Prognostic significance of early on-treatment evolution of circulating tumor DNA in advanced ER+/HER2- breast cancer.

IF 56.7 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2025-07-05 DOI:10.1016/j.annonc.2025.06.015

A Mamann, Y Pradat, F C Bidard, S Delaloge, L Cabel, I Faull, S Marques, T Bachelot, F Dalenc, T DE LA Motte Rouge, B Pistilli, J Samaniego, J S Frenel, C Levy, J M Ferrero, R Sabatier, S Ladoire, C Chakiba, A C Hardy, J Lemonnier, Y Mahi, F Andre, P H Cournede, S Michiels, E Bernard

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引用次数: 0

Abstract

Background: Patients with advanced estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer commonly develop resistance to treatment with hormone therapy and cyclin-dependent kinases 4/6 (CDK4/6) inhibitors. Responders cannot be distinguished from non-responders after the first cycle of treatment under current practice. We assessed circulating tumor DNA (ctDNA) measures at early time-points as prognostic markers.

Patients and methods: Paired plasma samples were collected at baseline and early on-treatment (median 28 days) from 369 patients with advanced ER+/HER2- breast cancer treated in the PADA-1 trial with hormone therapy and a CDK4/6 inhibitor. Cell-free DNA was profiled with a 497-gene panel (Guardant360 LDT).

Results: Baseline ctDNA levels including the mean variant allele frequency (VAF) (progression-free survival [PFS] HR = 1.07 [1.05, 1.09] P<0.001, overall survival [OS] HR = 1.08 [1.05, 1.11] P<0.001) and the number of driver somatic mutations (PFS HR = 1.13 [1.07, 1.19], P<0.001 and OS HR = 1.16 [1.07, 1.24], P<0.001) were prognostic. Early on-treatment ctDNA dynamics were also associated with outcomes, including the number of driver somatic mutations with VAF>0.5% at both timepoints (PFS HR = 1.39 [1.27,1.53] P<0.001 and OS HR = 1.51 [1.35,1.68] P<0.001) and the number of driver somatic mutations with a VAF increase (PFS HR = 1.31 [1.19,1.44] P<0.001 and OS HR = 1.10 [1.02,1.18] P=0.02). A ctDNA-based risk model incorporating baseline and dynamic ctDNA features was independently prognostic from RECIST in multivariable models (Test set: OS HR = 4.10 [1.93,8.72], P<0.001, PFS HR = 1.86 [1.16,2.97], P=0.009). The integration of ctDNA features into a clinical model improved survival discrimination for PFS (C-index 64.7% [s.d. 2.5] for a ctDNA & clinical model vs. 59.3% [s.d. 2.2] for a clinical only model, p=0.027) and for OS (C-index 70.0% [s.d 3.4] vs. 60.3% [s.d. 4.2], p=0.035).

Conclusions: Early on-treatment evolution of ctDNA is prognostic for both PFS and OS in advanced ER+/HER2- breast cancer. A ctDNA-based risk model improves upon traditional RECIST and clinical parameters, advocating for ctDNA as a prognostic biomarker in clinical practice.

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晚期ER+/HER2-乳腺癌循环肿瘤DNA治疗早期演变的预后意义

背景：晚期雌激素受体阳性，HER2阴性（ER+/HER2-）乳腺癌患者通常对激素治疗和细胞周期蛋白依赖性激酶4/6 （CDK4/6）抑制剂治疗产生耐药性。根据目前的做法，在第一个治疗周期后，不能区分反应者和无反应者。我们评估了循环肿瘤DNA （ctDNA）在早期时间点的测量作为预后标志物。患者和方法：在基线和治疗早期（中位28天）收集369例晚期ER+/HER2-乳腺癌患者的配对血浆样本，这些患者在PADA-1试验中接受激素治疗和CDK4/6抑制剂治疗。使用497基因面板（guarant360 LDT）分析无细胞DNA。结果：基线ctDNA水平包括平均变异等位基因频率（VAF）（两个时间点的无进展生存期[PFS] HR = 1.07 [1.05, 1.09] P0.5%）（PFS HR = 1.39[1.27,1.53]）结论：晚期ER+/HER2-乳腺癌的PFS和OS的早期治疗进展是预后因素。基于ctDNA的风险模型改进了传统的RECIST和临床参数，倡导ctDNA作为临床实践中的预后生物标志物。

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

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.