BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes
Open Access
- 19 October 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (10), e25806
- https://doi.org/10.1371/journal.pone.0025806
Abstract
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. 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. 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. 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.Keywords
This publication has 35 references indexed in Scilit:
- Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysisThe Lancet Oncology, 2010
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaThe New England Journal of Medicine, 2010
- Protocol for PTEN Expression by Immunohistochemistry in Formalin-fixed Paraffin-embedded Human Breast CarcinomaApplied Immunohistochemistry & Molecular Morphology, 2010
- BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcomeBritish Journal of Cancer, 2010
- Coexisting NRAS and BRAF Mutations in Primary Familial Melanomas with Specific CDKN2A Germline AlterationsJournal of Investigative Dermatology, 2010
- KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancerBritish Journal of Cancer, 2009
- Patterns of somatic mutation in human cancer genomesNature, 2007
- Gender-Related Differences in Outcome for Melanoma PatientsAnnals of Surgery, 2006
- Mutations of the BRAF gene in human cancerNature, 2002
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000