Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer
Hoppe, Reiner; Winter, Stefan; Lo, Wing-Yee; Michailidou, Kyriaki; Bolla, Manjeet K; Keeman, Renske; Wang, Qin; Dennis, Joe; Lush, Michael; Kalari, Krishna R; Goetz, Matthew P; Wang, Liewei; Cairns, Junmei; Weinshilboum, Richard; Shepherd, Lois; Chen, Bingshu E; Häberle, Lothar; Ruebner, Matthias; Beckmann, Matthias W; He, Wei; Larson, Nicole L; Armasu, Sebastian M; Schroth, Werner; Chowbay, Balram; Khor, Chiea Chuen; Abubakar, Mustapha; Antoniou, Antonis C; Brüning, Thomas; Castelao, Jose E; Chang-Claude, Jenny; Nbcs Collaborators,; Dörk, Thilo; Eccles, Diana M; Figueroa, Jonine D; Gago-Dominguez, Manuela; García-Sáenz, José A; Gündert, Melanie; Hack, Carolin C; Hamann, Ute; Han, Sileny; Hooning, Maartje J; Huebner, Hanna; Abctb Investigators,; John, Esther M; Ko, Yon-Dschun; Kristensen, Vessela N; Linn, Sabine; Margolin, Sara; Mavroudis, Dimitrios; Nevanlinna, Heli; Neven, Patrick; Obi, Nadia; Park-Simon, Tjoung-Won; Pylkäs, Katri; Rashid, Muhammad U; Romero, Atocha; Saloustros, Emmanouil; Sawyer, Elinor J; Tapper, William J; Tomlinson, Ian; Wendt, Camilla; Winqvist, Robert; Dunning, Alison M; Simard, Jacques; Hall, Per; Pharoah, Paul D P; Schwab, Matthias; Couch, Fergus J; Czene, Kamila; Fasching, Peter A; Easton, Douglas F; Schmidt, Marjanka K; Ingle, James N; Brauch, Hiltrud (2025-02-19)
Springer
19.02.2025
Hoppe, R., Winter, S., Lo, WY. et al. Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer. npj Breast Cancer 11, 18 (2025). https://doi.org/10.1038/s41523-025-00733-y
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https://creativecommons.org/licenses/by-nc-nd/4.0/
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202502211770
https://urn.fi/URN:NBN:fi:oulu-202502211770
Tiivistelmä
Abstract
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.
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.
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