Deep molecular profiling of biliary tract cancer uncovers novel biological mechanisms and therapeutic opportunities

BACKGROUND: International guidelines recommend molecular profiling for patients with advanced biliary tract cancer (BTC) eligible for systemic treatment, but the utility of deep, multi-omic approaches remains underexplored. MATERIALS AND METHODS: We report molecular and clinical results of patients with BTC and enrolled in the German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program between February 2014 and December 2021. Tumor whole-genome/whole-exome (WGS/WES) and RNA sequencing (RNAseq) were carried out according to MASTER's standardized workflow, and eligibility for molecularly informed therapies was discussed within MASTER's molecular tumor board. Treatments included strategies based on a composite homologous recombination deficiency (HRD) biomarker (TOP-ART score) or RNAseq-based findings (gene fusions/overexpression). RESULTS: Among 131 registered patients, genomic and transcriptomic profiling were successful in 115 (89%) and 89 (77%) cases, respectively. Comparative evaluation of molecular profiles highlighted ultra-rare distinctive features of BTC, including an enrichment of PTPRM gene fusions. MASTER-informed therapy was implemented in 23 (20.0%) patients, of whom 4 were treated according to the TOP-ART score while 12 according to RNAseq-based recommendations (gene fusions and/or overexpression), including 1 case with a MET fusion. Median progression-free survival (PFS) on molecularly informed therapy was 4.6 (3.7-12.7) months, with a PFS ratio (δ > 1.3)-based benefit rate of 60%. CONCLUSIONS: Multi-omic profiling of BTC within the MASTER program uncovered novel therapeutic opportunities. By the identification of ultra-rare and composite biomarkers, MASTER-guided therapies resulted in clinical benefit also in heavily pretreated patients.