Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice. Some ongoing clinical trials, as well as future areas of exploration for precision oncology in BTCs are highlighted.


While treatment of MSI-H/dMMR tumors with pembrolizumab is currently the only targeted, biomarker-based therapy FDA-approved for BTCs, there are many potentially actionable aberrations in BTCs, and comprehensive genomic profiling is highly recommended in the management of BTCs. Additional biomarker-based treatments such as NTRK/ROS1-targeted therapies, albeit very low prevalence in BTCs, and FGFR-targeted therapies, are likely candidates for near-term regulatory approvals. There are several targeted therapies FDA-approved for other indications (e.g., HER2-targeted agents) with potential relevance for precision oncology application in BTCs that could possibly be considered for off-label use on a case-by-case basis. Importantly, there are also several biomarker-driven and unselected clinical trials for many of these FDA-approved agents to expand into BTCs, as well as for novel targeted therapies, that should be watched and considered for enrollment. Biomarker-driven umbrella or basket trials will be of high interest to BTC research efforts, as well as facilitating the development of novel targeted agents and combinations thereof. Many of the mutations/aberrations observed in BTCs are often indolent drivers alone (e.g., IDH or FGFR2), and even where such drivers may be significantly beneficial to target as monotherapy, combination therapy targeting two or more drivers is likely to yield deeper and more durable responses. Well-designed preclinical models, that recapitulate in vivo properties and thus can accurately interrogate precise genomic contexts to derive and test such combination therapies, will be paramount in moving beyond empirical therapy into a new era of precision therapy for BTCs.

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