Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Sep;121(6):434-442.
doi: 10.1038/s41416-019-0526-2. Epub 2019 Jul 29.

Exploring the best treatment options for BRAF-mutant metastatic colon cancer

Julien Taieb  1   2 , Alexandra Lapeyre-Prost  3 , Pierre Laurent Puig  4   5 , Aziz Zaanan  3   4
Affiliations
Review

Exploring the best treatment options for BRAF-mutant metastatic colon cancer

Julien Taieb et al. Br J Cancer. 2019 Sep.

Abstract

The BRAFV600E mutation is a well-accepted poor prognostic factor in patients with metastatic colorectal cancer (mCRC), as it confers Ras-independent stimulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway involved in proliferation, migration, angiogenesis and the suppression of apoptosis. Analysis of the potential predictive value of BRAF for treatment efficacy is inherently confounded by this known prognostic impact. Currently, approved therapeutic strategies for patients with BRAF-mutant (BRAF-mt) mCRC are suboptimal, and uncertainty exists regarding how to best treat these patients. Based on the available evidence, it is currently not possible to confirm the superiority of any available treatment options cited in European Society for Medical Oncology and National Comprehensive Cancer Network guidelines (that is, doublet or triplet chemotherapy regimens plus anti-vascular endothelial growth factor or anti-epidermal growth factor receptors), even if triplet chemotherapy plus bevacizumab is the most accepted standard regimen. In this review, we highlight still-emerging strategies that could be deployed to combat BRAF-mt mCRC, including triplet chemotherapy plus available biologic agents, rationally derived combinations of targeted agents and immunotherapy. While it is clear that the needs of patients with BRAF-mt mCRC are currently unmet, we are cautiously optimistic that the recently renewed research interest in these patients will yield clinically relevant insights and therapeutic strategies.

PubMed Disclaimer

Conflict of interest statement

J.T. declared providing an advisory role for Roche, Merck, KGaA, Amgen Lilly, Baxalta, Servier and Sirtex Medical. A.L.P. declared a consultancy role for MERCK, MERCK SERONO and AMGEN/COHESIA. A.Z. had a consultancy role for Amgen, Baxter, Lilly, Merck Serono, MSD, Roche, Sanofi and Servier. P.L.P. declared a consultancy role for Amgen, Astrazeneca, Biocartis, Boehringer-Ingelheim, Merck, MSD, BMS, Roche and Sanofi.

Figures

Fig. 1
Fig. 1
The BRAF pathway. a Activated BRAF-mutated protein leads to phosphorylation and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 proteins, which subsequently phosphorylate and activate ERK1/2 proteins. After activation, ERK proteins phosphorylate a variety of substrates, including multiple transcription factors and regulate several key cellular activities, such as proliferation, differentiation and angiogenesis, to promote tumour growth. b Inhibition of BRAF suppresses the ERK-mediated negative feedback of the epidermal growth factor receptor (EGFR), resulting in EGFR activation, formation of RAF protein dimers and CRAF-mediated reactivation of the MAPK signalling pathway. c Preclinical studies have shown efficacy with combination drugs targeting BRAF (BRAF inhibitor), MEK (MEK inhibitor) and EGFR (anti-EGFR monoclonal antibody); this triplet combination might be an interesting therapeutic approach in patients with BRAF-mutated mCRC. d Crosstalk between the RAS/BRAF/MEK/ERK and the PI3K/AKT/mammalian target of rapamycin (mTor) signalling pathways after BRAF inhibition could play a determinant role in cell survival. Combining BRAF, EGFR and PI3K inhibitors could constitute another interesting therapeutic approach in patients with BRAF-mutated mCRC
See this image and copyright information in PMC

Comment in

References

    1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:E359–E386. doi: 10.1002/ijc.29210. - DOI - PubMed
    1. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016;27:1386–1422. doi: 10.1093/annonc/mdw235. - DOI - PubMed
    1. Lièvre A, Bachet J-B, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008;26:374–379. doi: 10.1200/JCO.2007.12.5906. - DOI - PubMed
    1. Douillard J-Y, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 2013;369:1023–1034. doi: 10.1056/NEJMoa1305275. - DOI - PubMed
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596. - DOI - PMC - PubMed

MeSH terms

Substances