The current retrospective chart review study reinforces the clinical effectiveness of eribulin in patients with MBC, including those with TNBC, when used according to the approved US indication in real-world clinical practice.

Topics: Breast Neoplasms; Furans; Humans; Ketones; Retrospective Studies; Triple Negative Breast Neoplasms; United States

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. MORAb-202 was highly cytotoxic to FRA-positive cells in vitro, with limited off-target killing of FRA-negative cells. Furthermore, MORAb-202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA-positive/negative cells. In vivo antitumor efficacy studies of MORAb-202 were conducted with a single administration of MORAb-202 in triple-negative breast cancer (TNBC) patient-derived xenograft (PDx) models expressing low and high levels of FRA. MORAb-202 exhibited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Furans; Humans; Immunoconjugates; Ketones; Mice; Patient-Specific Modeling; Primates; Triple Negative Breast Neoplasms; Vesicular Transport Proteins; Xenograft Model Antitumor Assays

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Furans; Humans; Ketones; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Progression-Free Survival; Retrospective Studies; Triple Negative Breast Neoplasms

Various molecular-targeting drugs have markedly improved the treatment of patients with breast cancer. As yet, therapies for triple-negative breast cancer are mainly cytotoxic agents. To investigate the novel therapy for triple-negative breast cancer, we herein examined the effects of a new combination therapy comprising a RAF/MEK inhibitor CH5126766, also known as VS-6766, which we originally discovered, and eribulin. The combination of CH5126766 and eribulin potently inhibited cell growth in the triple-negative breast cancer cell lines tested. The underlying mechanism in the efficacy of this combination treatment in vitro and in vivo was due to enhanced apoptosis through the suppression of survivin and Bcl-2 family proteins. We also showed the suppressed expression of programmed cell death ligand 1 (PD-L1) in combination therapy in vivo. We found that combination therapy with eribulin and CH5126766 for triple-negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses through suppression of PD-L1 might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple-negative breast cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; B7-H1 Antigen; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Coumarins; Female; Furans; Ketones; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; Oncogene Protein v-akt; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-raf; Random Allocation; Survivin; Triple Negative Breast Neoplasms; Tumor Stem Cell Assay

Anticancer agents are used for cancer therapy. Studies on the biological response to treatment with an agent facilitate its effective use. Eribulin mesylate (eribulin) is an anticancer agent. In this study, we found that c-Fos is upregulated in response to eribulin treatment in the triple-negative breast cancer cell lines MDA-MB-231 and HCC70, which have low eribulin sensitivity. c-Fos expression was not upregulated in other cell lines investigated, including high eribulin-sensitive cells. We hypothesized that c-Fos upregulation is involved in low eribulin sensitivity and thus used the c-Fos inhibitor, T-5224. In MDA-MB-231 and HCC70 cells, combined treatment with eribulin and T-5224 showed a stronger anticancer effect than treatment with eribulin alone in cell growth assays, cell death assays and a mouse xenograft tumor model, whereas T-5224 alone showed no anticancer effect. These results suggest that T-5224 may enhance the anticancer effect of eribulin. Our findings contribute to the improvement of cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzophenones; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colchicine; Female; Furans; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Ketones; Mice, Inbred BALB C; Mice, Nude; Microtubules; Paclitaxel; Proto-Oncogene Proteins c-fos; RNA, Messenger; Triple Negative Breast Neoplasms; Up-Regulation

Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model.. The PDOX model was established in the left 2. The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001).. Eribulin has clinical potential for triple-negative MPBC patients.

Topics: Animals; Biomarkers, Tumor; Cisplatin; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Furans; Humans; Ketones; Mice; Paclitaxel; Treatment Outcome; Triple Negative Breast Neoplasms; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

