BRAF Mutations as Actionable Targets: A Paradigm Shift in the Management of Colorectal Cancer and Novel Avenues

Abstract

BRAF mutations in colorectal cancer have been studied over the past several decades. BRAF V600E mutation, a class I mutation, is the most common oncogenic BRAF alteration in colorectal cancer. Until recently, the BRAF V600E mutation was not among actionable genes for colorectal cancer. However, recent discoveries have revealed therapeutic opportunities. The BRAF with or without MEK inhibition combined with epidermal growth factor receptor–directed therapy was recently found to be an effective therapy choice for patients with advanced-stage BRAF V600–mutant colorectal cancer. However, it is essential to distinguish patients with BRAF V600E–mutant mismatch repair–deficient colorectal cancer from those with mismatch repair–proficient colorectal cancer, as immune checkpoint inhibitor therapy is more appealing in this subset of patients with colorectal cancer. This review article discusses the molecular characteristics of class I, II, and III BRAF mutants and their impact on the clinical behavior of colorectal cancer. We also review the recent progress in the targetability of BRAF mutations in colorectal cancer, which has led to changes in clinical practice and elaborates on innovative therapeutic approaches to enhance the efficacy of BRAF-targeting therapies, to achieve more durable responses.