Reiner Hoppe, Stefan Winter, Wing-Yee Lo, Kyriaki Michailidou, Manjeet K Bolla, Renske Keeman, Qin Wang, Joe Dennis, Michael Lush, Krishna R Kalari, Matthew P Goetz, Liewei Wang, Junmei Cairns, Richard Weinshilboum, Lois Shepherd, Bingshu E Chen, Lothar Häberle, Matthias Ruebner, Matthias W Beckmann, Wei He, Nicole L Larson, Sebastian M Armasu, Werner Schroth, Balram Chowbay, Chiea Chuen Khor, Mustapha Abubakar, Antonis C Antoniou, Thomas Brüning, Jose E Castelao, Jenny Chang-Claude, Nbcs Collaborators, Thilo Dörk, Diana M Eccles, Jonine D Figueroa, Manuela Gago-Dominguez, José A García-Sáenz, Melanie Gündert, Carolin C Hack, Ute Hamann, Sileny Han, Maartje J Hooning, Hanna Huebner, Abctb Investigators, Esther M John, Yon-Dschun Ko, Vessela N Kristensen, Sabine Linn, Sara Margolin, Dimitrios Mavroudis, Heli Nevanlinna, Patrick Neven, Nadia Obi, Tjoung-Won Park-Simon, Katri Pylkäs, Muhammad U Rashid, Atocha Romero, Emmanouil Saloustros, Elinor J Sawyer, William J Tapper, Ian Tomlinson, Camilla Wendt, Robert Winqvist, Alison M Dunning, Jacques Simard, Per Hall, Paul D P Pharoah, Matthias Schwab, Fergus J Couch, Kamila Czene, Peter A Fasching, Douglas F Easton, Marjanka K Schmidt, James N Ingle, Hiltrud Brauch
{"title":"从一项研究芳香酶抑制剂治疗乳腺癌结果的候选基因研究中获得的经验教训。","authors":"Reiner Hoppe, Stefan Winter, Wing-Yee Lo, Kyriaki Michailidou, Manjeet K Bolla, Renske Keeman, Qin Wang, Joe Dennis, Michael Lush, Krishna R Kalari, Matthew P Goetz, Liewei Wang, Junmei Cairns, Richard Weinshilboum, Lois Shepherd, Bingshu E Chen, Lothar Häberle, Matthias Ruebner, Matthias W Beckmann, Wei He, Nicole L Larson, Sebastian M Armasu, Werner Schroth, Balram Chowbay, Chiea Chuen Khor, Mustapha Abubakar, Antonis C Antoniou, Thomas Brüning, Jose E Castelao, Jenny Chang-Claude, Nbcs Collaborators, Thilo Dörk, Diana M Eccles, Jonine D Figueroa, Manuela Gago-Dominguez, José A García-Sáenz, Melanie Gündert, Carolin C Hack, Ute Hamann, Sileny Han, Maartje J Hooning, Hanna Huebner, Abctb Investigators, Esther M John, Yon-Dschun Ko, Vessela N Kristensen, Sabine Linn, Sara Margolin, Dimitrios Mavroudis, Heli Nevanlinna, Patrick Neven, Nadia Obi, Tjoung-Won Park-Simon, Katri Pylkäs, Muhammad U Rashid, Atocha Romero, Emmanouil Saloustros, Elinor J Sawyer, William J Tapper, Ian Tomlinson, Camilla Wendt, Robert Winqvist, Alison M Dunning, Jacques Simard, Per Hall, Paul D P Pharoah, Matthias Schwab, Fergus J Couch, Kamila Czene, Peter A Fasching, Douglas F Easton, Marjanka K Schmidt, James N Ingle, Hiltrud Brauch","doi":"10.1038/s41523-025-00733-y","DOIUrl":null,"url":null,"abstract":"<p><p>The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.</p>","PeriodicalId":19247,"journal":{"name":"NPJ Breast Cancer","volume":"11 1","pages":"18"},"PeriodicalIF":7.6000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840073/pdf/","citationCount":"0","resultStr":"{\"title\":\"Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.\",\"authors\":\"Reiner Hoppe, Stefan Winter, Wing-Yee Lo, Kyriaki Michailidou, Manjeet K Bolla, Renske Keeman, Qin Wang, Joe Dennis, Michael Lush, Krishna R Kalari, Matthew P Goetz, Liewei Wang, Junmei Cairns, Richard Weinshilboum, Lois Shepherd, Bingshu E Chen, Lothar Häberle, Matthias Ruebner, Matthias W Beckmann, Wei He, Nicole L Larson, Sebastian M Armasu, Werner Schroth, Balram Chowbay, Chiea Chuen Khor, Mustapha Abubakar, Antonis C Antoniou, Thomas Brüning, Jose E Castelao, Jenny Chang-Claude, Nbcs Collaborators, Thilo Dörk, Diana M Eccles, Jonine D Figueroa, Manuela Gago-Dominguez, José A García-Sáenz, Melanie Gündert, Carolin C Hack, Ute Hamann, Sileny Han, Maartje J Hooning, Hanna Huebner, Abctb Investigators, Esther M John, Yon-Dschun Ko, Vessela N Kristensen, Sabine Linn, Sara Margolin, Dimitrios Mavroudis, Heli Nevanlinna, Patrick Neven, Nadia Obi, Tjoung-Won Park-Simon, Katri Pylkäs, Muhammad U Rashid, Atocha Romero, Emmanouil Saloustros, Elinor J Sawyer, William J Tapper, Ian Tomlinson, Camilla Wendt, Robert Winqvist, Alison M Dunning, Jacques Simard, Per Hall, Paul D P Pharoah, Matthias Schwab, Fergus J Couch, Kamila Czene, Peter A Fasching, Douglas F Easton, Marjanka K Schmidt, James N Ingle, Hiltrud Brauch\",\"doi\":\"10.1038/s41523-025-00733-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.</p>\",\"PeriodicalId\":19247,\"journal\":{\"name\":\"NPJ Breast Cancer\",\"volume\":\"11 1\",\"pages\":\"18\"},\"PeriodicalIF\":7.6000,\"publicationDate\":\"2025-02-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840073/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Breast Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41523-025-00733-y\",\"RegionNum\":2,\"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":"NPJ Breast Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41523-025-00733-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.
The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.
期刊介绍：
npj Breast Cancer publishes original research articles, reviews, brief correspondence, meeting reports, editorial summaries and hypothesis generating observations which could be unexplained or preliminary findings from experiments, novel ideas, or the framing of new questions that need to be solved. Featured topics of the journal include imaging, immunotherapy, molecular classification of disease, mechanism-based therapies largely targeting signal transduction pathways, carcinogenesis including hereditary susceptibility and molecular epidemiology, survivorship issues including long-term toxicities of treatment and secondary neoplasm occurrence, the biophysics of cancer, mechanisms of metastasis and their perturbation, and studies of the tumor microenvironment.
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