Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.

4104 Background: Nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) showed promising clinical outcomes in phase II trials for advanced biliary tract cancer (BTC) but did not demonstrate superiority over the control treatment in subsequent phase III clinical trials.In this study, we investigated predictive biomarkers of response to GemCis/nab-P in patients with advanced BTC using comprehensive genomic and transcriptomic analyses. Methods: This prospective cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received GemCis/nab-P at CHA Bundang Medical Center, Korea from July 2021 to December 2022. Targeted genomic (Oncomine Comprehensive Assay) and whole-transcriptome sequencing data for tissue samples collected before the initiation of systemic chemotherapy were used for biomarker discovery (n = 108). To identify genomic and transcriptomic features related to overall survival (OS) and progression-free survival (PFS), the log-rank test, Cox proportional hazards model, and Lasso Cox regression model were used. Results: Among the 119 enrolled patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% had extrahepatic cholangiocarcinoma, and 23.5% had gallbladder cancer. Most patients had metastatic or recurrent disease (68.9%). The median follow-up duration was 23.7 months (range 0.8–30.2), median PFS was 8.3 months (95% Confidence interval (CI), 7.0–11.5), and median OS was 19.8 months (95% CI, 15.3–not reached). The most common genetic aberrations were TP53 (53.7%), KRAS (29.6%), and ARID1A (16.7%) alterations. TP53 mutations were associated with a poor OS (p = 0.001) and PFS (p = 0.005). In the transcriptome analysis, genes associated with immune responses, especially tumor-associated macrophages, were upregulated in patients with worse OS and PFS. We constructed a Lasso-Cox regression model and identified VSIG4 (hazard ratio (HR): 3.0, p = 2.0 × 10 -4 for OS; HR: 2.4, p = 4.0 × 10 -4 for PFS), ITGA3 (HR: 2.6, p = 0.001 for OS; HR: 1.7, p = 0.020 for PFS), and CCL8 (HR: 1.6, p = 0.110 for OS; HR: 1.6, p = 0.039 for PFS) as effective predictors of poor clinical outcomes during GemCis/nab-P treatment. Conclusions: GemCis/nab-P showed promising survival outcomes in advanced BTC. Further, patients with TP53 mutations or high tumoral levels of VSIG4, ITGA3, and CCL8 showed a poor prognosis after GemCis/nab-P treatment. Clinical trial information: NCT04871321 .