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Review
. 2021 Jan 4;13(1):137.
doi: 10.3390/cancers13010137.

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Gianluca Mauri  1   2 , Erica Bonazzina  1 , Alessio Amatu  1 , Federica Tosi  1 , Katia Bencardino  1 , Viviana Gori  1   2 , Daniela Massihnia  1   2 , Tiziana Cipani  1 , Francesco Spina  1 , Silvia Ghezzi  1 , Salvatore Siena  1   2 , Andrea Sartore-Bianchi  1   2
Affiliations
Review

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Gianluca Mauri et al. Cancers (Basel). .

Abstract

The BRAFV600E mutation is found in 8-10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

Keywords: BRAF; FOLFOXIRI; colon cancer; immune checkpoint inhibitors; targeted agents.

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Conflict of interest statement

Salvatore Siena is advisory board member for Amgen, Bayer, BMS, CheckmAb, Clovis, Daiichi-Sankyo, Merck, Roche-Genentech, and Seattle Genetics. Andrea Sartore-Bianchi is advisory board member for Amgen, Bayer, Sanofi and Servier. The other authors declare no competing interests.

Figures

Figure 1
Figure 1
Schematic representation of pathways currently under investigations as actionable therapeutic targets harnessing BRAFV600E mutant metastatic colorectal cancer (mCRC). Legend: mAb = monoclonal antibodies; i = inhibitor. Vit = vitamin. Mut = mutation.
Figure 2
Figure 2
Current treatment options for BRAFV600E mutant metastatic colorectal cancer (mCRC). According to most recent studies, treatment opportunities for BRAFV600E mutant mCRC are fast developing if compared to only a decade ago. The panorama of treatment now includes the following options: surgery, combinations of cytotoxic drugs, targeted and immunological agents. All these approaches should be carefully evaluated when discussing the treatment approach to BRAFV600E mCRCs in multidisciplinary teams (MDT). Given the peculiarity of this subset of mCRCs, clinical trial enrolment should always be considered also in the upfront setting. Based on current evidence, MSI BRAFV600E mutant mCRC progressing to first line treatment with pembrolizumab should be managed as microsatellite stable (MSS) BRAFV600E mutant mCRC. Keys: * = Metastasectomy should be -considered in liver limited disease in case of response or prolonged disease control obtained with medical treatments even if relapse-free and overall survival is poorer than BRAF wild-type mCRCs. Legend: mCRC = metastatic colorectal cancer. SD = stable disease; PD = progressive disease; PR = partial response. “Dashed line” means consider. “Continuous line” means recommended.
Figure 3
Figure 3
PRISMA 2009 Flow diagram representing the systematic review performed on ClinicaTrial.gov on 23 December 2020 [65]. For more information, visit www.prisma-statement.org.
See this image and copyright information in PMC

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