Prognostic Significance of KRAS G12C Versus Non-G12C RAS Mutations in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis

BACKGROUND: KRAS G12C mutations occur in approximately 3-4% of metastatic colorectal cancer (mCRC) cases. While the introduction of KRAS G12C inhibitors has transformed the therapeutic landscape for this molecular subset, conflicting evidence exists regarding the independent prognostic impact of this mutation in inhibitor-naïve settings. Small sample sizes and methodological heterogeneity have limited individual studies, precluding definitive conclusions. To address this knowledge gap, we conducted a systematic review and meta-analysis to establish the prognostic significance of KRAS G12C mutations in mCRC. METHODS: A comprehensive systematic literature search was conducted across PubMed, Google Scholar, and Cochrane Library through August 2025. Studies comparing overall survival between KRAS G12C and non-G12C RAS-mutant mCRC were included. Hazard ratios (HR) were extracted or calculated from reconstructed individual patient data. Pooled analyses employed random-effects models. Quality assessment utilized the Newcastle-Ottawa Scale. RESULTS: Fourteen retrospective studies encompassing 9,308 patients (903 KRAS G12C, 8,405 non-G12C RAS) were included. The pooled analysis demonstrated that KRAS G12C mutations confer significantly worse prognosis, with a 28% increased risk of mortality compared to non-G12C RAS mutations (HR 1.28, 95% CI 1.10-1.48; p = 0.0015). A meta-analysis of difference in medians showed a pooled mOS difference of - 4.5 months (95% CI, -9.1 to 0.0; p = 0.05) and a pooled mPFS difference of - 1.3 months (95% CI, -2.4 to - 0.1; p = 0.03) for KRAS G12C versus non-G12C patients. Moderate heterogeneity was observed (I2=54.3%). Sensitivity analysis restricted to high-quality studies confirmed these findings (HR 1.31, 95% CI 1.11-1.54). No publication bias was detected. CONCLUSIONS: KRAS G12C mutations represent an independent adverse prognostic biomarker in mCRC, with a statistically significant 28% increased risk of mortality compared to other RAS mutations. The consistent hazard ratio across multiple sensitivity analyses supports a true prognostic effect. These findings have important implications for patient counseling and risk stratification. While the poor prognosis may provide rationale for prioritizing trial enrollment, translation into therapeutic decision-making requires caution, as prospective data demonstrating benefit from earlier use of KRAS G12C inhibitors are lacking.