# Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer

Source: https://onco.cc/key-papers/paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026/  
OnCo record `paper-cowzer-biliary-targeted-therapy-determinants-ccr-2026` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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%).

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Clinical Cancer Research
- Year: 2026
- DOI: 10.1158/1078-0432.ccr-26-0428
- Authors: Cowzer D, Walch H, Atri P, et al.
- 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.
- What it means: 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.

## Sources

- Cowzer et al., Clin Cancer Res 2026: molecular determinants of targeted therapy in 1,254 biliary tract cancers: https://doi.org/10.1158/1078-0432.ccr-26-0428
- PubMed: https://pubmed.ncbi.nlm.nih.gov/42360806/
- cBioPortal study biliary_tract_msk_2026 (Hepatobiliary Cancer, MSK 2026): https://www.cbioportal.org/study/summary?id=biliary_tract_msk_2026

## Connected records

- cancers: [Biliary tract cancer (all types)](https://onco.cc/cancers/biliary-tract-cancer/), [Biliary tract cancer (cholangiocarcinoma)](https://onco.cc/cancers/cholangiocarcinoma/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/)
- targets: [CDKN2A](https://onco.cc/targets/cdkn2a/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/), [MDM2](https://onco.cc/targets/mdm2/), [NTRK](https://onco.cc/targets/ntrk/), [SMAD4](https://onco.cc/targets/smad4/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- people: [Ghassan K. Abou-Alfa](https://onco.cc/people/ghassan-abou-alfa/)
- journals: [Clinical Cancer Research](https://onco.cc/journals/clinical-cancer-research/)
- biomarkers: [NTRK1/2/3 gene fusion](https://onco.cc/biomarkers/ntrk-fusion/)

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