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Review
. 2021 Aug;32(8):959-967.
doi: 10.1016/j.annonc.2021.03.206. Epub 2021 Apr 7.

Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines

A Grothey  1 , M Fakih  2 , J Tabernero  3
Affiliations
Free article
Review

Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines

A Grothey et al. Ann Oncol. 2021 Aug.
Free article

Abstract

Background: Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis.

Design: Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting.

Results: The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab.

Conclusions: The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.

Keywords: BRAF mutation; management; metastatic colorectal cancer; pathophysiology; prognostic markers.

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Conflict of interest statement

Disclosure AG: Honoraria from Aptitude Health and Elsevier; consulting or advisory role (fees paid to institution): Amgen, Array BioPharma, Bayer, Boston Biomedical, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Genentech, and Guardant Health; research funding (fees paid to institution): Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Eli Lilly, Genentech, and Pfizer; fees for travel/accommodation/expenses: Amgen, Bayer, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, Genentech, and Merck Sharp & Dohme. MF: Honoraria from Amgen; consulting or advisory role: Amgen, Array BioPharma, Bayer, Pfizer, Seattle Genetics, and Taiho; speaker bureau: Amgen and Guardant360; research funding (fees paid to institution): Amgen, AstraZeneca, and Novartis. JT: Consulting or advisory role: Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Foundation Medicine, Genentech, Genmab, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura, Menarini, Merck Serono, Merck Sharp & Dohme, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, Roche, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, and VCN Biosciences.

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