Clinical and molecular characteristics of Class II and III BRAF mutations in colorectal cancer

Class II and III BRAF mutations are uncommon events, with limited data on their clinical and biological characteristics. We investigated clinical and molecular features of BRAF mutation classes in a total of 24,402 patients with mismatch repair proficient CRC (MMRp). Samples collected between 2006 and 2023 were profiled using next-generation sequencing and whole-transcriptome sequencing. We identified 1268 (5.2%), 132 (0.54%), and 323 (1.3%) patients with class I, II, and III BRAF-mutated CRC. Patients with class III mutations had significantly better median overall survival (OS) than those with class I mutations (23.6 vs 17.4 months; HR = 1.26, CI: 1.08-1.47, p = 0.004). Transcriptomic analyses revealed that the MAPK pathway score was significantly lower for class II and III BRAF mutations without concurrent RAS mutations than for those with RAS co-mutations. The cetuximab score, an RNA expression-based predictor of EGFR therapy response, was significantly better for class II and III BRAF mutations than for class I. The cetuximab score significantly improved for only class III BRAF mutations when those with concurrent RAS mutations were excluded. The results of this large multi-institutional analysis of BRAF mutation classes reveal the prognostic value of class II and III BRAF mutations, and their distinct clinical and molecular features.