levoleucovorin and Microsatellite-Instability

To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.. ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.. Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.. Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Oxaliplatin

The MSI phenotype in colon cancer is a good prognostic factor, with an impact probably more pronounced for stage II than stage III tumor. This survival advantage may be related to the tumor-infiltrating lymphocytes observed in MSI tumors, thus explaining the existence of a probably more effective anti-tumor immune response. In addition, the MSI status would also be a biomarker able to predict the lack of efficacy of adjuvant 5-fluorouracil (5FU) chemotherapy. In contrast, as observed in MSS colon cancer, the MSI tumors would have a survival benefit with the addition of oxaliplatin to adjuvant 5FU chemotherapy. Based on these data, the "French National Thesaurus of Digestive Oncology" suggests for patients with MSI colon cancer, an adjuvant chemotherapy combining fluoropyrimidine and oxaliplatin for stage III, and surgery alone without adjuvant chemotherapy for stage II (excepted for pT4b tumors in which the combination of fluoropyrimidine and oxaliplatin may be a therapeutic option). Beyond these recommendations, the discussion of adjuvant treatment in MSI tumors should also include other factors such as the patient's age and comorbidities. The duration of the adjuvant treatment (3 or 6 months) and the regimen used (FOLFOX or XELOX) should be based on the recommendations of the international IDEA consortium pending the results of the translational studies of this trial. Finally, the promising results of immunotherapy in metastatic MSI colorectal led to the development of clinical trials evaluating "immune checkpoint blockers" in combination with FOLFOX in the treatment of stage III MSI colon cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Immunotherapy; Leucovorin; Lymphocytes, Tumor-Infiltrating; Microsatellite Instability; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Phenotype; Prognosis; Pyrimidines

Pancreatic cancer is typically diagnosed in the late stage of the disease, making it the fourth leading cause of cancer-related death in the United States. It is also one of the few cancers with an increasing incidence, particularly in the younger population. By 2030, it is expected to become the second leading cause of cancer-related death. Patients with pancreatic cancer encounter monthly medical costs 15 times higher than those without, with costs highest in the later stages of the disease. Treatments for pancreatic cancer include surgery (available to fewer than 20% of newly diagnosed patients) and, for advanced disease, chemotherapy with gemcitabine with nab-paclitaxel or FOLFIRINOX, which can increase overall survival (OS) by a few months. Economic and outcome analyses of clinical data find no significant difference in OS between the 2 regimens, although FOLFIRINOX carries a much higher rate of serious adverse effects, limiting its use to patients with good performance status. In 2017, the FDA approved immunotherapy for patients with microsatellite instability-high or mismatch repair-deficient solid tumors, which occurs in approximately 1% of pancreatic cancer diagnoses. Several immunotherapies and targeted therapies are currently in clinical trials and may significantly alter the trajectory of the disease. However, they typically cost more than $100,000 per year, putting significant strain on payers. Thus, it is important that payers plan now for the potential arsenal of new treatments and identify opportunities to manage their utilization as well as patients with the disease to contain costs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cost Control; Cost-Benefit Analysis; Deoxycytidine; Early Detection of Cancer; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Microsatellite Instability; Oxaliplatin; Pancreatic Neoplasms; Terminal Care

Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Topics: Albumins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Irinotecan; Leucovorin; Microsatellite Instability; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Multiple primary malignancy is defined as two or more malignancies detected in an individual person. In particular, synchronous quintuple primary malignancy is extremely rare. A 52-year-old male with anal pain and intermittent blood-tinged stool was diagnosed with malignancies in the stomach, jejunum, ascending colon, transverse colon and rectum. He underwent a subtotal gastrectomy, segmental resection of the jejunum and total protocolectomy with end ileostomy. The postoperative pathologic findings were moderate differentiated gastric adenocarcinoma (pT1bN0M0, pStageIA), combined adenocarcinoma and neuroendocrine carcinoma of the jejunum (pT3N0M0, pStageIIA), three mucinous adenocarcinoma of the ascending colon (pT3N0M0, pStageIIA), transverse colon (pT1N0M0, pStageI) and rectum (pT3N1aM0, pStageIIIB). The tumors did not lack MLH-1 and MSH-2 expression, as the markers (bat26, D5S346, bat25, D2S123) suggest MSI-H presence. Adjuvant chemoradiotherapy was started according to regimen, FOLFOX 4 for advanced rectal cancer. Six years post-operation, the patient is currently attending regular follow-ups without recurrence or metastasis.

