In a retrospective analysis of three large next generation sequencing databases of 9643 patients with metastatic colorectal cancer (mCRC), 965 patients were identified with BRAF-mutated tumors, of which 208 (22%) carried BRAF mutations outside of codon 600 (non-V600). Overall, prevalence of non-V600 BRAF mutations was 2.2%. Patients with non-V600 BRAF-mutant mCRC were significantly younger, more often male, less likely to have high-grade tumors or right-sided primary tumors compared to those with V600E BRAF-mutant mCRC. Additionally, patients with non-V600 BRAF mutations were more likely to have concomitant RAS mutations than patients with V600E BRAF mutations (26% vs 2%; P<.001), but less likely to have microsatellite instability (6% vs 30%; P<.001). Importantly, patients with non-V600 BRAF-mutant mCRC had significantly longer median overall survival (OS) compared to those with V600E BRAF-mutant or BRAF wildtype mCRC (60.7 months vs 11.4 months vs 43.0 months; P<.001). When adjusting for other variables associated with OS, non-V600 mutations remained significantly associated with OS (HR 0.18, P<.001). The investigators concluded that non-V600 BRAF mutations define a clinically distinct molecular subtype of mCRC with an excellent prognosis, and that these findings have immediate clinical implications.
In an accompanying editorial, the authors commented that this study highlights the importance of non-V600 BRAF mutations as a separate disease category in mCRC, with a different prognosis and therapeutic needs compared to V600E BRAF-mutated CRC. The authors raised several questions for future investigation, including how presence of non-V600 mutations can be used to guide treatment selection and intensity, whether epidermal growth factor receptor-targeted therapies may be more effective in this patient population, and if targeting the MEK/ERK pathway might be a potential route for investigation.