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
{"title":"晚期ER+/HER2-乳腺癌循环肿瘤DNA治疗早期演变的预后意义","authors":"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","doi":"10.1016/j.annonc.2025.06.015","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Patients and methods: </strong>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).</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7000,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Prognostic significance of early on-treatment evolution of circulating tumor DNA in advanced ER+/HER2- breast cancer.\",\"authors\":\"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\",\"doi\":\"10.1016/j.annonc.2025.06.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Patients and methods: </strong>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).</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":56.7000,\"publicationDate\":\"2025-07-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.annonc.2025.06.015\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.annonc.2025.06.015","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Prognostic significance of early on-treatment evolution of circulating tumor DNA in advanced ER+/HER2- breast cancer.
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.
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.
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