Topics: Adenocarcinoma, Mucinous; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cancer Pain; Chemoradiotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Endoscopy, Gastrointestinal; Fluorouracil; Gastrectomy; Gastrointestinal Hemorrhage; Humans; Ileostomy; Jejunal Neoplasms; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Rectal Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

Microsatellite instability is the consequence of a deficient mismatch repair system. It has a key role in the diagnostic strategy of Lynch syndrome, where tumours are all characterized by the presence of this phenotype. Microsatellite instability is therefore essential in the selection of colorectal cancer patients in whom a germline analysis of Mismatch Repair genes is possibly indicated. Moreover, microsatellite instability tumours are associated with a good prognosis and a resistance to fluorouracil-based adjuvant chemotherapy, which has a clinical application mainly in stage II colon cancer patients in whom adjuvant chemotherapy has a less beneficial effect than in stage III and outcome in presence of microsatellite instability is excellent. Recent data suggest that impact of microsatellite instability on benefit to fluorouracil-based adjuvant chemotherapy is dependent of the molecular mechanism involved in this genetic instability since an improved survival has been reported with adjuvant fluorouracil in microsatellite instability colorectal cancers of germline origin but not in sporadic cases. Predictive value of microsatellite instability on response to fluorouracil/oxaliplatin adjuvant chemotherapy has been less evaluated but recent studies suggest that the favorable outcome of Microsatellite instability tumours is maintained in patients receiving FOLFOX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Organoplatinum Compounds; Prognosis; Treatment Outcome

Microsatellite instability (MSI) phenotype occurs in approximately 15 to 24% of colorectal cancer (CRC) patients and may be sporadic or hereditary. It reflects a mutator phenotype in the tumor due to a lack of mismatch repair system. MSI is indeed one of the characteristics of CRCs occurring in Lynch syndrome and some sporadic cases. CRCs with MSI have a better prognosis than CRCs with microsatellite stability (MSS). This is explained partly by a more important anti-tumor immune response and by apoptosis of tumor cells in which mutations accumulate. However, in some retrospective studies, microsatellite instability in stage II CRCs was associated with no benefit to or even a deleterious effect of 5-FU alone based adjuvant therapy. Nevertheless, results obtained in stage III CRCs with FOLFOX type adjuvant chemotherapy remain favorable in retrospective studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Mutation; Neoplasm Staging; Organoplatinum Compounds; Prognosis

Pathological diagnosis is essential today for the individualized therapy of colorectal cancer. In the routine analysis of colorectal carcinomas the molecular-pathological detection of a KRAS mutation predicts unresponsiveness to EGFR-targeted antibody therapies. Moreover, the detection of mismatch-repair deficiency or high-degree microsatellite instability indicates unresponsiveness to 5-FU monotherapy. Colorectal carcinomas with high-grade microsatellite instability and their associated morphologic subtypes, such as the medullary carcinoma, exhibit a low risk of distant metastasis and might be considered as carcinomas with low need for adjuvant chemotherapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; DNA Mismatch Repair; DNA Mutational Analysis; Drug Resistance, Neoplasm; ErbB Receptors; Fluorouracil; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Microsatellite Instability; Nerve Tissue Proteins; Organoplatinum Compounds; Panitumumab; Pharmacogenetics; Practice Guidelines as Topic; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; RNA-Binding Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Chromosomal Instability; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Prognosis; Rectal Neoplasms; Risk Factors

This study aimed to investigate the effect of the mFOLFOX6 regimen combined with SHR-1210 on immune function and prognosis in patients with microsatellite instability CRC. For this purpose, 60 patients with microsatellite instability CRC in our hospital from January 2019 to October 2020 were randomly divided into control and observation groups. The control group was treated with the mFOLFOX6 regimen, and the observation group was treated with s SHR-1210. After continuous treatment for 3 months, the clinical effects of the two groups were compared; CD4+, CD8+, CD4+/CD8+; IgA, IgG, IgM; Incidence of adverse reactions and PFS. The results showed that compared with the control group (30.00%), the total clinical effective rate in the observation group (53.33%) was significantly higher (P < 0.05). After treatment, CD4+, CD4+/ CD8+ decreased significantly and CD8+ increased significantly, and the change range of the observation group was significantly less than the control group (P < 0.05. The levels of IgA, IgG and IgM in the two groups decreased significantly after treatment, and the decrease in the observation group was significantly less than the control group (P < 0.05). There was no significant difference in the incidence of abnormal liver function, bleeding, proteinuria, neurotoxicity, gastrointestinal reaction, leucopenia and hypertension between the two groups (P > 0.05). PFS in the observation group was significantly prolonged after treatment (P < 0.05). In general, the mFOLFOX6 regimen combined with SHR-1210 is effective in the treatment of microsatellite instability CRC. It can not only improve the immune function, but also not increase adverse reactions, prolong the survival time, and has a high clinical reference value.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Leucovorin; Microsatellite Instability; Organoplatinum Compounds

Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population.. A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients.. Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels.. In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors.. VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Bone Neoplasms; Camptothecin; Cell Count; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Prognosis; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; ras Proteins; Risk Assessment; Young Adult

Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation.. AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee.. The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status.. AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017-000977-35), Februray 28th, 2017.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Italy; Leucovorin; Microsatellite Instability; Organoplatinum Compounds; Prospective Studies

Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association.. Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence.. Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence.. In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.. NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome; Young Adult

The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials.. Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors.. Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P < .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients.. In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Rate; Time Factors; Young Adult

Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI.. Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS).. In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14).. Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT00026273.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Microsatellite Repeats; Neoplasm Recurrence, Local

The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC).. Patients were assigned to oxaliplatin, leucovorin and 5-FU for 12 cycles (group A, FOLFOX6) or oxaliplatin and capecitabine for eight cycles (group B, CAPOX). Primary endpoint was disease-free survival (DFS). Tumors were classified as mismatch repair proficient (pMMR) or deficient (dMMR) according to MLH1, PMS2, MSH2 and MSH6 protein expression. KRAS exon two and BRAF V600E mutational status were also assessed.. Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5-83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9-83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4-89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one-two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions.. No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size.. ANZCTR 12610000509066 . Date of Registration: June 21, 2010.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer.. We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided.. Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16).. Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Class I Phosphatidylinositol 3-Kinases; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Phosphatidylinositol 3-Kinases; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

High-level microsatellite instability (MSI-H) has been reported as a prognostic marker in colon cancer. We here analysed the prognostic significance of MSI and mutations of the Beta2-Microglobulin (B2M) gene, which occur in about 30% of MSI-H colon cancer, in the cohort of the prospective FOGT-4 (Forschungsruppe Onkologie Gastrointestinale Tumoren, FOGT) trial.. Microsatellite instability status was determined using standard protocols (NCI/ICG-HNPCC panel and CAT25) in 223 colon cancer lesions. Beta2-Microglobulin mutation status was evaluated by exon-wise sequencing in all MSI-H lesions.. Patients with MSI-H (n=34) colon cancer presented with a significantly lower risk of relapse after 12 months of follow-up compared with MSS (n=189) colon cancer patients (5 year time to relapse: MSI-H 0.82 vs MSS 0.66, P=0.03). No significant difference in overall survival was detected. Beta2-Microglobulin mutations were identified in 10 (29.4%) out of 34 MSI-H colon cancers and were associated with a complete absence of disease relapse or tumour-related death events (P=0.09).. The risk of late disease relapse was significantly lower in patients with MSI-H compared with MSS colon cancer. Moreover, B2M mutations may contribute to the favourable outcome of MSI-H colon cancer patients and should therefore be evaluated as a potential prognostic marker in future clinical trials.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; Prospective Studies; Treatment Outcome

The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.. Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.. MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.. Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Chemotherapy, Adjuvant; Chromosomes, Human, Pair 18; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Immunohistochemistry; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Loss of Heterozygosity; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Research Design; Smad4 Protein

Colorectal cancer (CRC) patients whose tumours have microsatellite instability (MSI) do not benefit from adjuvant 5-fluorouracil. However, the predictive value of MSI is not known for FOLFOX, now recommended in adjuvant setting.. MSI phenotype was assessed by the pentaplex method. Three-year relapse and disease-free survival (DFS) of patients treated for CRC with FOLFOX 4 in an adjuvant setting were compared according to MSI phenotype.. A total of 105 patients (19 MSI, 86 microsatellite stable, MSS) were included. Stage II patients more frequently exhibited MSI (58%) than MSS (21%); (p=0.002). Patients with MSI relapsed significantly less than those with MSS (10.5% vs. 35.0%; p=0.04). DFS was similar for MSI and MSS (p=0.1). In univariate analysis, stage (p=0.0006) and MSI status (p=0.017) were significant predictors of DFS.. MSI status was associated with significantly fewer relapses and a better prognosis. FOLFOX4 did not alter survival of patients with MSI and can be administered to them.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds

Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) -based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.. Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.. Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).. Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Survival Analysis; Young Adult

Although several clinical factors which show the benefit of adjuvant chemotherapy (AC) in early-stage colon cancer use for evaluating the risk of relapse, there is no consensus on which risk factors are more reliable. In this study, we evaluated both the utility of MSI and the daily practice of the Turkish oncologists in stage II and III colon cancer.. We conducted an online questionnaire which was consisting of twenty questions including the treatment choices and duration about stage II-III colon cancer depending on sidedness and risk factors for relapse.. More than 65% of the oncologists declared the use of MSI testing in stage II colon cancer without considering any risk factors. In stage 3 colon cancer oncologists had an equal decision "to do or not to do" in MSI testing. More than 50% of the oncologists had preferred XELOX protocol in high-risk stage II (T4N0) colon cancer, while three out of four preferred observation in low-risk stage II (T3N0) patients without risk factors. Two-thirds of the oncologists had preferred 6 months of treatment in stage II colon cancer with at least one risk factor.. Turkish oncologists participating to this trial had declared conflicting results about adjuvant treatment in early-stage colorectal cancer in their daily practice compared with the updated guidelines, especially, MSI evaluation utility in stage III colon cancers, adjuvant chemotherapy (AC) duration, and oxaliplatin adding to AC in elderly and stage II patients.

