Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer
Publication date
2025-02-19
Authors
Hoppe, Reiner
Winter, Stefan
Lo, Wing Yee
Michailidou, Kyriaki
Bolla, Manjeet K.
Keeman, Renske
Wang, Qin
Dennis, Joe
Lush, Michael
Kalari, Krishna R.
Editors
Advisors
Supervisors
Document Type
Article
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License
cc_by_nc_nd
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.
Keywords
Oncology, Radiology Nuclear Medicine and imaging, Pharmacology (medical)
Citation
Hoppe, R, Winter, S, Lo, W Y, Michailidou, K, Bolla, M K, Keeman, R, Wang, Q, Dennis, J, Lush, M, Kalari, K R, Goetz, M P, Wang, L, Cairns, J, Weinshilboum, R, Shepherd, L, Chen, B E, Häberle, L, Ruebner, M, Beckmann, M W, He, W, Larson, N L, Armasu, S M, Schroth, W, Chowbay, B, Khor, C C, Abubakar, M, Antoniou, A C, Brüning, T, Castelao, J E, Chang-Claude, J, NBCS Collaborators, C, Dörk, T, Eccles, D M, Figueroa, J D, Gago-Dominguez, M, García-Sáenz, J A, Gündert, M, Hack, C C, Hamann, U, Han, S, Hooning, M J, Huebner, H, ABCTB Investigators, I, John, E M, Ko, Y D, Kristensen, V N, Linn, S, Margolin, S, Mavroudis, D, Nevanlinna, H, Neven, P, Obi, N, Park-Simon, T W, Pylkäs, K, Rashid, M U, Romero, A, Saloustros, E, Sawyer, E J, Tapper, W J, Tomlinson, I, Wendt, C, Winqvist, R, Dunning, A M, Simard, J, Hall, P, Pharoah, P D P, Schwab, M, Couch, F J, Czene, K, Fasching, P A, Easton, D F, Schmidt, M K, Ingle, J N & Brauch, H 2025, 'Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer', NPJ breast cancer, vol. 11, no. 1, 18. https://doi.org/10.1038/s41523-025-00733-y