Applying Precision to the Management of BRAF-Mutant Metastatic Colorectal Cancer

Identifying the presence or absence of a BRAF^V600E mutation is paramount for the management of patients with metastatic colorectal cancer (mCRC) as there are distinct predictive and prognostic implications, as well as unique therapeutic approaches for this molecular subtype. Traditional cytotoxic doublet chemotherapy has historically been ineffective for this poor prognostic group, thereby highlighting the critical need for novel targeted therapies to drive management. Unlike the early success achieved with BRAF-inhibitor monotherapy for patients with BRAF^V600E-mutated metastatic melanoma, response rates were found to only be 5% in early-phase clinical trials for patients with BRAF^V600E mCRC. A deeper understanding of predominant resistance mechanisms in BRAF^V600E mCRC after exposure to BRAF inhibition has resulted in innovative combinatorial approaches targeting the mitogen-activated protein kinase (MAPK) pathway, revitalizing the treatment portfolio for these patients. Of note, in recent years non-V600 BRAF mutations have been appreciated as a distinct molecular subset in mCRC, representing 2–4% of patients with a unique clinical presentation and complex signaling biology. These mutations, referred to as “atypical” BRAF mutations, warrant individual clinical investigation and demand innovative drug development that leverages known signaling class biology. Here, we summarize the current molecular and clinicopathologic understanding of BRAF^V600E mCRC, as well as the landmark clinical trials that have led to successful targeted therapy for this historically aggressive subtype of colorectal cancer. Additionally, we briefly describe the current understanding of patients with atypical BRAF mutations, highlighting the importance of continued research efforts to appropriately treat this evolving subset of BRAF mutations.