Topics: Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Neoplasm Recurrence, Local; Neoplasm Staging; Oncologists

The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.. Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.. DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biological Assay; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; DNA Damage; DNA Mutational Analysis; Female; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoadjuvant Therapy; Organoplatinum Compounds; Progression-Free Survival; Randomized Controlled Trials as Topic

BACKGROUNDImmune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODSA database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTSNine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSIONA small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATIONClinicalTrials.gov, NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Databases, Genetic; DNA Helicases; DNA-Binding Proteins; Female; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Male; Microsatellite Instability; Middle Aged; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Retreatment; SMARCB1 Protein; Survival Rate; Transcription Factors

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease Progression; DNA Mismatch Repair; Drug Resistance, Neoplasm; Female; Fluorouracil; Hepatectomy; Humans; Immune Checkpoint Inhibitors; Leucovorin; Liver Neoplasms; Microsatellite Instability; Neoadjuvant Therapy; Nivolumab; Organoplatinum Compounds; Treatment Outcome

Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) show a significant response to checkpoint inhibitor therapies, but the economic impact of these therapies is unknown. A decision analytic model was used to explore the effectiveness and cost burden of MSI-H/dMMR mCRC treatment.. The treatment of hypothetical patients with MSI-H/dMMR mCRC was simulated in 2 treatment scenarios: a third-line treatment and an exploratory first-line treatment. The treatments compared were nivolumab, ipilimumab and nivolumab, trifluridine and tipiracil (third-line treatment), and mFOLFOX6 and cetuximab (first-line treatment). Disease progression, drug toxicity, and survival rates were based on the CheckMate 142, study of TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies (RECOURSE), and Cancer and Leukemia Group B/Southwest Oncology Group 80405 trials. The analyzed outcomes included survival (life-years), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).. Ipilimumab with nivolumab was the most effective strategy (10.69 life-years and 9.25 QALYs for the third line; 10.69 life-years and 9.44 QALYs for the first line) in comparison with nivolumab (8.21 life-years and 6.76 QALYs for the third line; 8.21 life-years and 7.00 QALYs for the first line), trifluridine and tipiracil (0.74 life-years and 0.07 QALYs), and mFOLFOX6 and cetuximab (2.72 life-years and 1.63 QALYs). However, neither checkpoint inhibitor therapy was cost-effective in comparison with trifluridine and tipiracil (nivolumab ICER, $153,000; ipilimumab and nivolumab ICER, $162,700) or mFOLFOX6 and cetuximab (nivolumab ICER, $150,700; ipilimumab and nivolumab ICER, $158,700).. This modeling analysis found that both single and dual checkpoint blockade could be significantly more effective for MSI-H/dMMR mCRC than chemotherapy, but they were not cost-effective, largely because of drug costs. Decreases in drug pricing and/or the duration of maintenance nivolumab could make ipilimumab and nivolumab cost-effective. Prospective clinical trials should be performed to explore the optimal duration of maintenance nivolumab.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cost-Benefit Analysis; DNA Mismatch Repair; Drug Costs; Female; Fluorouracil; Humans; Ipilimumab; Leucovorin; Male; Microsatellite Instability; Middle Aged; Nivolumab; Organoplatinum Compounds; Quality-Adjusted Life Years

We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC).. We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression.. The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60-4.60, P < 0.001) and poor 5-year cancer-specific survival (HR: 2.90, 95% CI = 1.28-6.57, P = 0.011).. p53-mild expression status was found to be an independent prognostic marker in adjuvant FOLFOX-treated patients with stage III and high-risk stage II CRC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Progression-Free Survival; Tumor Suppressor Protein p53; Young Adult

Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR.. Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-β, and PI3K).. Mutation of genes within the WNT, P53, RTK-RAS, TGF-β, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-β pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-β pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-β pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-β pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation.. Mutation in genes within TGF-β pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Capecitabine; Chemotherapy, Adjuvant; Colon; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaloacetates; Palliative Care; Prognosis; Rectum; Signal Transduction; Survival Analysis; Transforming Growth Factor beta

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Capecitabine; Chemoradiotherapy, Adjuvant; Cholangiocarcinoma; DNA Mutational Analysis; Drug Resistance, Neoplasm; Fluorouracil; Humans; Inguinal Canal; Leucovorin; Liver; Liver Neoplasms; Lymphatic Metastasis; Male; Microsatellite Instability; Neoplasm, Residual; Nivolumab; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Programmed Cell Death 1 Receptor; Treatment Outcome

Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic features. However, the prognostic impact of the hypermutated tumors is not clearly established.. We analyzed tumor mutation burden (TMB) from targeted next-generation sequencing data of 40 major genes in 516 patients with colorectal cancer. TMB was defined as total number of nonsynonymous mutations per tumor. Cutoff value for TMB-high was chosen by which best discriminated relapse-free survival (RFS) using the Contal and O'Quigley method.. In the TCGA data, mutation count of the selected 40 genes reflected the whole exome mutation burden (Pearson correlation = 0.873,. TMB-high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Capecitabine; Chemotherapy, Adjuvant; Colon; Colorectal Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Female; Fluorouracil; High-Throughput Nucleotide Sequencing; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Prognosis; Rectum; Retrospective Studies

