{"entity":{"id":"paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026","kind":"paper","name":"Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer","aka":[],"tldr":"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.","summary":"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%).\n\nTargeted 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.","asOf":"2026-09-24","links":[{"label":"Cowzer et al., Clin Cancer Res 2026: molecular determinants of targeted therapy in 1,254 biliary tract cancers","url":"https://doi.org/10.1158/1078-0432.ccr-26-0428"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/42360806/"},{"label":"cBioPortal study biliary_tract_msk_2026 (Hepatobiliary Cancer, MSK 2026)","url":"https://www.cbioportal.org/study/summary?id=biliary_tract_msk_2026"}],"tags":[],"related":[],"cancers":["gallbladder","cholangiocarcinoma","biliary-tract-cancer"],"sections":[],"technologies":[],"targets":["her2","kras","mdm2","smad4","cdkn2a"],"drugs":[],"companies":[],"institutions":["mskcc"],"pathways":[],"terms":[],"trials":[],"people":["ghassan-abou-alfa"],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2026,"doi":"10.1158/1078-0432.ccr-26-0428","pmid":"42360806","authors":"Cowzer D, Walch H, Atri P, et al.","paperType":"observational","findings":["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."],"whatItMeans":"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.","caveats":["Single tertiary centre; treatment choice was not randomised, so the PFS gain may reflect selection.","Actionability graded by OncoKB levels."],"changedPractice":false,"participants":1254},"route":"/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/","neighbours":{"cancer":[{"id":"biliary-tract-cancer","kind":"cancer","name":"Biliary tract cancer (all types)","route":"/cancers/biliary-tract-cancer/"},{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"}],"target":[{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"mdm2","kind":"target","name":"MDM2","route":"/targets/mdm2/"},{"id":"ntrk","kind":"target","name":"NTRK","route":"/targets/ntrk/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"person":[{"id":"ghassan-abou-alfa","kind":"person","name":"Ghassan K. Abou-Alfa","route":"/people/ghassan-abou-alfa/"}],"journal":[{"id":"clinical-cancer-research","kind":"journal","name":"Clinical Cancer Research","route":"/journals/clinical-cancer-research/"}],"biomarker":[{"id":"ntrk-fusion","kind":"biomarker","name":"NTRK1/2/3 gene fusion","route":"/biomarkers/ntrk-fusion/"}]}}