Clinical utility of NGS in patient stratification for first-line chemotherapy in locally advanced/advanced GBC: A pilot study demonstrating the hypothesis.

Abstract

e16244 Background: Gallbladder cancer is highly prevalent in Asian countries and is associated with poor survival outcomes. Platinum-based chemotherapy remains the standard of care in advanced disease; however, treatment responses are heterogeneous, and predictive molecular determinants of chemotherapy sensitivity are poorly defined. Methods: This retrospective study included 13 patients with locally advanced gallbladder cancer treated with first-line cisplatin and gemcitabine. Patients were stratified as responders or non-responders based on radiological response assessed by RECIST criteria at three months. Somatic mutation profiling was performed using the TarGT IndieGene panel covering 1,212 genes. Mutations were mapped to established cancer hallmark pathways to evaluate biological enrichment patterns while accounting for tumor heterogeneity. Results: Responders showed a relatively restricted hallmark enrichment pattern, predominantly involving sustained proliferative signaling, genomic instability, tumor invasion and metastasis, and evasion of growth suppressors, with most hallmarks exhibiting low-to-moderate enrichment scores (1+ to 3+). Hallmarks related to immune evasion, tumor-associated inflammation, and reprogramming of energy metabolism were largely absent in responders. The cumulative hallmark scores in this group ranged from 8 to 14 ( < 15), indicating limited oncogenic complexity.In contrast, non-responders demonstrated pronounced and consistent enrichment across multiple hallmark categories. High-level enrichment (3+) was frequently observed for sustained proliferative signaling, genomic instability, evasion of growth suppressors, resistance to cell death, sustained angiogenesis, and replicative immortality. Additionally, immune evasion, tumor-associated inflammation, and metabolic reprogramming—absent in responders—were selectively enriched in non-responders. These patterns resulted in higher cumulative hallmark scores ranging from 17 to 22 ( > 15). Non-responders also exhibited significantly shorter median PFS compared to responders (7 vs. 15 months; p = 0.03). Conclusions: Non-responding gallbladder cancers are characterized by extensive activation of multiple cancer hallmarks, reflecting greater biological complexity, heterogeneity, and adaptive capacity that may underlie resistance to platinum-based chemotherapy. This is a high impact finding. Validation in larger cohorts is warranted to adopt in routine clinics. The cumulative hallmark scores for each of the patients based on the p-value of the enrichment. id status hallmarks (10) Score 2 responder 7 14 7 responder 7 13 9 responder 7 8 10 responder 7 9 12 responder 7 13 1 nonresponder 7 17 3 nonresponder 8 22 4 nonresponder 8 19 5 nonresponder 9 21 6 nonresponder 10 22 8 nonresponder 9 21 11 nonresponder 7 20 13 nonresponder 8 20