Results from the pivotal IDEA trial, which evaluated 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy, are incorporated into the NCCN Guidelines for Colon Cancer. The guidelines recommend that for patients with low-risk stage III disease, the preferred regimen is CAPEOX for 3 months or FOLFOX for 3 to 6 months. For patients with high-risk stage III disease, the preferred regimen is CAPEOX for 3 to 6 months or FOLFOX for 6 months. In metastatic disease, tumor sidedness should be a consideration when choosing a biologic. For

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Fluorouracil; Humans; Leucovorin; Medical Oncology; Microsatellite Instability; Mutation; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Practice Guidelines as Topic; Proctectomy; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Societies, Medical; United States

Patients with MSI colorectal tumor have good prognosis and cannot benefit from 5-fluorouracil (5-Fu)-based chemotherapy reported by previous studies. While, single nucleotide polymorphisms (SNP) of ERCC1 and XRCC1 have be proved to influence clinical outcome of colorectal cancer patients treated with oxaliplatin-based chemotherapy. We aim to study the correlation between molecular status and clinical- pathological features, and their effect on CRC patients' clinical outcome treated with mFOLFOX6 adjuvant chemotherapy. In this study, MSI status was determined in tumors and paired normal tissues from 101 colorectal cancer (CRC) patients. We also examined SNP of ERCC1 (c. C354T) and XRCC1 (c.G1196A) in 83 and 85 patients' blood. MSI was found to be significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). CEA and CA19-9 levels was positive correlated significantly by Spearman correlation analysis (Pearson's r = 0.823, p < 0.0001). No significant correlation was found between MSI status and ERCC1/XRCC1 polymorphisms. We found greater drop of CEA level in mFOLFOX6 sensitive group than low sensitive group after mFOLFOX6 adjuvant chemotherapy according to MSI status, ERCC1 and XRCC1 SNP. MSI was significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). The MSI status, ERCC1 and XRCC1 polymorphisms may influence the clinical outcome of colorectal cancer patients treated with mFOLFOX6 adjuvant chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Prognosis; X-ray Repair Cross Complementing Protein 1

The impact of microsatellite instability (MSI) on survival in stage III colon cancer treated with adjuvant 5-fluorouracil-oxaliplatin combination (FOLFOX) chemotherapy is not clear. We evaluated the association between MSI and survival in this population.. We analyzed 598 patients with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification; tumors were classified as high MSI (MSI-H, ≥2 unstable markers), low MSI (MSI-L, 1 unstable marker), or microsatellite stable (MSS, no unstable marker).. Of 598 patients, 8.4% showed MSI-H. Tumors classified as MSI-H were more commonly located in the ascending colon (54.0 vs. 27.7%, p < 0.0001) and had poorly differentiated features (32.0 vs. 8.0%, p < 0.0001). After the median follow-up of 52.8 months, 5-year disease-free (DFS) and overall survival (OS) rates were 77.0 and 85.9%, respectively. In univariate analysis, pathologic T4 (pT4) and pathologic N2 (pN2) was associated with reduced DFS (p < 0.0001 and p < 0.0001, respectively) and OS (p = 0.002 and p = 0.001, respectively), whereas MSI status did not affect either DFS (p = 0.114) or OS (p = 0.525). In patients with pN2 tumors; however, MSI-H was associated with better survival compared with MSS/MSI-L; DFS and OS in patients with MSI-H/pN2 were comparable to those in patients with pN1 tumors.. In patients with stage III colon cancer treated with adjuvant FOLFOX, pT4 and pN2 was associated with reduced survival, but MSI status alone did not affect survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colon, Ascending; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Microsatellite Instability; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Tumor Burden; Young Adult

In patients with colorectal cancer (CRC), the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival. However, the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial. Therefore, we reviewed various clinicopathological features, including BRAF status, in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors, including overall survival. Similar to previous studies conducted in Eastern countries, the incidence of the BRAF V600E mutation in the current study was relatively low (5.7%). BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability (MSI) status. This mutation was significantly associated with a proximal tumor location (P = 0.002); mucinous, signet ring cell, and serrated tumor components (P < 0.001, P = 0.003, and P = 0.008, respectively); lymphovascular invasion (P = 0.004); a peritumoral lymphoid reaction (P = 0.009); tumor budding (P = 0.046); and peritoneal seeding (P = 0.012). In conclusion, the incidence of the BRAF V600E mutation was relatively low in this study. BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs, such as a proximal location; mucinous, signet ring cell, and serrated components; and marked peritumoral lymphoid reactions.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Immunochemistry; Kaplan-Meier Estimate; Leucovorin; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Survival Analysis; Tumor Suppressor Protein p53

Testing for mismatch repair (MMR) status in colorectal cancer (CRC) may provide useful prognostic and predictive information. We evaluated the impact of such testing on real-world practice regarding adjuvant chemotherapy for patients with resected CRC.. A total of 175 patients with stage II and III mismatch repair-deficient (MMRD) CRC were identified from an Australian population-based study of incident CRCs. Their treatment decisions were compared with those for a cohort of 773 stage-matched patients with mismatch repair-proficient (MMRP) CRCs. The effect of MMR status, age, and pathologic characteristics on treatment decisions was determined using multiple regression analysis.. Overall, 32% of patients in stage II and 71% of patients in stage III received adjuvant chemotherapy. Among the stage II patients, those with MMRD cancer were less likely to receive chemotherapy than were MMRP cases (15% vs. 38%; p < .0001). In this group, the treatment decision was influenced by age, tumor location, and T stage. MMR status influenced the treatment decision such that its impact diminished with increasing patient age. Among patients with stage III tumors, no difference was found in the chemotherapy rates between the MMRD and MMRP cases. In this group, age was the only significant predictor of the treatment decision.. The findings of this study suggest that knowledge of the MMR status of sporadic CRC influences treatment decisions for stage II patients, in an era when clear recommendations as to how these findings should influence practice are lacking.. Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair found in 15% of sporadic colorectal cancers. Until recently, expert guidelines on the role of MSI as a valid biomarker in the selection of stage II patients for adjuvant chemotherapy were lacking. Conducted at a time when the clinical utility of routine MSI testing was unclear, this study found that clinicians were influenced by MSI status in selecting stage II patients for chemotherapy. Furthermore, the impact of MSI on treatment decisions was greatest in younger patients and declined progressively until age 80 years, when no effect was found.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Regression Analysis

Low methylation status of LINE-1 in tumors is associated with poor survival in patients with colon cancer. Eastern Cooperative Oncology Group performance status (ECOG-PS) is a method to assess the functional status of a patient. We retrospectively evaluated the relationship between ECOG-PS and LINE-1 methylation in colorectal cancers (CRCs) and their prognostic impact in CRC or colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX).. LINE-1 methylation and microsatellite instability were analyzed in stage III or high-risk stage II CRCs (n = 336). LINE-1 methylation levels were correlated with clinicopathological features, including PS and recurrence-free survival (RFS). The association between the tumoral LINE-1 methylation level and PS was observed (OR = 2.56, P < 0.001). Differences in LINE-1 methylation levels in cancer tissue between the PS 0 and 1 groups were significant in patients older than 60 years (P = 0.001), the overweight body mass index group (P = 0.005), and the stage III disease group (P = 0.008). Prognostic significances of LINE-1 methylation status or combined PS and LINE-1 methylation statuses were identified in stage III colon cancers, not in stage III and high-risk stage II CRCs. Low LINE-1 methylation status was closely associated with a shorter RFS time. The difference between PS(0)/LINE-1(high) and PS(≥1)/LINE-1(low) was significant, which suggests that colon cancer patients with concurrent PS(≥1)/LINE-1 (low) have a higher recurrence rate.. PS was associated with LINE-1 methylation in CRC tissue. LINE-1 methylation was associated with RFS in stage III colon cancer patients who were treated with adjuvant FOLFOX chemotherapy. Combined PS and LINE-1 methylation status might serve as a useful predictor of cancer recurrence.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA Methylation; Female; Fluorouracil; Humans; Leucovorin; Long Interspersed Nucleotide Elements; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome

The SCAN colorectal cancer systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for colorectal cancer in Singapore.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Five international guidelines were evaluated-those developed by the National Comprehensive Cancer Network for colon (2014) and rectal (2014) cancer, the European Society of Medical Oncology for advanced (2012) and early (2013) cancer and the National Institute of Clinical Excellence (2011). Recommendations on systemic therapy in colorectal cancer were produced.. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of colorectal cancer.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Metastasectomy; Microsatellite Instability; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Singapore

Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T(17) intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T(17) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin.. We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17).. HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor samples with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009).. About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; HSP110 Heat-Shock Proteins; Humans; Introns; Leucovorin; Male; Microsatellite Instability; Models, Molecular; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Sequence Deletion; Surface Plasmon Resonance; Survival Analysis; Treatment Outcome

Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy.. We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease.. Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437).. Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Analysis; Treatment Outcome

The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer.. This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used.. The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2 %) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9 %; log-rank, P = 0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95 % confidence interval 1.03-3.23, P = 0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P = 0.732).. Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.

