BRAF mutation shows stage-specific prognostic impact in colon cancer.

Poor survival with BRAF mutation is limited to metastatic disease.

Microsatellite instability modifies the prognostic effect of BRAF mutation.

BRAF mutation is linked to distinct metastatic and perineural invasion patterns.

BRAF mutation is a clinically important molecular alteration in colon cancer, but its prognostic significance varies and remains incompletely defined across disease stage and microsatellite instability (MSI) status. This study evaluates the prognostic impact of BRAF mutation and its association with tumor characteristics that may explain its context-dependent behavior.

Adults with stage I–IV colon cancer in the National Cancer Database (2004–2020) who underwent surgical resection and had documented BRAF mutation and MSI status were identified. Multivariable Cox regression assessed overall survival by BRAF status, stratified by stage and MSI. Logistic regression evaluated associations between BRAF mutation and tumor features, including metastatic disease and perineural invasion (PNI). Effect modification was assessed using interaction terms with stratified analyses when significant.

Among 5937 patients, 31.4% had BRAF-mutated tumors. BRAF mutation was strongly associated with MSI (OR = 6.66, p < 0.001). Overall, BRAF mutation was associated with worse survival (HR = 1.35, p < 0.001), but this effect was limited to stage IV disease (HR = 1.45, p < 0.001). Prognostic effects differed by MSI status: BRAF mutation was associated with worse survival in MSS tumors (HR = 1.61, p < 0.001) but not in MSI tumors (HR = 0.95, p = 0.581). Among MSS tumors, BRAF mutation was associated with higher odds of metastasis (OR = 1.30) and PNI (OR = 1.35), whereas among MSI tumors it was associated with lower odds of metastasis (OR = 0.60).

BRAF-mutated colon cancer demonstrates substantial biological and prognostic heterogeneity driven by MSI status and disease stage.

Colon cancer

BRAF mutation

Microsatellite instability

Prognosis. NCDB

© 2026 The Authors. Published by Elsevier Ltd.