{"title":"激素治疗抵抗性hr阳性和her2阴性乳腺癌的基因组图谱。","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":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","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":"{\"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\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"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}","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}
Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer.
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.
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.
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