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. 2011;6(10):e25806.
doi: 10.1371/journal.pone.0025806. Epub 2011 Oct 19.

BRAF mutations in advanced cancers: clinical characteristics and outcomes

Hazem El-Osta  1 , Gerald Falchook, Apostolia Tsimberidou, David Hong, Aung Naing, Kevin Kim, Sijin Wen, Filip Janku, Razelle Kurzrock
Affiliations

BRAF mutations in advanced cancers: clinical characteristics and outcomes

Hazem El-Osta et al. PLoS One. 2011.

Abstract

Background: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.

Methods: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome.

Results: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients.

Conclusions: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

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Conflict of interest statement

Competing Interests: Dr Razelle Kurzrock received commercial research grants from GlaxoSmithKline, AstraZeneca, Genentech and Bayer. Dr Gerald Falchook received commercial research grant from GlaxoSmithKline. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Kaplan Meier curve showing progression-free survival on best standard systemic treatment comparing patients with mutBRAF vs. wtBRAF metastatic colorectal cancer.
(One patient with inadequate records on prior treatment was excluded).
Figure 2
Figure 2. Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with BRAF mutation who showed any decrease vs. no decrease in size of target lesions on phase 1 trial.
(Patients who did not have tumor measurements at the time of last follow-up (N = 9) or patients who were not enrolled in a phase 1 trial after referral (N = 13) were excluded).
Figure 3
Figure 3. Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with mutBRAF treated with RAF/MEK targeting agents or other phase 1 trials.
Tic marks represent patients still alive at the last follow-up. (Of 80 patients with BRAF mutations, 56 received a RAF/MEK targeting agents, 11 received a non RAF/MEK targeting agents and 13 were not enrolled on a phase 1 trial).
Figure 4
Figure 4. Forest plot summarizing the clinical factors affecting overall survival after referral and displaying their hazard ratio and 95% Confidence interval calculated by Cox proportional hazards regression model in patients with mutBRAF advanced cancer.
Figure 5
Figure 5. Forest plot summarizing the clinical factors affecting overall survival after referral and displaying their hazard ratio and 95% Confidence interval calculated by Cox proportional hazards regression model in patients with wtBRAF advanced cancer.
Figure 6
Figure 6. Kaplan Meier estimate of overall survival from time of diagnosis comparing patients with melanoma with V600K BRAF mutation vs. other BRAF mutations.
Tic marks represent patients who were alive and censored at time of last follow up. (One patient for whom the time of diagnosis was unknown was excluded.)
See this image and copyright information in PMC

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