8 research outputs found
BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes
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)β=β0.39, 95%CI: 0.20-0.77, Pβ=β0.007), lung (ORβ=β0.38, 95%CI: 0.19-0.73, pβ=β0.004) and retroperitoneal metastases (ORβ=β0.34, 95%CI: 0.13-0.86, pβ=β0.024) and more brain metastases (ORβ=β2.05, 95%CI: 1.02-4.11, Pβ=β0.043) 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, pβ=β0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, pβ=β0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, pβ=β0.02) and lung metastases (91.6% vs. 47.7%, pβ=β0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, pβ=β0.046 and 78 vs. 322 months, pβ=β0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR)β=β0.16, 95%CI: 0.03-0.89, pβ=β0.037) and any decrease in tumor size after referral (HRβ=β0.07, 95%CI: 0.015-0.35, pβ=β0.001) 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