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In 1,254 biliary cancer patients sequenced at one centre, a third had a top-tier druggable change (22% of gallbladder cancers), targeted drugs delayed progression but did not lengthen life, and HER2-driven tumours sometimes lost HER2 at relapse.
A prospectively maintained cohort of 1,254 patients with histologically confirmed biliary tract cancer underwent molecular profiling with an FDA-authorised targeted next-generation sequencing assay. 59% harboured at least one OncoKB alteration and 32.2% (intrahepatic 40%, extrahepatic 15%, gallbladder 22%) had a level 1 or 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-driven and ERBB2-driven tumours respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumours, whereas IDH-, FGFR-, BRAF- and NTRK-driven tumours retained the primary driver; acquired resistance was associated with alterations in RAS, MEK, MET, MYC and CDKN2A.
For gallbladder cancer the points that matter are that HER2 can disappear under HER2-directed pressure, that SMAD4 co-mutation predicts a worse response, and that sequencing at progression, not just at diagnosis, may be needed to guide the next line.
Shares Ghassan K. Abou-Alfa, NTRK1/2/3 gene fusion, SMAD4, NTRK.
Shares Ghassan K. Abou-Alfa, Biliary tract cancer (all types), HER2, Biliary tract cancer (cholangiocarcinoma).
Shares Ghassan K. Abou-Alfa, SMAD4, Memorial Sloan Kettering Cancer Center, Gallbladder cancer.
Shares Ghassan K. Abou-Alfa, Memorial Sloan Kettering Cancer Center, HER2, Gallbladder cancer.
Shares Ghassan K. Abou-Alfa, Biliary tract cancer (all types), Biliary tract cancer (cholangiocarcinoma), Gallbladder cancer.
Shares Biliary tract cancer (all types), HER2, Biliary tract cancer (cholangiocarcinoma), Gallbladder cancer.