Topics: Adenocarcinoma, Mucinous; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Rate; Young Adult

The prognostic impact of CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI status in colorectal cancer patients treated with adjuvant FOLFOX. Stages II and III sporadic colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Eight CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, CDKN2A (p16), RUNX3 and SOCS1) and five microsatellite markers were examined. Disease-free survival (DFS) was analyzed according to CIMP and MSI status. A total of 322 patients were included: male/female 192/130, median age 61 years (range 30-78), proximal/distal location 118/204 and Stages II/III 43/279. CIMP status was high in 25 patients (7.8%) and 21 patients (6.5%) had MSI-high tumor. CIMP/MSI status was not significantly associated with DFS: 3-year DFS 100% in CIMP(-)/MSI(+), 84% in CIMP(-)/MSI(-), 82% in CIMP(+)/MSI(-) and 75% in CIMP(+)/MSI(+) (p = 0.33). Results of exploratory analysis showed that concurrent methylation at NEUROG1 and CDKN2A (p16) was associated with shorter DFS: 3-year DFS 69% in NEUROG1(+)/CDKN2A (p16)(+) versus 87% in NEUROG1(-)/CDKN2A (p16)(-) (p = 0.006). In conclusion, concurrent methylation of NEUROG1 and CDKN2A (p16) is associated with recurrence following adjuvant FOLFOX in Stages II/III colorectal cancer.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; CpG Islands; DNA Methylation; DNA, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Polymerase Chain Reaction; Prognosis; Retrospective Studies; Survival Rate

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA-Binding Proteins; Fluorouracil; Hispanic or Latino; Humans; Leucovorin; Male; Microsatellite Instability; Organoplatinum Compounds; Risk Factors; Treatment Outcome

The aim was to determine the values of p53 tumour expression and microsatellite instability (MSI) phenotype to predict benefit from adjuvant chemotherapy of colon cancer by 5-fluorouracil and leucovorin (FL) alone or with oxaliplatin (FOLFOX).. This retrospective study included 233 unselected patients with stage III colon cancer treated by FL (n = 124) or FOLFOX (n = 109). The impact of p53 expression and MSI on disease-free survival (DFS) was defined using univariate and multivariate analyses. A Cox proportional hazards model was specifically designed to evaluate the interaction between chemotherapy and these genetic alterations.. In univariate analyses, addition of oxaliplatin significantly improved DFS provided that tumour overexpressed p53 [hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.19-0.82; P = 0.01] or displayed MSI phenotype (HR 0.17; 95% CI 0.04-0.68; P = 0.01). In multivariate analyses, p53 was confirmed as an independent factor predictive of benefit from FOLFOX (P = 0.03), while the interaction of MSI with chemotherapy could not be determined in the absence of relapse in the MSI group treated with FOLFOX.. Our observations indicate that MSI status and p53 expression may influence the impact of oxaliplatin on adjuvant treatment of stage III colon cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Tumor Suppressor Protein p53

Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2(null) mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype.. We generated and examined mice with a conditional Msh2 disruption (Msh2(LoxP)), permitting tissue-specific gene inactivation. ECMsh2(LoxP/LoxP) mice carried an EIIa-Cre transgene, and VCMsh2(LoxP/LoxP) mice carried a Villin-Cre transgene. We combined the VCMsh2(LoxP) allele with either Msh2(Delta7null) (VCMsh2(LoxP/null)) or Msh2(G674D) mutations (VCMsh2(LoxP/G674D)) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging.. Embryonic fibroblasts from ECMsh2(LoxP/LoxP) mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2(LoxP/LoxP) mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2(LoxP/LoxP) mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2(LoxP/G674D) but not VCMsh2(LoxP/null) tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2(LoxP/G674D) animals.. Msh2(LoxP/LoxP) mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development.

Topics: Adenocarcinoma; Adenoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Genotype; Immunohistochemistry; Integrases; Intestinal Neoplasms; Leucovorin; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Microsatellite Instability; Mutation; MutS Homolog 2 Protein; Organoplatinum Compounds; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Burden

Colon cancer with DNA mismatch repair (MMR) defects reveals distinct clinical and pathologic features, including a better prognosis but reduced response to 5-fluorouracil (5-FU)-based chemotherapy. A current standard treatment for recurrent or metastatic colon cancer uses capecitabine plus oxaliplatin (CAPOX), or continuous-infusion fluorouracil plus oxaliplatin (FOLFOX). This study investigated the effect of MMR status on the treatment outcomes for CAPOX and FOLFOX as first-line combination chemotherapy in recurrent or metastatic colon cancer. We analyzed 171 patients who had been treated with CAPOX or FOLFOX as first-line combination chemotherapy in recurrent or metastatic colon adenocarcinoma between February 2004 and July 2008. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. The microsatellite instability (MSI) was analyzed by polymerase chain reaction (PCR) amplification, using fluorescent dye-labeled primers specific to microsatellite loci. Tumors with MMR defect were defined as those demonstrating a loss of MMR protein expression (MMR-D) and/or a microsatellite instability-high (MSI-H) genotype. In all, 75 patients (44%) received FOLFOX, and 96 patients (56%) received CAPOX as first-line combination chemotherapy. The incidence of colon cancer with MMR defect was 10/171 (6%). Colon cancers with MMR defect (MSI-H and/or MMR-D) are more commonly located in proximal to the splenic flexure (p=0.03). The MMR status did not significantly influence the overall response (p=0.95) to first-line CAPOX or FOLFOX treatment in patients with recurrent or metastatic colon cancer. According to the MMR status, there was no significant difference for PFS (p=0.50) and OS (p=0.47) in patients with recurrent or metastatic colon cancer treated with first-line CAPOX or FOLFOX. In colon cancers with MMR defect, there was no significant difference for PFS (p=0.48) and OS (p=0.56) between CAPOX and FOLFOX as first-line combination chemotherapy. However, in MMR intact, there was significant difference for OS between CAPOX and FOLFOX (p=0.04). OS was significantly better in patients treated with CAPOX when compared to patients with FOLFOX. The MMR status does not predict the effect of oxaliplatin-based combination chemotherapy as 1st line in recurrent or metastatic colon cancers. CAPOX in the first-line treatment of recurrent or metastatic colon cancer with MMR intacts showed a superior OS c

