RAS Mutations as Prognostic Biomarkers in Digestive Cancers: From Binary Classification to Variant-Specific and Context-Dependent Risk Stratification.

In digestive cancers, activating RAS mutations - primarily KRAS, less frequently NRAS - are among the most prevalent oncogenic drivers. Their clinical significance depends strongly on the tumor type, disease stage, treatment context, and specific RAS variant. In colorectal cancer (CRC), RAS alterations are well-established predictors of resistance to anti-EGFR therapy. However, KRAS G12C-mutant tumors represent a distinct subgroup with demonstrated sensitivity to KRAS G12C inhibitors. However, growing evidence supports the negative prognostic impact of RAS mutations on both primary CRC and colorectal cancer liver metastases (CRLM) in both post-resection and adjuvant therapies. In pancreatic ductal adenocarcinoma (PDAC), where KRAS alterations are nearly universal, prognostic evaluation has evolved from a binary mutant versus wild-type classification to a more refined approach based on mutation subtype (e.g., G12D/V vs. G12R) and KRAS mutant dosage, both of which influence clinical outcomes. In biliary tract cancers, KRAS mutations occur in a relevant subset and are consistently associated with poor survival. Liquid biopsy approaches increasingly enable noninvasive detection and longitudinal monitoring. In gastric cancer, RAS alterations are less frequent overall but may identify biologically aggressive subsets and may also be associated with inferior outcomes under HER2-targeted therapy in selected populations. This review synthesizes contemporary data supporting RAS alterations as prognostic biomarkers across digestive cancers, highlights practical considerations for integrating variant-level RAS information into risk stratification and trial designs, and discusses how emerging RAS-directed therapies may reshape the prognostic significance of specific molecular subsets.