Understanding Genomic Instability Score in Platinum-Treated Advanced Pancreatic Ductal Adenocarcinoma

Background/Objectives: First-line treatment selection for advanced (locally advanced or metastatic) pancreatic ductal adenocarcinoma (PDAC) is currently based on clinical characteristics rather than predictive biomarkers. While homologous recombination deficiency (HRD) is associated with increased sensitivity to platinum-based chemotherapy, established predictive biomarkers, such as pathogenic alterations in BRCA1, BRCA2, and PALB2, identify only a small subset of patients who are likely to benefit from platinum-based first-line treatment. The Genomic Instability Score (GIS) may capture broader HRD-associated genomic scarring beyond single-gene testing and support biomarker-guided platinum selection. However, the clinical utility of the GIS in PDAC remains uncertain, and no PDAC-specific GIS cutoff has yet been established. Methods: In this retrospective multicenter cohort, 127 patients with advanced PDAC underwent TruSight Oncology 500 HRD testing between 2022 and 2025. GIS was evaluable in 99 patients; 80 received first-line therapy. The primary endpoint was time to failure of the first-line strategy (TFS). An exploratory candidate GIS cutoff for platinum sensitivity was identified using maximally selected log-rank statistics, and survival was analyzed using Kaplan-Meier estimates and Cox regression. Results: In the first-line platinum cohort, an exploratory GIS threshold of 39 showed the greatest discrimination for treatment failure-free survival (TFS) within this cohort. Patients with GIS ≥ 39 had significantly longer TFS than those with GIS < 39 (9.9 vs. 5.9 months; HR 0.33, 95% CI 0.13-0.80; p = 0.015), and this association remained significant after multivariable adjustment. Among individual genes, BRCA2-mutated tumors exhibited significantly higher GIS than BRCA2-wild-type tumors (median 54 vs. 19; FDR-adjusted p = 0.002), although 30% of GIS-high tumors lacked BRCA1/2 mutations. Combined stratification by GIS and first-line treatment demonstrated a stepwise improvement in overall survival, with median OS of 8.2 months in non-platinum/GIS < 39 patients, 15.1 months in platinum/GIS < 39 patients, and 30.7 months in platinum/GIS ≥ 39 patients (p = 0.002). Conclusions: GIS may identify patients with advanced PDAC who experience favorable outcomes during first-line platinum-based chemotherapy. The observed association between higher GIS and improved treatment outcomes supports further investigation of GIS as a biomarker for treatment stratification in advanced PDAC and warrants prospective validation.