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This review examines the role of molecular testing and targeted therapies in these malignant neoplasms.<\/jats:p><\/jats:sec><jats:sec id=\"ab-srv250001-2\"><jats:title>Observations<\/jats:title><jats:p>Patients with hepatobiliary cancers have poor outcomes. Precision oncology studies have shown that while many common molecular alterations are not currently targetable in hepatocellular carcinoma (HCC), a large number of actionable alterations characterize biliary tract cancers (BTCs), with several therapies now approved by the US Food and Drug Administration. Immunotherapy is increasingly adopted in clinical practice, either as monotherapy or combined with cytotoxic chemotherapy, for both HCC and BTCs. Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for <jats:italic>NTRK<\/jats:italic> fusions; selpercatinib for <jats:italic>RET<\/jats:italic> fusions; dabrafenib and trametinib combination for <jats:italic>BRAF<\/jats:italic> V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden \u226510 mutations\/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue\u2013agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. N-of-1 clinical trials using customized drug combinations matched to the tumor\u2019s molecular profile have yielded encouraging results and provide a promising framework for future clinical trial design.<\/jats:p><\/jats:sec><jats:sec id=\"ab-srv250001-3\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Molecular testing and gene- and immune-targeted therapies are transforming hepatobiliary cancer treatment. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamasurg.2025.0242","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T15:45:09Z","timestamp":1742399109000},"page":"576","source":"Crossref","is-referenced-by-count":18,"title":["Molecular Testing and Targeted Therapies in Hepatobiliary Cancers"],"prefix":"10.1001","volume":"160","author":[{"given":"Diamantis I.","family":"Tsilimigras","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razelle","family":"Kurzrock","sequence":"additional","affiliation":[{"name":"Medical College of Wisconsin Cancer Center and Linda T. and John A. 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