Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer
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.
Overview
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.
- Level 1 or 2 actionable alteration in 32.2% overall: intrahepatic 40%, extrahepatic 15%, gallbladder 22%.
- KRAS 17%, MTAP deletion 12.8%, MDM2 amplification 6.5%, MET amplification 1.5% as emerging targets.
- Targeted therapy improved progression-free but not overall survival; ERBB2-driven tumours lost ERBB2 at progression while IDH, FGFR, BRAF and NTRK drivers were retained.
For gallbladder cancer the sobering points 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.
- Single tertiary centre; treatment choice was not randomised, so the PFS gain may reflect selection.
- Actionability graded by OncoKB levels.
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