Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer

Abstract Purpose: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer (BTC); however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. Experimental Design: We analyzed a prospectively maintained cohort of 1254 patients with histologically confirmed BTC who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. Results: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2- and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. Conclusions: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted next-generation sequencing of BTC and affirms the use of precision medicine in patients with these diseases. Characterization of genomic heterogeneity and therapeutic resistance has the potential to inform ongoing drug development efforts for BTC.