%0 Journal Article
%A Hoppe, Reiner
%A Winter, Stefan
%A Lo, Wing-Yee
%A Michailidou, Kyriaki
%A Bolla, Manjeet K
%A Keeman, Renske
%A Wang, Qin
%A Dennis, Joe
%A Lush, Michael
%A Kalari, Krishna R
%A Goetz, Matthew P
%A Wang, Liewei
%A Cairns, Junmei
%A Weinshilboum, Richard
%A Shepherd, Lois
%A Chen, Bingshu E
%A Häberle, Lothar
%A Ruebner, Matthias
%A Beckmann, Matthias W
%A He, Wei
%A Larson, Nicole L
%A Armasu, Sebastian M
%A Schroth, Werner
%A Chowbay, Balram
%A Khor, Chiea Chuen
%A Abubakar, Mustapha
%A Antoniou, Antonis C
%A Brüning, Thomas
%A Castelao, Jose E
%A Chang-Claude, Jenny
%A Nbcs Collaborators
%A Dörk, Thilo
%A Eccles, Diana M
%A Figueroa, Jonine D
%A Gago-Dominguez, Manuela
%A García-Sáenz, José A
%A Gündert, Melanie
%A Hack, Carolin C
%A Hamann, Ute
%A Han, Sileny
%A Hooning, Maartje J
%A Huebner, Hanna
%A Abctb Investigators
%A John, Esther M
%A Ko, Yon-Dschun
%A Kristensen, Vessela N
%A Linn, Sabine
%A Margolin, Sara
%A Mavroudis, Dimitrios
%A Nevanlinna, Heli
%A Neven, Patrick
%A Obi, Nadia
%A Park-Simon, Tjoung-Won
%A Pylkäs, Katri
%A Rashid, Muhammad U
%A Romero, Atocha
%A Saloustros, Emmanouil
%A Sawyer, Elinor J
%A Tapper, William J
%A Tomlinson, Ian
%A Wendt, Camilla
%A Winqvist, Robert
%A Dunning, Alison M
%A Simard, Jacques
%A Hall, Per
%A Pharoah, Paul D P
%A Schwab, Matthias
%A Couch, Fergus J
%A Czene, Kamila
%A Fasching, Peter A
%A Easton, Douglas F
%A Schmidt, Marjanka K
%A Ingle, James N
%A Brauch, Hiltrud
%T Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.
%J npj Breast cancer
%V 11
%N 1
%@ 2374-4677
%C London
%I Nature Publ. Group
%M DKFZ-2025-00398
%P 18
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39971965
%R 10.1038/s41523-025-00733-y
%U https://inrepo02.dkfz.de/record/298978