A recent study presented at the 2025 ASCO Gastrointestinal Cancers Symposium provided valuable insights into the genomic landscape of biliary tract cancers (BTCs) and its implications for targeted therapy outcomes. Targeted therapies have demonstrated antitumor efficacy in a specific group of patients with actionable genetic alterations; nevertheless, the majority of patients either do not respond to these therapies or develop acquired resistance over time.
This study analyzed data from a prospectively maintained cohort of patients with histologically confirmed BTC who underwent next-generation sequencing, which explored the mechanisms of response and resistance to targeted therapy.
Overall, 1254 patients underwent molecular profiling. A total of 61.2% of patients had intrahepatic cholangiocarcinoma, 16.8% had extrahepatic cholangiocarcinoma, and 22.1% had gallbladder cancer. The study identified several oncogenic drivers that can predict a positive response to matched targeted therapy. The most frequently altered genes among microsatellite-stable tumors were TP53 (36%), CDKN2A (21%), ARID1A (18%), KRAS (17%), and IDH1/2 (16%). Notably, genomic profiles differed significantly based on the anatomic subsite. Patients with these alterations demonstrated meaningful progression-free survival (PFS) when treated with matched targeted therapy. Specifically, median PFS was 4.2 months for IDH1/2 alterations, 7.4 months for FGFR2, 8.2 months for ERBB2, not reached for MSI-high (lower confidence interval at 10.15 months), and 16.6 months for BRAF V600E. Importantly, clinical factors or co-occurring genomic alterations did not impact outcomes.
The study also explored mechanisms of acquired resistance to targeted therapy by profiling paired pre- and post-progression samples. This included the emergence of recurrent oncogenic alterations in FGFR2-, RAS-, MEK-, and MET-driven tumors, as well as off-target MYC amplification and CDKN2A loss. Loss of the oncogenic driver at progression was only observed for ERBB2-driven tumors.
This study acknowledged limitations in the design but concluded that matched targeted therapy offers meaningful PFS, particularly in patients with MSI-high BTC treated with immunotherapy. The findings also suggest the role of ERBB2 heterogeneity and loss as a potential mechanism of resistance to HER2-targeted therapy. The identification of specific oncogenic drivers that predict response, coupled with the elucidation of mechanisms of acquired resistance, represent critical steps toward developing more effective treatment strategies for these aggressive cancers.
Cowzer D, Walch HS, Atri P, et al. Molecular and clinical determinants of targeted therapy (TT) outcomes in biliary tract cancer (BTC): analysis of a prospectively maintained next generation sequencing (NGS) biorepository. Presented at: ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA; Virtual. Abstract 555.
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