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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.* ; 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.* ; 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.*

Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.

npj Breast Cancer 11:18 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Estrogen-receptor; Induced Apoptosis; Therapy; Polymorphisms; Association; Anastrozole; Suppression; Toxicity; Survival; Efficacy
ISSN (print) / ISBN 2374-4677
e-ISSN 2374-4677
Journal npj Breast Cancer
Quellenangaben Volume: 11, Issue: 1, Pages: , Article Number: 18 Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research (IDF)
Grants Ovarian Cancer Research Fund
European Union
National Cancer Institute Intramural Research Program, National Institutes of Health
NIHR Cambridge Biomedical Research Centre
Government of Canada through Genome Canada
Canadian Institutes of Health Research
Breast Cancer Research Foundation
Komen Foundation for the Cure
Department of Defence
Post-Cancer GWAS initiative
National Institutes of Health
European Community
PSRSIIRI-701 grant
NIH
EU Horizon 2020 Research and Innovation Programme
Quebec Breast Cancer Foundation
Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec
Cancer Research UK