Prognostic Role Of BRAF Mutation Research Articles

Prognostic role of BRAF mutation in malignant cutaneous melanoma.

e21599Background: Prognostic role of BRAF mutation is not well-studied in malignant cutaneous melanoma. We conducted a large retrospective study using a state-wide database to assess the clinical c...

Prognostic Role of BRAF Mutations in Colorectal Cancer Liver Metastases.

The impact of tumor biology on prognosis in patients with colorectal liver metastasis (CRLM) has been the topic of intense research. Specifically, the presence of BRAF mutations has been recently associated with adverse long-term outcomes. We examined the existing literature on the prognostic implications of BRAF mutations in patients with CRLM. A structured review of the literature was performed between 5/1/2016 and 6/1/2016 using the PubMed database. Original research articles published between 1/1/2010 and 4/01/2016 were considered eligible. The primary end-points were overall survival (OS)/disease-specific survival (DSS) and recurrence-free survival (RFS) among patients with BRAF mutated CRLM who underwent resection. Eight studies were included. All studies reported on OS/DSS, while 6 reported on RFS. BRAF mutant status was a strong independent predictor of both worse OS/DSS and RFS in 7 and 4 studies, respectively. BRAF-mutant lesions are consistently associated with poor prognosis. Consequently, the indications of CRLM resection in this patient group should be reconsidered.

Prognostic Role of BRAF Mutation in Stage II/III Colorectal Cancer Receiving Curative Resection and Adjuvant Chemotherapy: A Meta-Analysis Based on Randomized Clinical Trials.

Background and ObjectiveStudies examining the prognostic value of the BRAF mutation on relapse-free survival (RFS), disease-free survival (DFS) and overall survival (OS) in stage II/III colorectal cancer (CRC) patients receiving curative resection and adjuvant chemotherapy so far showed discrepant results. Therefore, a meta-analysis of relevant studies was performed for clarification.MethodsRandomized trials of stage II/III colorectal cancer treated with curative resection followed by adjuvant chemotherapy were selected to conduct a meta-analysis. The necessary descriptive and statistical information such as hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from published survival data.ResultsSeven phase III randomized clinical trials (RCTs) including 1,035 BRAF mutation stage II/III CRC patients receiving curative resection and adjuvant chemotherapy were analyzed. Overall, BRAF mutation resulted in poorer OS (HR = 1.42, 95% CI: 1.25–1.60; P < 0.00001), and poorer DFS (HR = 1.26, 95% CI: 1.07–1.48, P = 0.006) compared with BRAF wild-type CRC. The prognostic role on RFS could not be elucidated in the meta-analysis because of limited data.ConclusionsBRAF mutation was significantly related with shorter DFS and OS among stage II/III CRC patients receiving adjuvant chemotherapy after curative resection. Its prognostic role for RFS needs to be further analyzed when more data is available.

Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research.

This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including "targeted therapy", immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi-institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population.

Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication.

BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.

The Prognostic Role of BRAF Mutation in Metastatic Colorectal Cancer Receiving Anti-EGFR Monoclonal Antibodies: A Meta-Analysis

BackgroundBRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC) undergoing anti-EGFR monoclonal antibodies (moAbs), but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs.MethodsEligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR) for overall response rate (ORR), Hazard ratios (HRs) for Progression free survival (PFS) and Overall survival (OS) were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden’s criteria.ResultsA total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4%) patients with known BRAF status. Patients with BRAF wild-type (WT) showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29–0.51) and an improved OS (HR 0.35 [0.29–0.42]), compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43]) and larger OS benefit (HR 0.26 [0.20,0.35]) in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53]) in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43–1.33]). The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected.ConclusionsThe results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective trials are required to confirm the predictive role of BRAF status.

Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803.

Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Harboring BRAF Mutations

To investigate the prevalence, distribution, and prognostic role of BRAF mutations in a large cohort of white patients with non-small-cell lung cancer (NSCLC). A retrospective series of 1,046 NSCLCs-comprising 739 adenocarcinomas (ADCs) and 307 squamous cell carcinomas (SCCs)-was investigated for BRAF mutations. High-resolution melting analysis followed by sequencing and strip hybridization assay were used. All patients were also analyzed for KRAS and EGFR mutations. BRAF mutations were present in 36 ADCs (4.9%) and one SCC (0.3%; P = .001). Twenty-one of the mutations (56.8%) were V600E, and 16 (43.2%) were non-V600E. V600E mutations were significantly more prevalent in females (16 of 187 patients; 8.6%) than in males (five of 552 patients; 0.9%), as indicated by multivariate logistic regression analysis (hazard ratio [HR], 11.29; P < .001). V600E-mutated tumors showed an aggressive histotype characterized by micropapillary features in 80% of patients and were significantly associated with shorter disease-free and overall survival rates on both univariate (HR, 2.67; P < .001 and HR, 2.97; P < .001, respectively) and multivariate analyses (HR, 2.19; P = .011 and HR, 2.18; P = .014, respectively). All non-V600E mutations were found in smokers (P = .015) and were associated with neither clinicopathologic parameters nor prognosis. BRAF and EGFR were concomitantly mutated in two tumors. We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with NSCLC. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations.