A BEACON of hope for BRAF-mutant metastatic colorectal cancer

Abstract

CRC is the second leading cause of cancer-related death, and the third most common cancer globally (1). Approx imate ly 10–15% of CRC harbor a BRAF mutat ion (2) . This molecular subtype of CRC is more commonly associated with right-sided tumours, more advanced stage at presentation, and mucinous histopathology (3). BRAF-mutant CRC are more frequently found in microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumours compared to microsatellite stable (MSS) tumours (4) and are associated with higher mutation burden and CpG island methylator phenotype (CIMP)-high status (5). The presence of a BRAF mutation results in activation of BRAF kinase and sustained downstream activation of the RAS-RAF-mitogen-activated protein kinase (MAPK) signaling pathway. This disruption to key cellular responses drives cancer cell proliferation and survival, which in turn leads to more aggressive tumour biology (2). The presence of a BRAF mutation is considered a poor prognostic biomarker, translating to poor patient outcomes. Compared to BRAF-wildtype CRC, BRAF-mutant CRC are associated with a 70% increase in mortality (6) and a median overall survival (mOS) of 12 vs. 25 months in patients with BRAFwildtype CRC (7).