Background: Cholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients. Methods: All consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional-hazards models. Results: Of the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in theFGFR2(N = 21),IDH1(N = 7) andBRCA2(N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49–12.78), 5.65 (95% CI, 3.71–7.13), 5.55 (2.79–12.58) and 29.01 (24.21–42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p= 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p= 0.002) and OS (p= 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p< 0.001). Conclusions: Patients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies.
背景：胆管癌（CCA）预后较差且治疗选择有限，这促使靶向治疗在其管理中应用日益广泛。本研究开展了规模最大的单中心回顾性分析之一，旨在评估胆管癌患者接受个体化靶向药物治疗后的临床结局。 方法：纳入2010年1月至2023年4月期间在伦敦大学学院医院连续接受全身治疗的所有胆管癌患者。本研究主要目的是评估接受分子引导治疗的胆管癌患者的治疗反应、生存结局及临床获益预测因素。采用Kaplan-Meier法和Cox比例风险模型评估患者人口学特征、疾病特征及生存结局。 结果：在227例连续入组的胆管癌患者中，162例（71%）进行了分子谱分析，其中56例（35%）符合条件，55例接受了分子靶向治疗。组织学分类包括肝内型（32例）、肝外型（11例）、肝门型（4例）及未知亚型（9例）。多数患者（34例）基于基因组分析结果在二线治疗中接受靶向药物。常见基因组变异集中于FGFR2（21例）、IDH1（7例）和BRCA2（6例）基因。一线、二线、三线全身治疗后的中位无进展生存期（PFS）及总生存期（OS）分别为8.44个月（95% CI：7.49-12.78）、5.65个月（95% CI：3.71-7.13）、5.55个月（95% CI：2.79-12.58）和29.01个月（95% CI：24.21-42.91）。胆管癌亚型与FGFR/BRCA分子变异状态均与PFS或OS无显著关联，但既往胆管癌相关手术史可预测OS（p=0.02）。根据二线靶向药物最佳总体缓解进行分层分析显示，其与PFS（p=0.002）和OS（p=0.02）存在显著关联。二线靶向治疗持续时间与OS密切相关（p<0.001）。 结论：接受靶向治疗的患者取得了良好的临床结局，特别是在获得良好治疗反应及接受长期靶向药物治疗的患者群体中。液体活检可可靠提供扩展分子谱信息，有助于为个体化治疗筛选适宜患者。
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