Management of BRAF Gene Alterations in Metastatic Colorectal Cancer: From Current Therapeutic Strategies to Future Perspectives

Abstract

BRAF mutations constitute an important poor prognostic factor in metastatic colorectal cancer (mCRC) and the development of treatments in this context is of great necessity to prolong patient survival. Although the association between BRAF mutations and microsatellite instability (MSI) has been known for several years, previous clinical trials have revealed that the former has a limited prognostic impact and that immune checkpoint inhibitors offer a significant survival benefit to mCRC patients with both characteristics. Furthermore, the genomic classification of BRAF mutations according to their molecular functions enables greater understanding of the characteristics of mCRC patients with BRAF mutations, with therapeutic strategies based on this classification made more ideal to improve poor prognosis through the delivery of targeted therapies. Recently, a phase III trial was conducted in previously treated mCRC patients with BRAF V600E–mutated tumors and revealed that the combination therapy approach of BRAF inhibition and anti–epidermal growth factor receptor antibody therapy with or without MEK inhibition was more efficacious than standard chemotherapy alone. This review discusses current treatment strategies and future perspectives in BRAF-mutated mCRC.

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream)

“…The presence of this variant is considered a poor prognostic factor with a median overall survival below 20 months in mCRC [ 28 ]. Patients with this mutation and microsatellite-stable (MSS) tumours have a poorer prognosis, whereas, for those with microsatellite instability (MSI), this mutation is associated with sporadic carcinoma and a better prognosis [ 29 ]. In fact, BRAF -driven tumours follow a different path compared to the “classical adenoma-carcinoma” hypothesis and are associated with sessile serrated adenomas [ 30 ].…”

“…Beyond anti-EGFR treatments, patients with BRAF V600E tumours were treated with immunotherapy for anti-PD-L1 in the CheckMate 142 clinical trial [ 32 ], as it was shown that PD-L1 is upregulated by EGFR activation. Results from this clinical trial suggest that BRAF V600E may regulate PD-L1 expression [ 33 ], although other clinical trials showed that the presence of the BRAF V600E mutation is not a predictor of anti-PD-1 treatment response [ 29 ], suggesting that they might act independently. In fact, a combination of anti-PD-L1 and anti-BRAF treatments is suggested to be an interesting approach [ 34 ].…”

The emerging era of personalized medicine in advanced colorectal cancer

“…Mutations of BRAF is the most common mutation in the RAF family occurring in 10–15% of CRC 123,124 . It results in phosphorylation of MEK and ERK leading to increased activation of the MAPK pathway and confers resistance to anti‐EGFR therapy 125 . Molecular profiling prior to treatment initiation can allow better tailoring of therapy, with anti‐EGFR drugs best used on patients with BRAF, KRAS and NRAS wild‐type CRC 126,127 .…”

“…123,124 It results in phosphorylation of MEK and ERK leading to increased activation of the MAPK pathway and confers resistance to anti-EGFR therapy. 125 Molecular profiling prior to treatment initiation can allow better tailoring of therapy, with anti-EGFR drugs best used on patients with BRAF, KRAS and NRAS wild-type CRC. 126,127 Recently, the BEACON study provided a crucial breakthrough using the combination of a BRAF inhibitor with an EGFR inhibitor which showed improved overall survival in BRAF-mutant advanced CRC.…”

Current Targeted Therapy for Metastatic Colorectal Cancer

“…Interestingly, non-V600 BRAF mutation was independently and significantly associated with improved OS [110]. Given that monotherapy with a BRAF-targeting tyrosine kinase inhibitor for patients with mCRC has failed, some combination regimens have been tested in multiple clinical trials [111].…”