{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T17:26:27Z","timestamp":1788629187904,"version":"build-2803163510"},"reference-count":142,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Biliary tract cancer (BTC) remains among the most challenging malignancies with a poor prognosis and limited treatment options, particularly in pretreated patients. As most patients experience disease progression after first-line treatment, effective second-line and subsequent treatments are required. Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. Moreover, most clinical trials demonstrated modest efficacy of molecular-targeted agents for molecularly unselected pretreated advanced BTC. Patients with advanced BTC carry a relatively high druggable genetic alteration rate and have shown promising responses to molecular-matched therapies targeting gene alterations such as FGFR2 fusions\/rearrangements, IDH1 mutation, and HER2 overexpression\/amplification. Additionally, tumor-agnostic approaches, including BRAF V600E, NTRK fusion, and RET fusion, have expanded the treatment options for some patients. Immune checkpoint inhibitors have shown limited efficacy as mono- or combination therapy in patients with pretreated advanced BTC. Therefore, developmental efforts have shifted to immune checkpoint inhibitor and other combinations such as vascular endothelial growth factor receptor inhibitors or radiation. In addition to refining combination strategies to enhance the therapeutic potential of immune checkpoint inhibitor, future research should focus on elucidating the tumor microenvironment. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.<\/jats:p>","DOI":"10.1093\/jjco\/hyaf052","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T12:19:42Z","timestamp":1742213982000},"page":"675-690","source":"Crossref","is-referenced-by-count":2,"title":["Systemic therapy for pretreated advanced biliary tract cancer: past developments and recent advances"],"prefix":"10.1093","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4098-5217","authenticated-orcid":false,"given":"Naohiro","family":"Okano","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Kyorin University Faculty of Medicine , 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611 ,","place":["Japan"]},{"name":"Division of Hematology and Oncology, Mayo Clinic , 5881 E Mayo Blvd, Phoenix, AZ 85054 ,","place":["United 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