Impact of BRAF Gene Mutation in Nonmetastatic Colorectal Cancer on Disease Progression and Survival Outcomes

ABSTRACT Background and Aim Colorectal cancer (CRC) is a major global health concern, with molecular and histopathological subtypes influencing disease progression. Mutations in the v‐Raf murine sarcoma viral oncogene homolog B (BRAF) gene, particularly the V600E variant, define a subset associated with aggressive features. The impact of BRAF mutations on early‐stage CRC prognosis and their interaction with mismatch repair (MMR) status remains less characterized. Methods We conducted a retrospective analysis of prospectively collected data from two tertiary institutions on Stage II–III CRC patients. BRAF/MMR subgroups were defined (BRAFmut/pMMR, BRAFmut/dMMR, BRAFwt/pMMR, and BRAFwt/dMMR). Associations with patient/tumor characteristics, adjuvant treatment, and long‐term outcomes were assessed. Univariate and multivariate analyses were used to evaluate disease recurrence and mortality. Results Of 157 eligible patients, univariate analyses indicated poorer outcomes for those with pMMR CRC. Multivariate analysis examining disease recurrence and death highlights that pMMR patients perform worse, but significantly, this analysis revealed that BRAFmut is a significant predictor of mortality in the nonmetastatic setting, irrespective of MMR status. Conclusions Nonmetastatic BRAFmut CRC carries a dismal prognosis, irrespective of MMR status. Routine testing for BRAF V600E mutation alongside MMR assessment is advocated to inform personalized management, potentially impacting surveillance, adjuvant therapy decisions, and eligibility for targeted therapies.