Global insights into survival outcomes and unmet therapeutic needs in <i>KRAS</i> -mutant gallbladder cancer: A comprehensive federated network analysis.

Abstract

4141 Background: Gallbladder cancer (GBC) is an aggressive malignancy with limited systemic options and poor survival. KRAS targeted therapeutic are emerging across solid tumors, yet their prognostic relevance in GBC remains poorly defined. We evaluated the real-world impact of KRAS mutations on survival in patient with advanced gallbladder cancer utilizing a large, federated health data network. Methods: A retrospective cohort study was performed using the TriNetX Global Collaborative Network. Adults (≥18y) with GBC were grouped by genomic testing into KRAS-mutant (KRAS MT ) or KRAS-wild type (KRAS WT ). Propensity-score matching (PSM) was performed 1:1 adjusting for demographics and comorbidities, yielding 604 patients per cohort. Outcomes were assessed from 1 to 1825 days after index diagnosis. The primary endpoint was overall survival (OS). Kaplan-Meier (KM) estimates, log-rank testing, and hazard ratios (HR) were generated. Results: After PSM, median follow-up was 358.5 (11,7 months) vs 491 (16.1 months) days for KRAS WT and KRAS MT cohorts, respectively. Death occurred in 214 (35.4%) KRAS WT vs 305 (50.5%) KRAS MT patients (risk difference −15.1%, 95% CI −20.6 to −9.5; p &lt; 0.001). Median OS was 1326 days (43.5 months) for KRAS WT vs 694 days (22.8 months) for KRAS MT patients, with survival probability at end of time window of 48.74% vs 32.49%. Kaplan-Meier survival analysis demonstrated significantly worse OS in the KRAS MT cohort (log-rank χ² = 10.76; p = 0.001). Hazard ratio favored KRAS WT (HR 0.747; 95% CI 0.627–0.890; p = 0.011), indicating 34% higher mortality in KRAS MT patients. Conclusions: In this large real-world PSM analysis, KRAS mutations conferred poor prognosis in GBC patients with significantly higher mortality and shorter survival. These differences highlight pivotal clinical implications amid the growing role of KRAS-targeted therapeutics. Ensuring expanded trial access, including early-line KRAS-targeted therapies, is necessary to reach this rare and clinically fragile patient population.