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; DNA Mismatch Repair; Female; Fluorouracil; Follow-Up Studies; Humans; Immunoenzyme Techniques; Infusions, Intravenous; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Polymerase Chain Reaction; Prognosis; Survival Rate; Young Adult

Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy.. We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy.. There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors.. The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; DNA Mismatch Repair; Female; Fluorouracil; Genetic Markers; Genotype; Humans; Immunohistochemistry; Leucovorin; Male; Microsatellite Instability; Middle Aged; Organoplatinum Compounds; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Tumor Suppressor Protein p53

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Organoplatinum Compounds; Polymerase Chain Reaction

Topics: Adaptor Proteins, Signal Transducing; Adenosine Triphosphatases; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Repair Enzymes; DNA-Binding Proteins; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Nuclear Proteins; Organoplatinum Compounds

The CpG island methylator phenotype (CIMP) is a distinct epigenetic phenotype in colorectal carcinoma with concordant methylation in multiple promoter CpG islands. The relationship between CpG island methylation and clinical outcomes among colorectal cancer patients treated with chemotherapy has been a controversial subject. Utilizing real-time polymerase chain reaction (PCR; MethyLight technology), we quantified DNA methylation in 13 CpG island loci (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, MINT1, MINT31, IGFBP3, MGMT, and WRN) in 30 metastatic microsatellite stable colorectal carcinomas in phase I/II clinical trials of combination chemotherapy (5-fluorouracil, irinotecan, leucovorin, and gefitinib). Tumor response was assessed by CT scans performed at baseline and every 6 weeks thereafter. Overall CIMP-high status (either >or=9/13 or >or=7/13 methylated markers; identifying 3 or 5 CIMP-high tumors, respectively) and methylation in CACNA1G, IGF2, MLH1, NEUROG1, RUNX3, MINT31, and WRN were associated with worse survival (all p < 0.01). Although not statistically significant, there was a trend toward resistance to chemotherapy among tumors with CpG island methylation. In conclusion, CpG island methylation may predict poor survival in metastatic microsatellite stable colorectal carcinoma treated with chemotherapy. Additional studies are necessary to examine the role of DNA methylation in treatment efficacy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; CpG Islands; DNA Methylation; Female; Fluorouracil; Gefitinib; Humans; Irinotecan; Leucovorin; Male; Massachusetts; Microsatellite Instability; Middle Aged; Quinazolines; Survival Rate

Most results from clinical trials of neoadjuvant chemotherapy for gastric carcinoma are certain. Meanwhile, microsatellite instability (MSI) is thought to be a new mechanism of cell canceration. This study was to investigate the influence of neoadjuvant chemotherapy on MSI in gastric carcinoma.. Two microsatellite loci D2S123 and D3S1298 in tumor samples from 48 patients with gastric carcinoma, received preoperative chemotherapy of 5-fluorouracil (5-FU) and leucovorin (CF), were analyzed by polymerase chain reaction (PCR), electrophoresis on 8% denatured polyacrylamide gel, and silver staining. The microsatellite statuses of preoperative and postoperative specimens were compared. Chi-square test was used to analyze the influence of neoadjuvant chemotherapy on MSI in gastric carcinoma.. The detection rate of MSI was significantly higher in preoperative samples than in postoperative samples (31.3% vs. 12.5%, P=0.026). After neoadjuvant chemotherapy, 9 cases changed from MSI-positive to MSI-negative, while no MSI-negative cases became MSI-positive.. The neoadjuvant chemotherapy regimen of 5-FU/CF can induce some MSI-positive gastric carcinoma change to MSI-negative, but has no effect on MSI-negative cases.

Topics: Antineoplastic Combined Chemotherapy Protocols; DNA, Neoplasm; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Microsatellite Repeats; Neoadjuvant Therapy; Stomach Neoplasms