Applying Precision to the Management of BRAF-Mutant Metastatic Colorectal Cancer
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REVIEW ARTICLE
Applying Precision to the Management of BRAF‑Mutant Metastatic Colorectal Cancer Benny Johnson1 · Scott Kopetz1
© Springer Nature Switzerland AG 2020
Abstract Identifying the presence or absence of a BRAFV600E 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 BRAFV600E-mutated metastatic melanoma, response rates were found to only be 5% in early-phase clinical trials for patients with BRAFV600E mCRC. A deeper understanding of predominant resistance mechanisms in BRAFV600E 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 BRAFV600E 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.
1 Unique Clinical, Pathologic, and Molecular Features of the BRAF Mutation Colorectal cancer (CRC) remains the fourth most common cancer diagnosis and the second most common cause of cancer-related deaths in the USA [1] Due to the limitations of early detection, variability of clinical presentation and an increased incidence of young-onset disease, many patients present with metastatic disease not amenable to curative resection. Underlying innate chemotherapy resistance and rate of progression are intimately related to the unique molecular subtype of CRC, therefore a biomarkerdriven clinical (prognostic, predictive) and research (novel targets) focus represents the best path forward to enhance * Scott Kopetz [email protected] 1
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA
patient outcomes [2]. CRC develops from normal colon tissue after numerous epigenetic and genetic aberrations occur [3]. In metastatic colorec
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