Genomic pathway alterations and their prognostic impact in biliary tract cancer: Insights from a multinational cohort treated with cisplatin, gemcitabine, and durvalumab

IF 7.1 1区医学 Q1 ONCOLOGY

European Journal of Cancer Pub Date : 2025-10-03 DOI:10.1016/j.ejca.2025.116035

Chiara Pirrone , Umberto Malapelle , Francesco Pepe , Federica Lo Prinzi , Federico Nichetti , Anna Saborowski , Lorenzo Antonuzzo , Silvia Camera , Tomoyuki Satake , Frederik Peeters , Caterina Vivaldi , Tiziana Pressiani , Jessica Lucchetti , Jin Won Kim , Oluseyi Abidoye , Ilario Giovanni Rapposelli , Stefano Tamberi , Fabian Finkelmeier , Guido Giordano , Chiara Pircher , Andrea Casadei-Gardini

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引用次数: 0

Abstract

Background

Biliary tract cancers (BTC) are aggressive malignancies with limited therapeutic options. Recent advances have integrated immunotherapy into the standard of care, yet outcomes remain heterogeneous, emphasizing the need for molecular biomarkers to guide patient selection. This study aimed to assess the prognostic impact of pathway-level genomic alterations in patients with BTC treated with first-line cisplatin, gemcitabine, and durvalumab.

Methods

This retrospective, multicenter study included 735 patients with advanced BTC, of whom 197 underwent comprehensive genomic profiling using the FoundationOne® CDx assay. Pathways were classified based on the presence of key gene alterations, and their association with overall survival (OS) and progression-free survival (PFS) was assessed through univariate and multivariate analyses. Tumor mutational burden (TMB) was also evaluated as a potential biomarker.

Results

HRD/BRCAness pathway alterations were associated with significantly improved OS (23.3 vs. 13.8 months, HR 0.51, 95 % CI 0.27–0.93, p = 0.0295) and PFS (13.2 vs. 8.1 months, HR 0.53, 95 % CI 0.32–0.89, p = 0.0153). TGF-β pathway alterations were linked to longer PFS (16.0 vs. 8.1 months, HR 0.53, 95 % CI 0.28–0.99, p = 0.0473) but did not independently predict OS. High TMB (>10 mut/Mb) was associated with improved OS (NR vs. 11.0 months, HR 0.34, 95 % CI 0.14–0.85, p = 0.0206) and PFS (NR vs. 7.6 months, HR 0.40, 95 % CI 0.13–0.96, p = 0.043). However, no single pathway was significantly correlated with early treatment response.

Conclusions

HRD/BRCAness and TGF-β pathway alterations, along with high TMB, emerged as potential prognostic biomarkers in patients with BTC treated with chemo-immunotherapy. These findings, if prospectively confirmed and validated, support the integration of molecular profiling into routine clinical practice to improve patient stratification and treatment outcomes in this challenging tumor type.

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胆道癌的基因组通路改变及其预后影响：来自顺铂、吉西他滨和杜伐单抗治疗的多国队列的见解

胆道肿瘤（BTC）是侵袭性恶性肿瘤，治疗选择有限。最近的进展已将免疫治疗纳入标准治疗，但结果仍然不一致，强调需要分子生物标志物来指导患者选择。本研究旨在评估一线顺铂、吉西他滨和杜伐单抗治疗的BTC患者通路水平基因组改变对预后的影响。方法本回顾性多中心研究纳入了735例晚期BTC患者，其中197例采用FoundationOne®CDx检测进行了全面的基因组分析。根据关键基因改变的存在对途径进行分类，并通过单因素和多因素分析评估其与总生存期（OS）和无进展生存期（PFS）的关系。肿瘤突变负荷（Tumor mutational burden， TMB）也被评估为潜在的生物标志物。结果shrd /BRCAness通路改变与OS（23.3个月vs 13.8个月，HR 0.51, 95 % CI 0.27-0.93, p = 0.0295）和PFS（13.2个月vs 8.1个月，HR 0.53, 95 % CI 0.32-0.89, p = 0.0153）显著改善相关。TGF-β通路改变与更长的PFS相关（16.0 vs. 8.1个月，HR 0.53, 95 % CI 0.28-0.99, p = 0.0473），但不能独立预测OS。高TMB （>10 mut/Mb）与改善OS （NR vs. 11.0个月，HR 0.34, 95 % CI 0.14-0.85, p = 0.0206）和PFS （NR vs. 7.6个月，HR 0.40, 95 % CI 0.13-0.96, p = 0.043）相关。然而，没有单一途径与早期治疗反应显著相关。结论shrd /BRCAness和TGF-β通路改变以及高TMB是化疗免疫治疗BTC患者的潜在预后生物标志物。如果这些发现得到前瞻性的证实和验证，将支持将分子谱分析整合到常规临床实践中，以改善这种具有挑战性的肿瘤类型的患者分层和治疗结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Cancer 医学-肿瘤学

CiteScore

11.50

自引率

4.80%

发文量

953

审稿时长

23 days

期刊介绍： The European Journal of Cancer (EJC) serves as a comprehensive platform integrating preclinical, digital, translational, and clinical research across the spectrum of cancer. From epidemiology, carcinogenesis, and biology to groundbreaking innovations in cancer treatment and patient care, the journal covers a wide array of topics. We publish original research, reviews, previews, editorial comments, and correspondence, fostering dialogue and advancement in the fight against cancer. Join us in our mission to drive progress and improve outcomes in cancer research and patient care.