In the present study, the breast cancer patient-derived orthotopic xenograft (PDOX) model was used to identify an effective drug for a highly aggressive triple negative breast cancer (TNBC).. The TNBC tumor from a patient was implanted in the right 4th inguinal mammary fat pad of nude mice to establish a PDOX model. Three weeks later, 19 mice were randomized into the untreated-control group (n=10) and the eribulin treatment group (n=9, eribulin, 0.3 mg/kg, i.p., day 1).. On day 8, eribulin significantly inhibited tumor volume compared to the control group (p<0.01). Eribulin regressed tumors in 3 mice (33.3%) and apparently eradicated them in 6 mice (66.7%). At day 14, tumor regrowth was observed in 2 mice of the eribulin group, which was undetectable on day 8. However, 44.4% (4 out of 9) of the mice in the eribulin group were tumor-free on day 14.. A single low-dose eribulin was efficacious on a highly aggressive TNBC. The breast cancer PDOX model can be used to identify highly effective drugs for TNBC.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Furans; Histocytochemistry; Humans; Ketones; Mice; Neoplasm Metastasis; Triple Negative Breast Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Iron is required for the proliferation of cancer cells, and its depletion suppresses tumor growth. Eribulin mesylate (eribulin), a non-taxane microtubule inhibitor, disrupts the tumor microenvironment via vascular remodeling and obstruction of the epithelial-mesenchymal transition (EMT). Herein, we investigated the effects of the iron chelator on tumor-related properties of breast cancer cells and the effects of iron chelator plus eribulin on tumor growth in vivo.. Two triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and BT-549, and one hormone-receptor positive breast cancer cell line, MCF-7, were used in our study. Cell proliferation, cell migration, cell cycle position, and gene expression were analyzed via MTT assays, wound-healing assays, flow cytometry, and quantitative real-time-polymerase chain reaction, respectively. For the in vivo experiments, mice with breast cancer xenografts were treated with the inhibitors, alone or together, and tumor volume was determined.. Iron chelator inhibited breast cancer cell proliferation and decreased the proportion of S-phase cells. Conversely, it induced hypoxia, angiogenesis, EMT, and immune checkpoints, as determined by quantifying the expression of marker mRNAs in MDA-MB-231 and MCF-7 cells. Eribulin suppressed the expression of the hypoxia and EMT related marker mRNAs in the presence of iron chelator. Iron chelator plus eribulin inhibited tumor growth in vivo to a greater extent than did either inhibitor alone.. Although iron chelator induces oncogenic events (hypoxia, angiogenesis, EMT, and immune checkpoints), it may be an effective treatment for breast cancer when administered in combination with eribulin.

Topics: Animals; Antigens, CD; B7-H1 Antigen; Cadherins; Cell Cycle; Cell Line, Tumor; Deferasirox; Deferoxamine; Epithelial-Mesenchymal Transition; Female; Furans; Humans; Iron; Iron Chelating Agents; Iron Deficiencies; Ketones; Mice; Mice, Inbred BALB C; Mice, Nude; RNA, Messenger; RNA, Neoplasm; Triple Negative Breast Neoplasms; Tubulin Modulators; Tumor Microenvironment; Xenograft Model Antitumor Assays

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Line, Tumor; Cell Survival; Everolimus; Female; Furans; Humans; Ketones; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms

Eribulin mesylate (eribulin) is currently used for the treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress the epithelial-mesenchymal transition (EMT) of cancer cells and promote tumor vascular remodeling. In this study, we investigated the expression of markers for EMT and hypoxia in sets of clinical specimens collected before and after eribulin treatment to verify its unique mechanisms.. The expression of markers for EMT and cellular hypoxia [E-cadherin, N-cadherin, vimentin, and carbonic anhydrase 9 (CA9)] was examined immunohistochemically in MBC tissues collected from 20 patients before and after chemotherapy with either eribulin (n=10) or paclitaxel (n=10).. An increase of E-cadherin and decrease of CA9 expression were observed in MBC tissues from patients with objective clinical responses to eribulin treatment. Patients with E-cadherin-positive conversion and CA9-negative conversion had significantly higher response rates (p=0.004 and p=0.024, respectively) and prolonged time to treatment failure (p=0.018 and p=0.038, respectively) than patients without changes in marker expression.. Expression of EMT and hypoxia markers in clinical samples from patients with MBC was suppressed by eribulin treatment. The results provide additional clinical data on improved survival of patients treated with eribulin and the mechanism of response.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Biomarkers, Tumor; Cadherins; Carbonic Anhydrase IX; Cell Hypoxia; Epithelial-Mesenchymal Transition; Female; Furans; Humans; Ketones; Middle Aged; Paclitaxel; Retrospective Studies; Triple Negative Breast Neoplasms; Vascular Remodeling; Vimentin

