Clinico-genomic landscape of Indian gallbladder cancer: Actionable alterations and opportunities for precision therapy.

Abstract

e16231 Background: Gallbladder carcinomas (GBC) are the predominant biliary tract malignancies with marked geographic variation and a female-biased, middle-aged patient population. Most patients present with advanced disease, and adjuvant chemotherapy offers limited survival benefit. Mutation profiling can reveal actionable alterations and immunogenomic contexts to guide precision therapeutics and potential trial design. Methods: This study analyzed 115 FFPE-tumor samples from patients undergoing treatment for GBC across multiple hospitals in India, who had opted to undergo molecular genetic testing for somatic variants with 4baseCare’s comprehensive gene panels. Results: The cohort was predominantly female (70.3%), particularly 50 and older (73.07%), and largely derived (85.5%) from high-incidence regions of India. Nearly all patients (98.5%) presented with stage IV disease; adenocarcinoma was the most predominant histological type (61%) Among the IHC markers tested, CK7 and CK19 were frequently positive in evaluated samples, while CK20 and PD-L1 were largely negative. Recurrent genomic alterations included ERBB2 (10.7%), BRCA2 (6.8%), SMAD4 (6.8%), CDKN2A (3.9%), and MDM2 (3.9%), with copy-number amplifications involving ERBB2 and MDM2. Most commonly affected pathways were cell-cycle regulation (37%), RTK signaling (16%), PI3K/AKT/mTOR signaling (11%), DNA damage repair (7%), and chromatin remodeling/DNA methylation (6%). TMB was predominantly low, with only 4.8% demonstrating high TMB. 93.1% samples in a subset were microsatellite marker stable. Overall, 4.76% of samples harbored alterations potentially targetable with FDA-approved therapies. Conclusions: The data reveal a predominance of mutations in RTK/cell-cycle–DNA damage pathways indicating that GBC patients may benefit from targeted therapy. Although actionable targets were identified in a minority of cases, CGP delineates clinically relevant subsets that may benefit from targeted agents, pathway-directed therapies, or immunotherapy where biomarkers align. Routine integration of CGP in advanced GBC may refine treatment selection, improve trial stratification, and support biomarker-driven precision oncology approaches in this high-incidence population.