The Association of NRAS and BRAF Mutations with Overall Survival and Surgical Outcomes in Stage IV Colorectal Cancer.

BACKGROUND: NRAS and BRAF mutations occur in approximately 5% and 12% of colorectal cancers, respectively, but their prognostic significance in Stage IV disease remains unclear. We hypothesized that NRAS and BRAF mutations confer worse survival and surgical outcomes, with effects modified by tumor location and microsatellite instability (MSI). METHODS: We conducted a retrospective cohort study using the National Cancer Database (2021-2023) of adults with clinical Stage IV colorectal cancer, stratified by NRAS and BRAF mutation status. A subset analysis included patients undergoing surgical resection. The primary outcome was two-year overall survival, with a secondary outcome of positive surgical margins. Cox proportional hazards and logistic regression were used for survival and surgical outcomes. RESULTS: Of 22,595 patients, 77.1% had no mutation, 15.3% BRAF, 6.2% NRAS, and 1.5% concurrent mutations. BRAF-mutant tumors were more often right-sided (51.2% vs. 26.0%, p<0.001) and MSI (28.8% vs. 4.6%, p<0.001), while NRAS-mutant tumors resembled those without mutations. On multivariable analysis, NRAS (HR=1.13, 95% CI 1.01-1.26, p=0.04), concurrent mutations (HR=1.29, 95% CI 1.05-1.60, p=0.02), and BRAF (HR=1.87, 95% CI 1.73-2.02, p<0.001) were associated with increased two-year mortality. MSI status modified this effect, with MSI/BRAF tumors associated with lower mortality (HR=0.54, p<0.001), while right-sided tumor location independently predicted increased mortality (HR=1.38, p<0.001). Only BRAF-mutant tumors were associated with an increased risk of positive surgical margins (OR=1.52, p<0.001). CONCLUSIONS: BRAF mutations confer worse survival and surgical outcomes than NRAS mutations. MSI modifies BRAF-associated risk, while right-sided location independently predicts survival. These findings refine risk stratification and surgical decision-making.