Biology-driven stratification of advanced biliary tract cancer treated with nab-paclitaxel plus gemcitabine-cisplatin: A prospective observational cohort study

Background & Aims: Nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit. Approach & Results: This prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade =>3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment. Conclusions: This study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.