Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.

中文翻译：

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通过分子表征拓宽晚期胆道癌的治疗视野。


胆道癌（BTC）由一组罕见且异质性预后不良的肿瘤组成，其中肝内胆管癌的发病率近年来不断增加。吉西他滨和顺铂联合化疗是晚期 BTC 的既定一线治疗方法，与单一疗法相比，具有显着但适度的生存优势。尽管最近的一项随机研究结果显示 5-氟尿嘧啶和奥沙利铂化疗可带来生存获益，但二线治疗尚无公认的标准治疗方法。从历史上看，研究未选择的 BTC 靶向治疗的临床试验未能证明显着的临床益处。最近，BTC 分子探索的进展揭示了这些肿瘤内复杂的生物异质性，并且还确定了可操作的基因组畸变，例如成纤维细胞生长因子受体 2 (FGFR2) 基因融合、异柠檬酸脱氢酶 (IDH) 和 BRAF 突变。这为选定的患者带来了预期增加的反应和持久的临床益处的希望。几种靶向药物现已进入临床开发，并取得了一些令人鼓舞的结果。在这里，我们回顾了当前快速发展的先进 BTC 治疗前景，包括靶向治疗和免疫治疗。我们还讨论了 BTC 最近的努力和成功如何克服与罕见癌症精准医疗相关的障碍。最终，晚期 BTC 的治疗很可能在不久的将来成为分子选择，希望最终改善这种疾病患者的黯淡预后。