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BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

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Listed:
  • Hazem El-Osta
  • Gerald Falchook
  • Apostolia Tsimberidou
  • David Hong
  • Aung Naing
  • Kevin Kim
  • Sijin Wen
  • Filip Janku
  • Razelle Kurzrock

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.

Suggested Citation

  • Hazem El-Osta & Gerald Falchook & Apostolia Tsimberidou & David Hong & Aung Naing & Kevin Kim & Sijin Wen & Filip Janku & Razelle Kurzrock, 2011. "BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes," PLOS ONE, Public Library of Science, vol. 6(10), pages 1-13, October.
    • Handle: RePEc:plo:pone00:0025806
    DOI: 10.1371/journal.pone.0025806
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    1. Helen Davies & Graham R. Bignell & Charles Cox & Philip Stephens & Sarah Edkins & Sheila Clegg & Jon Teague & Hayley Woffendin & Mathew J. Garnett & William Bottomley & Neil Davis & Ed Dicks & Rebecca, 2002. "Mutations of the BRAF gene in human cancer," Nature, Nature, vol. 417(6892), pages 949-954, June.
    2. Christopher Greenman & Philip Stephens & Raffaella Smith & Gillian L. Dalgliesh & Christopher Hunter & Graham Bignell & Helen Davies & Jon Teague & Adam Butler & Claire Stevens & Sarah Edkins & Sarah , 2007. "Patterns of somatic mutation in human cancer genomes," Nature, Nature, vol. 446(7132), pages 153-158, March.
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