Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen; Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria.
ESMO Open. 2024 Aug;9(8):103630. doi: 10.1016/j.esmoop.2024.103630. Epub 2024 Jul 16.
Biliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting.
We carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy.
A total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35).
Patients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors.
胆道癌（BTC）在临床和分子特征方面具有较高的死亡率和显著的异质性。本研究旨在对 BTC 患者进行分子特征分析，重点关注同源重组修复（HRR）基因中的基因组改变，这是在真实环境中进行的。
我们对 2016 年至 2023 年间在奥地利的五家中心和一家德国综合癌症中心接受治疗的 256 名 BTC 患者进行了回顾性分析，利用全面的基因组分析平台评估 HRR 状态及其与铂类化疗后临床结局的相关性。
共有 67 名患者（27.5%）表现出 HRR 基因突变（HRRm），最常见的致病性改变为 BAP1（9%）、ARID1A（7.8%）和 ATM（6.1%）。接受铂类药物治疗的 HRRm 患者和非 HRRm 患者的一线治疗失败时间（TFS）分别为 7.9 和 6.7 个月[风险比（HR）0.89；P=0.49]。在 HRRm 组中，6、18 和 24 个月的总生存率（OS）估计值分别为 82%、45%和 39%（中位数 16.01 个月），在 HRR 组中分别为 81%、42%和 22%（中位数 15.68 个月）（Fleming-Harrington 检验 P=0.0004；对数秩检验 P=0.022）。多变量分析中无显著意义（HR 0.72；95%置信区间 0.489-1.059；P=0.095）。二线治疗中观察到 HRRm 状态与分子指导治疗策略之间的相互作用。二线治疗中，接受伊立替康为基础的方案与再次接受铂类药物治疗的 OS 相当（12.36 个月对 10.13 个月；HR 0.92；P=0.85）。与二线铂类药物治疗的非 HRRm 患者相比，HRRm 患者并未观察到更好的结局（HR 1.45；P=0.35）。
BTC 中 HRRm 患者在铂类一线化疗后 OS 方面可能具有优势，这可能归因于增强了靶向治疗的机会。需要进一步研究以阐明 BTC 中 HRR 的范围，并详细说明对铂类药物或多聚（ADP-核糖）聚合酶（PARP）抑制剂的靶向治疗的临床意义敏感性。