Triple-negative breast cancers are defined as tumors negative for estrogen receptors, progesterone receptors and human EGFR2. These tumors exhibit diverse biological behavior and have a poor prognosis; chemotherapy is the mainstay of treatment. The first case involves a young woman with cerebral and cerebellar metastases who achieved a persistent objective response to fourth-line eribulin. In the second case, a woman who became metastatic during adjuvant therapy with anthracyclines and taxanes, and was refractory to capecitabine + bevacizumab, achieved a partial response and local symptom improvement with eribulin + bevacizumab. Last, a poly-treated patient demonstrated reasonable response and longer progression-free interval on third-line eribulin relative to previous lines of chemotherapy which is unusual in this clinical setting.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Ductal, Breast; Female; Furans; Humans; Ketones; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC.. We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses.. The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone.. We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

Topics: Apoptosis; bcl-X Protein; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Furans; Histone Deacetylase Inhibitors; Humans; Ketones; Mitogen-Activated Protein Kinases; Peptides, Cyclic; Signal Transduction; Survivin; Triple Negative Breast Neoplasms

We report the case of a 50-year-old woman with a triple-negative Ki67 80% breast cancer with liver metastases, who obtained a radiological long-lasting complete response after treatment with eribulin. The patient initially experienced progressive disease after a standard anthracycline/taxane-based adjuvant chemotherapy, a first-line treatment for metastatic disease with paclitaxel-bevacizumab, and a second-line maintenance treatment with bevacizumab and capecitabine. Eribulin was administered according to a 1.23 mg/m2 scheme on days 1 and 8 every 3 weeks, and the treatment was always well tolerated. After 45 cycles of therapy, we still detected radiological evidence of complete response on liver sites of disease. This case report underlines the great efficacy of eribulin as third-line treatment for metastatic disease in a very aggressive form of breast cancer.

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Female; Furans; Humans; Ketones; Liver; Liver Neoplasms; Middle Aged; Triple Negative Breast Neoplasms

Real-world data are critical to demonstrate the consistency of evidence and external generalizability of randomized controlled trials (RCTs). This study examined characteristics and outcomes of metastatic triple-negative breast cancer (mTNBC) patients treated with eribulin mesylate at community oncology practices in the United States.. Physicians identified mTNBC patients initiating eribulin between 1 January 2011 and 1 January 2014 and abstracted data into an electronic case report form (eCRF). Eribulin treatment in the metastatic setting was categorized as early use (EU, first-/second-line) and late use (LU, third-line or later). Patient characteristics, overall survival (OS), disease response (per treating physician), and adverse events (AEs) rates in each group, respectively, are reported.. Overall 252 eCRFs were completed: 125 (49.6%) EU and 127 (50.4%) LU. The median age at metastatic diagnosis was 53 years and 42.1% were stage IV at their initial diagnosis. The median duration of follow-up from the initiation of first-line treatment was 24 months. Rates of disease response (complete or partial per treating physician) were 69.9% in the EU group and 48.8% in the LU group. The five most commonly reported adverse events during eribulin were as follows: fatigue (65.1%), weakness (40.1%), decreased appetite (32.5%), neutropenia (31.0%), and leukopenia (27.4%). Discontinuation of eribulin due to AE was observed in 4.0% of patients. Median OS from initiation of eribulin was 23.0 months (95% CI: 18.7-27.3) among EU and 14.7 (95% CI: 12.6-16.9) among LU.. In the real-world eribulin-treated mTNBC, patients have more sites of metastatic disease and exposure to greater numbers of prior therapies compared to RCTs. The median OS of 14.7 months among LU patients is consistent with, and slightly longer than the 13.1 months and 14.4 months reported in the EMBRACE and Study 301 clinical trials, respectively.

Topics: Adult; Aged; Antineoplastic Agents; Female; Furans; Humans; Ketones; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Survival Analysis; Treatment Outcome; Triple Negative Breast Neoplasms; United States

Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo.. Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC. Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Doxorubicin; Female; Furans; Humans; Hydrazines; Ketones; MCF-7 Cells; Mice; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

