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A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
12:24

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Published on: September 30, 2021

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

Darren Cowzer1, Henry Walch2, Pranita Atri2

  • 1Memorial Sloan Kettering Cancer Center New York United States.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 26, 2026
PubMed
Abstract

Insights

Genomic profiling reveals actionable targets in biliary tract cancer (BTC), but targeted therapies offer limited survival benefits. Understanding resistance mechanisms is key for developing new precision medicines for BTC.

Area of Science:

  • Oncology
  • Genomics
  • Precision Medicine

Background:

  • Biliary tract cancer (BTC) exhibits actionable genomic alterations across all subtypes.
  • Targeted therapies in BTC have not yet demonstrated a significant survival advantage over traditional cytotoxic treatments.
  • Mechanisms of therapeutic resistance in BTC require further investigation.

Purpose of the Study:

  • To analyze actionable genomic alterations in a large cohort of BTC patients.
  • To compare the efficacy of targeted therapy versus cytotoxic chemotherapy.
  • To identify genomic correlates of resistance to targeted therapies in BTC.

Main Methods:

  • Molecular profiling of 1254 BTC patients using a targeted next-generation sequencing assay.
  • Definition of actionable alterations and comparison of patient outcomes based on treatment modality.
  • Evaluation of genomic changes associated with acquired resistance using longitudinal samples.

Main Results:

  • 59% of patients had at least one actionable OncoKB alteration; 32.2% had a level 1/2 alteration.
  • Emerging targets include KRAS, MTAP deletions, MDM2, and MET amplifications.
  • Targeted therapy improved progression-free survival but not overall survival; resistance mechanisms involved alterations in RAS, MEK, MET, MYC, and CDKN2A.

Conclusions:

  • Comprehensive molecular profiling demonstrates the utility and limitations of targeted next-generation sequencing for BTC.
  • Precision medicine is affirmed as a valuable approach for BTC treatment.
  • Characterizing genomic heterogeneity and resistance mechanisms can guide future drug development for BTC.

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