Abstract
BACKGROUND: KRAS mutation is a prominent biomarker in colorectal cancer (CRC) and is associated with resistance to anti-EGFR therapy in metastatic disease. However, its prognostic value across stages and its association with survival within common treatment pathways remain incompletely defined in large real-world cohorts. METHODS: We performed a retrospective cohort study using the National Cancer Database, identifying 52,534 patients with CRC diagnosed between 2010 and 2021 with documented KRAS mutation status. Demographic, clinicopathological, and treatment variables were analyzed. Overall survival (OS) was evaluated using Kaplan–Meier methods and multivariable Cox proportional hazards models, performed overall and stratified by AJCC stage. Exploratory analyses evaluated the association of KRAS status with OS within stage-specific treatment pathways. RESULTS: KRAS-mutant tumors comprised 39.9% of the cohort and were more frequently right-sided and metastatic at presentation and were less often poorly differentiated. KRAS mutation was independently associated with worse OS in the overall cohort (HR 1.12). Stage-specific associations were modest but statistically significant in stage II (HR 1.14), stage III (HR 1.16), and stage IV disease (HR 1.07). In exploratory treatment-pathway analyses, KRAS mutation was associated with inferior OS in several common regimens (e.g., surgery + chemotherapy in stage III and stage IV). CONCLUSION: KRAS mutation independently predicts poorer survival in CRC, particularly in earlier stages, and influences outcomes under multiple therapeutic regimens. These findings underscore the importance of KRAS testing to optimize individualized treatment strategies and guide novel interventions targeting KRAS-mutant CRC.