The recently developed reagent, eribulin mesylate (eribulin), is a microtubule dynamics inhibitor with a mechanism of action that differs from those of taxanes and vinca alkaloids. This drug is considered to be a promising chemotherapeutic agent for the treatment of locally advanced or metastatic breast cancer (MBC). In this study, we investigated if variables such as tumor expression of β-tubulin class III, glutathione S-transferase pi (GSTP) 1 or transducin-like enhancer of split (TLE) 3 might act as predictive factors on the therapeutic effect of eribulin chemotherapy.. The subjects included 52 patients with MBC who underwent chemotherapy with eribulin. The expression levels of Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor (HER) 2, Ki67, β-tubulin class III, GSTP-1 and TLE-3 were evaluated using immunostaining employing needle biopsy specimens.. Patients with TLE3-negative tumors displayed significantly poorer outcomes regarding progression-free survival than patients with TLE3-positive tumors when prognosis within the group of patients with triple-negative breast cancer (TNBC) lesions was analyzed (p = 0.011, log-rank). In contrast, no such difference in prognosis was found in a comparison of TLE-3 positive/negative patients in the group of all patients (p = 0.433, log-rank) or of patients with non-TNBC lesions (p = 0.659, log-rank). Based on a univariate analysis of 22 TNBC cases, a better progression-free survival correlated significantly with a positive TLE3 expression in the tumor (p = 0.025). A multivariate logistic regression analysis including 22 patients with TNBC also showed that a positive TLE3 expression significantly correlated with a better progression-free survival (p = 0.037).. Our findings suggest that TLE3 is a useful marker for predicting the therapeutic effect of eribulin chemotherapy for TNBC.

Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Co-Repressor Proteins; Disease-Free Survival; Female; Furans; Gene Expression Regulation, Neoplastic; Glutathione S-Transferase pi; Humans; Ketones; Middle Aged; Triple Negative Breast Neoplasms; Tubulin; Tubulin Modulators

Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker.. TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively.. Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063).. The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Disease Progression; Female; Furans; Humans; Ketones; Lymphocytes, Tumor-Infiltrating; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Treatment Outcome; Triple Negative Breast Neoplasms

Based on data from two multicenter, phase III clinical trials (Studies 301 and 305), eribulin (a microtubule dynamics inhibitor) is indicated in the European Union (EU) for patients with locally advanced or metastatic breast cancer (MBC) after ≥1 prior chemotherapy for advanced disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting. Data from Studies 305 and 301 were pooled to investigate the efficacy of eribulin in various subgroups of patients who matched the EU label, including those with human epidermal growth factor receptor 2 (HER2)-negative and triple-negative disease.. In Study 305 (NCT00388726), patients were randomized 2:1 to eribulin mesylate 1.4 mg/m(2) (equivalent to eribulin 1.23 mg/m(2) [expressed as free base]) intravenously on days 1 and 8 every 21 days] or treatment of physician's choice after 2-5 prior chemotherapies (≥2 for advanced disease), including an anthracycline and a taxane (in early/advanced setting). In Study 301 (NCT00337103), patients were randomized 1:1 to eribulin (as above) or capecitabine (1.25 g/m(2) orally twice daily on days 1-14 every 21 days) following ≤3 prior chemotherapies (≤2 for advanced disease), including an anthracycline and a taxane. Efficacy end points were investigated in the intent-to-treat population and subgroups, pooled as discussed above.. Overall, 1644 patients were included (eribulin: 946; control: 698); baseline characteristics were well matched. Overall survival was significantly longer with eribulin versus control (P < 0.01), as were progression-free survival and clinical benefit rate (both P < 0.05). Significant survival benefits with eribulin versus control were observed in a wide range of patient subgroups, including HER2-negative or triple-negative disease (all P < 0.05).. Our findings underline the survival benefit achieved by eribulin used according to EU label in the overall MBC population and in various subgroups of interest, including patients with HER2-negative and triple-negative disease.

Topics: Adjuvants, Pharmaceutic; Anthracyclines; Antineoplastic Agents; Bridged-Ring Compounds; Clinical Trials, Phase III as Topic; Disease-Free Survival; Female; Furans; Humans; Ketones; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids; Triple Negative Breast Neoplasms

Diagnosis of triple-negative breast cancer (TNBC) is associated with adverse prognosis, particularly in cases of chemotherapy resistance. The goal of this analysis was to compare TNBC vs. non-TNBC cell lines and those of distinct TNBC subtypes with regard to sensitivity to eribulin in vitro.. Breast cancer cell lines were subjected to cell-viability assays, apoptosis analyses, migration and invasion experiments, and quantitative real-time polymerase chain reaction after exposure to eribulin.. Eribulin reduced cell viability in TNBC and non-TNBC cell lines in the sub-nanomolar range. Furthermore, exposure to eribulin induced apoptosis and decreased the rate of migration and invasion. Genes known to induce malignant transformation were differentially expressed after eribulin treatment.. Eribulin had a strong antiproliferative effect on breast cancer cell lines, although we did not observe a significant difference between TNBC and non-TNBC cell lines with regard to sensitivity to eribulin.

