Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early ERBB2-Positive Breast Cancer: 10-Year Analysis of the ShortHER Randomized Clinical Trial.

IF 20.1 1区医学 Q1 Biochemistry, Genetics and Molecular Biology

Jama Oncology Pub Date : 2025-04-01 DOI:10.1001/jamaoncol.2024.6872

Maria Vittoria Dieci, Giancarlo Bisagni, Stefania Bartolini, Alessio Schirone, Luigi Cavanna, Antonino Musolino, Francesco Giotta, Anita Rimanti, Ornella Garrone, Elena Bertone, Katia Cagossi, Samanta Sarti, Antonella Ferro, Federico Piacentini, Enrico Orvieto, Melinda Sanders, Federica Miglietta, Davide Massa, Sara Balduzzi, Pierfranco Conte, Roberto D'Amico, Valentina Guarneri

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引用次数: 0

Abstract

Importance: For patients with early ERBB2 (formerly HER2)-positive breast cancer, there is a need to identify biomarkers to guide treatment de-escalation.

Objective: To evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free (DDFS) and overall survival (OS) for patients with ERBB2-positive early breast cancer.

Design, setting, and participants: The ShortHER randomized clinical trial was a multicentric trial in Italy that enrolled patients with ERBB2-positive breast cancer from December 2007 to October 2013. Patients received 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Tumor samples were evaluated for TILs. Herein, patients were evaluated at a median follow-up of 9 years, and data were analyzed from February 2023 to August 2024.

Intervention: Four cycles of anthracycline-based chemotherapy followed by 4 courses of taxanes combined with trastuzumab for 1 year (long arm) or 3 courses of taxanes combined with trastuzumab for 9 weeks followed by reduced-dose anthracycline-based chemotherapy for 3 courses (short arm).

Main outcomes and measures: The association of TILs with DDFS and OS was assessed with Cox models.

Results: Of 1253 patients enrolled in the ShortHER trial, 866 women (median [IQR] age, 56 [48-64] years) had evaluable TILs. In Cox models with relevant factors, each 5% TIL increment was associated with improved DDFS (hazard ratio [HR], 0.87; 95% CI, 0.80-0.95; P = .001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P = .01). The 10-year OS rate was 91.3% for patients with TILs 20% or higher, 93.3% for patients with TILs 30% or higher, and 98.1% for patients with TILs 50% or higher, resulting higher vs lower TIL counterparts. Patients with TILs lower than 20% showed a better outcome with the long vs short treatment (10-year DDFS, 88.7% vs 81.0%), whereas patients with TILs 20% or higher showed the opposite (10-year DDFS, 87.1% vs 92.2%; P for interaction = .01). Similarly, patients with TILs 20% or higher had a 10-year OS rate of 89.3% in the long arm vs 93.1% in the short arm (HR, 0.36; 95% CI, 0.10-1.36); patients with TILs lower than 20% had a 10-year OS rate of 91.3% in the long arm vs 86.9% in the short arm (HR, 1.36; 95% CI, 0.82-2.23; P for interaction = .06).

Conclusions and relevance: This follow-up analysis of the ShortHER randomized clinical trial is, to our knowledge, the first demonstration of an independent effect of TILs in terms of OS for patients with ERBB2-positive early breast cancer treated with adjuvant chemotherapy and anti-ERBB2 therapy. Patients with TILs 20% or higher who de-escalated trastuzumab duration and chemotherapy dose were not exposed to an excess risk of distant relapse or death.

Trial registration: EudraCT: 2007-004326-25.

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早期erbb2阳性乳腺癌的肿瘤浸润淋巴细胞和生存结局：10年短期随机临床试验分析

重要性：对于早期ERBB2（以前的HER2）阳性乳腺癌患者，需要确定生物标志物来指导治疗降级。目的：探讨erbb2阳性早期乳腺癌患者肿瘤浸润淋巴细胞（til）与远处无病（DDFS）和总生存（OS）的关系。设计、环境和参与者：ShortHER随机临床试验是2007年12月至2013年10月在意大利进行的一项多中心试验，招募了erbb2阳性乳腺癌患者。患者接受9周或1年的辅助曲妥珠单抗联合化疗。对肿瘤样本进行TILs评估。本研究中位随访时间为9年，数据分析时间为2023年2月至2024年8月。干预：4个周期的蒽环类化疗后，紫杉烷联合曲妥珠单抗4个疗程，持续1年（长臂），或紫杉烷联合曲妥珠单抗3个疗程，持续9周，然后减少剂量的蒽环类化疗3个疗程（短臂）。主要结局和指标：采用Cox模型评估TILs与DDFS和OS的相关性。结果：在ShortHER试验的1253名患者中，866名女性（中位[IQR]年龄，56[48-64]岁）具有可评估的TILs。在有相关因素的Cox模型中，TIL每增加5%与DDFS的改善相关(风险比[HR]， 0.87；95% ci, 0.80-0.95；P = .001)和OS (HR, 0.89；95% ci, 0.81-0.98；p = 0.01)。TILs为20%或更高的患者10年OS率为91.3%，TILs为30%或更高的患者为93.3%，TILs为50%或更高的患者为98.1%，结果是更高或更低的TIL。TILs低于20%的患者在长期治疗和短期治疗中表现出更好的结果（10年DDFS， 88.7%对81.0%），而TILs为20%或更高的患者则表现相反(10年DDFS， 87.1%对92.2%；P为相互作用= 0.01)。同样，TILs为20%或更高的患者，10年OS率在长臂组为89.3%，在短臂组为93.1% (HR, 0.36；95% ci, 0.10-1.36)；TILs低于20%的患者，10年OS在长臂组为91.3%，在短臂组为86.9% (HR, 1.36；95% ci, 0.82-2.23；P为相互作用= .06)。结论及相关性：据我们所知，这项对ShortHER随机临床试验的随访分析首次证明了TILs对接受辅助化疗和抗erbb2治疗的erbb2阳性早期乳腺癌患者的OS有独立影响。TILs为20%或更高的患者，如果曲妥珠单抗持续时间和化疗剂量降低，则不会暴露于远处复发或死亡的过度风险。试验注册：draft: 2007-004326-25。

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

Jama Oncology Medicine-Oncology

CiteScore

37.50

自引率

1.80%

发文量

423

期刊介绍： At JAMA Oncology, our primary goal is to contribute to the advancement of oncology research and enhance patient care. As a leading journal in the field, we strive to publish influential original research, opinions, and reviews that push the boundaries of oncology science. Our mission is to serve as the definitive resource for scientists, clinicians, and trainees in oncology globally. Through our innovative and timely scientific and educational content, we aim to provide a comprehensive understanding of cancer pathogenesis and the latest treatment advancements to our readers. We are dedicated to effectively disseminating the findings of significant clinical research, major scientific breakthroughs, actionable discoveries, and state-of-the-art treatment pathways to the oncology community. Our ultimate objective is to facilitate the translation of new knowledge into tangible clinical benefits for individuals living with and surviving cancer.