Prognostic Modeling Integrating RAS and SMAD4 Status in Patients with BRAF Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer

We aimed to develop a clinic-molecular prognostic nomogram for patients with microsatellite stable and BRAF wild-type metastatic colorectal cancer (mCRC) using comprehensive genomic profiling (CGP) and clinical data taking advantage from a prospectively maintained dataset at three Italian Institutions and three randomized trials. The overall cohort was split into development and validation sets. The prognostic model was built on the development set using prespecified landmark intervals. Genomic and clinical predictors were identified within a stability-selection framework based on an L1-penalized Cox model and subsequently incorporated into a stratified Cox model with metastasectomy modeled as a time-dependent covariate. The overall cohort included 1071 patients. Stability selection identified RAS (SST: 98%) and SMAD4 (SST: 92%) as the only genomic alterations providing additional prognostic information beyond the prespecified clinical model. In the overall population, patients with RAS/SMAD4 double wild-type tumors had the most favorable overall survival, whereas RAS mutations, SMAD4 alterations, and RAS/SMAD4 co-alterations were associated with inferior outcomes. The final nomogram integrated RAS/SMAD4 with clinical variables and metastasectomy. In the development cohort, time-dependent AUCs were 0.723 and 0.736 at 1 and 4 years, respectively. In the validation cohort, AUCs were 0.657 and 0.711 at the same time points. These findings suggest that prognostically relevant genomic information in MSS, BRAF wild-type mCRC may be captured by targeted NGS panels including RAS and SMAD4. By integrating these alterations with clinical variables and time-updated information on metastasectomy, this clinic-molecular nomogram provides individualized dynamic survival estimates.