Topics: Antimitotic Agents; Cell Line, Tumor; Female; Furans; Humans; Ketones; Triple Negative Breast Neoplasms

There has been considerable progress in the treatment of metastatic breast cancer. However, the identification of optimal cytotoxic agents in patients with triple-negative breast cancer (TNBC) (negative for hormone receptors and human epidermal growth factor receptor 2) remains a therapeutic challenge. We conducted a comparative effectiveness analysis of 4 cytotoxic agents in patients with TNBC.. We retrospectively identified patients who received single-agent chemotherapy with eribulin, capecitabine, gemcitabine, or vinorelbine from 19 community oncology clinics across the United States. Data collection included baseline patient and disease characteristics, prior therapies, performance status, duration of current therapy, growth-factor use and other supportive care, and dose-limiting toxicities and associated dose reductions or delays or skipped doses. Time to treatment failure (TTF) was measured from the first cycle of chemotherapy until disease progression, discontinuation due to toxicity, or death. TTF was estimated using the Kaplan-Meier method and Cox proportional hazards modeling adjusted for clustering on the practice site. To control for selection bias, which is inherent in observational studies, a propensity score-weighted TTF analysis was also conducted.. Data from 225 patients were included in the analysis (eribulin, 47 patients; capecitabine, 69; gemcitabine, 56; and vinorelbine, 53). The median age of each group was <60 years, with the exception of the gemcitabine group (63 years). The 4 groups were comparable with respect to age, performance status, duration of disease-free survival, presence of comorbidities, and hemoglobin level before the start of chemotherapy. Median lines of therapy of eribulin, capecitabine, gemcitabine, and vinorelbine and were 4th, 2nd, 3rd, and 3rd, respectively. The median durations of treatment were ~2 months with eribulin, capecitabine, and gemcitabine compared with 1.6 months with vinorelbine. Using eribulin as the reference drug, and with adjustment for line of therapy and associated prognostic factors, the propensity score-weighted Cox regression analysis did not identify significant between-treatment differences in TTF (hazard ratios [95% CI] vs eribulin: capecitabine, 1.15 [0.75-1.76]; gemcitabine, 0.62 [0.34-1.13]; and vinorelbine, 1.0 [0.67-1.67]).. In this assessment of patients with TNBC treated in a community oncology setting, eribulin was utilized in later lines compared with the other agents. However, comparable drug activity was reported among the 4 agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Capecitabine; Cytotoxins; Deoxycytidine; Disease-Free Survival; Female; Furans; Gemcitabine; Humans; Ketones; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms; Vinblastine; Vinorelbine

The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biomimetic Materials; Cell Line, Tumor; Cell Movement; Cell Survival; Chemokine CXCL12; Epitopes; Furans; Humans; Ketones; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Neoplasm Metastasis; Protein Binding; Proteins; Receptors, CXCR4; Signal Transduction; Survival Analysis; Triple Negative Breast Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated.. Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER-)/progesterone receptor (PR-)/human epithelial growth receptor 2 (HER2-) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting.. Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model.. Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Epithelial-Mesenchymal Transition; Female; Furans; Gene Expression; Humans; Ketones; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Phenotype; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

The patient was a 40-year-old woman who was aware of a tumor in her left breast that was gradually increasing in size. Ultrasonography revealed a hypoechoic mass with a skin cyst, approximately 3 cm in size, in the C area of the left breast. Core needle biopsy indicated estrogen receptor (ER) -negative, progesterone receptor (PR) -negative, and human epidermal growth factor receptor 2 (HER2) -negative squamous cell carcinoma. Overall examination did not indicate distant metastasis. A diagnosis of T4bN2aM0, stage IIIB triple-negative left breast cancer was made. Eribulin was administered at a dose of 1.4 mg/m2. The effect of eribulin was considered to be long-term stable disease( long-term SD). The patient did not experience severe adverse events during treatment. After 24 weeks of eribulin treatment, mastectomy of the left breast with axillary lymph node dissection was performed. At present, 1 year after surgery, the patient is alive with no recurrence. We conclude that eribulin chemotherapy is useful for the treatment of patients with squamous cell carcinoma of the breast.

Topics: Adult; Biopsy, Large-Core Needle; Carcinoma, Squamous Cell; Combined Modality Therapy; Furans; Humans; Ketones; Neoplasm Staging; Triple Negative Breast Neoplasms