Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer.

IF 3 3区医学 Q2 ONCOLOGY

Breast Cancer Research and Treatment Pub Date : 2025-09-01 Epub Date: 2025-07-12 DOI:10.1007/s10549-025-07759-7

Rohan Chaubal, Elizabeth Talker, Jaya Chitra, Rasika Kadam, Nilesh Gardi, Riddhi Ursekar, Anushree Kadam, Ankita Singh, Suhani Sale, Shwetali Pandey, Mrudula Madhav, Aishwarya Raja, Rushikesh Mukhare, Pallavi Parab, Nitin Shetty, Kunal Gala, Suyash Kulkarni, Khushboo A Gandhi, Seema Gulia, Shalaka Joshi, Tanuja Shet, Sudeep Gupta

{"title":"Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer.","authors":"Rohan Chaubal, Elizabeth Talker, Jaya Chitra, Rasika Kadam, Nilesh Gardi, Riddhi Ursekar, Anushree Kadam, Ankita Singh, Suhani Sale, Shwetali Pandey, Mrudula Madhav, Aishwarya Raja, Rushikesh Mukhare, Pallavi Parab, Nitin Shetty, Kunal Gala, Suyash Kulkarni, Khushboo A Gandhi, Seema Gulia, Shalaka Joshi, Tanuja Shet, Sudeep Gupta","doi":"10.1007/s10549-025-07759-7","DOIUrl":null,"url":null,"abstract":"Purpose: We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.Methods: HR+/HER2-negative patients who were disease-free for ≥2 years were considered hormone therapy-sensitive (n = 19), while those who experienced disease progression within 2 years were considered hormone therapy-resistant (n = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (n = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (n = 35) and sensitive (n = 19) patients.Results: In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, p = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of PIK3CA and/or TP53 mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as PIK3CA H1047X, AKT1 p.E17K, CDH1 p.R63X, CDKN2A p.X50*, ERBB2 p.D769Y, and ESR1 p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.Conclusion: Hormone therapy-resistant HR+/HER2-negative breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":" ","pages":"247-259"},"PeriodicalIF":3.0000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331804/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research and Treatment","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10549-025-07759-7","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/12 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.

Methods: HR+/HER2-negative patients who were disease-free for ≥2 years were considered hormone therapy-sensitive (n = 19), while those who experienced disease progression within 2 years were considered hormone therapy-resistant (n = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (n = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (n = 35) and sensitive (n = 19) patients.

Results: In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, p = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of PIK3CA and/or TP53 mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as PIK3CA H1047X, AKT1 p.E17K, CDH1 p.R63X, CDKN2A p.X50*, ERBB2 p.D769Y, and ESR1 p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.

Conclusion: Hormone therapy-resistant HR+/HER2-negative breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.

Abstract Image

查看原文本刊更多论文

激素治疗抵抗性hr阳性和her2阴性乳腺癌的基因组图谱。

目的：我们旨在描述激素受体阳性(HR+)/ her2阴性乳腺癌患者激素治疗耐药和敏感表型的基因组图谱。方法：HR+/ her2阴性的无病≥2年的患者被认为是激素治疗敏感（n = 19），而2年内出现疾病进展的患者被认为是激素治疗抵抗（n = 48）。对来自耐药患者（n = 19）的配对（treatment-naïve和复发部位）肿瘤和生殖系来源的DNA进行全外显子组测序（WES），对来自耐药（n = 35）和敏感（n = 19）患者的血浆来源的循环肿瘤DNA （ctDNA）进行靶向下一代测序（NGS）。结果：在19例耐药患者中，复发部位的突变负担高于treatment-naïve样本（中位数 0.883 vs 0.655 突变/mb， p = 0.03），有64个驱动突变(中位数treatment-naïve vs复发部位；2/样本vs. 3/复发)，其中15例（78.9%）患者中8个基因中的21个突变被归类为可操作的，18例（94.7%）患者中观察到分支进化轨迹，13例（68.4%）患者的干细胞克隆中存在PIK3CA和/或TP53突变。35例耐药患者的ctDNA分析在25例（71.4%）患者中鉴定出27个可操作的热点突变，如PIK3CA H1047X、AKT1 p.E17K、CDH1 p.R63X、CDKN2A p.X50*、ERBB2 p.D769Y和ESR1 p.E380Q。在19例激素治疗敏感疾病患者中，在样本采集时处于缓解期，ctDNA分析显示10例（52.6%）患者发生驱动突变，其中2例随后复发并死亡。结论：激素治疗耐药的HR+/ her2阴性乳腺癌是多克隆的，在复发时获得可操作的改变，中等深度的ctDNA成功地识别了许多克隆突变，提示液体活检监测在这些患者中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Breast Cancer Research and Treatment 医学-肿瘤学

CiteScore

6.80

自引率

2.60%

发文量

342

审稿时长

1 months

期刊介绍： Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.