The association of NRAS and BRAF mutations with overall survival and surgical outcomes in stage IV colorectal cancer

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).

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 who underwent surgical resection. The primary outcome was 2-year overall survival; a secondary outcome was positive surgical margins. Cox proportional hazards and logistic regression were used to analyze survival and surgical outcomes.

Of 22,595 patients, 77.1% had no mutation, 15.3% had BRAF mutations, 6.2% had NRAS mutations, and 1.5% had concurrent mutations. BRAF-mutant tumors were more often right-sided (51.2% vs 26.0%; P <.001) and exhibited MSI (28.8% vs 4.6%; P <.001), whereas NRAS-mutant tumors resembled those without mutations. On multivariable analysis, NRAS mutations (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P =.04), concurrent mutations (HR, 1.29; 95% CI, 1.05-1.60; P =.02), and BRAF mutations (HR, 1.87; 95% CI, 1.73-2.02; P <.001) were associated with increased 2-year mortality. MSI status modified this effect, with MSI/BRAF-mutant tumors associated with lower mortality (HR, 0.54; P <.001), whereas a right-sided tumor location independently predicted increased mortality (HR, 1.38; P <.001). Only BRAF-mutant tumors were associated with an increased risk of positive surgical margins (odds ratio, 1.52; P <.001).

BRAF mutations confer worse survival and poorer surgical outcomes than NRAS mutations. MSI modifies BRAF-associated risk, whereas a right-sided location independently predicts survival. These findings refine risk stratification and surgical decision-making.