TY  - JOUR
AU  - Hoppe, Reiner
AU  - Winter, Stefan
AU  - Lo, Wing-Yee
AU  - Michailidou, Kyriaki
AU  - Bolla, Manjeet K
AU  - Keeman, Renske
AU  - Wang, Qin
AU  - Dennis, Joe
AU  - Lush, Michael
AU  - Kalari, Krishna R
AU  - Goetz, Matthew P
AU  - Wang, Liewei
AU  - Cairns, Junmei
AU  - Weinshilboum, Richard
AU  - Shepherd, Lois
AU  - Chen, Bingshu E
AU  - Häberle, Lothar
AU  - Ruebner, Matthias
AU  - Beckmann, Matthias W
AU  - He, Wei
AU  - Larson, Nicole L
AU  - Armasu, Sebastian M
AU  - Schroth, Werner
AU  - Chowbay, Balram
AU  - Khor, Chiea Chuen
AU  - Abubakar, Mustapha
AU  - Antoniou, Antonis C
AU  - Brüning, Thomas
AU  - Castelao, Jose E
AU  - Chang-Claude, Jenny
AU  - Nbcs Collaborators
AU  - Dörk, Thilo
AU  - Eccles, Diana M
AU  - Figueroa, Jonine D
AU  - Gago-Dominguez, Manuela
AU  - García-Sáenz, José A
AU  - Gündert, Melanie
AU  - Hack, Carolin C
AU  - Hamann, Ute
AU  - Han, Sileny
AU  - Hooning, Maartje J
AU  - Huebner, Hanna
AU  - Abctb Investigators
AU  - John, Esther M
AU  - Ko, Yon-Dschun
AU  - Kristensen, Vessela N
AU  - Linn, Sabine
AU  - Margolin, Sara
AU  - Mavroudis, Dimitrios
AU  - Nevanlinna, Heli
AU  - Neven, Patrick
AU  - Obi, Nadia
AU  - Park-Simon, Tjoung-Won
AU  - Pylkäs, Katri
AU  - Rashid, Muhammad U
AU  - Romero, Atocha
AU  - Saloustros, Emmanouil
AU  - Sawyer, Elinor J
AU  - Tapper, William J
AU  - Tomlinson, Ian
AU  - Wendt, Camilla
AU  - Winqvist, Robert
AU  - Dunning, Alison M
AU  - Simard, Jacques
AU  - Hall, Per
AU  - Pharoah, Paul D P
AU  - Schwab, Matthias
AU  - Couch, Fergus J
AU  - Czene, Kamila
AU  - Fasching, Peter A
AU  - Easton, Douglas F
AU  - Schmidt, Marjanka K
AU  - Ingle, James N
AU  - Brauch, Hiltrud
TI  - Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.
JO  - npj Breast cancer
VL  - 11
IS  - 1
SN  - 2374-4677
CY  - London
PB  - Nature Publ. Group
M1  - DKFZ-2025-00398
SP  - 18
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39971965
DO  - DOI:10.1038/s41523-025-00733-y
UR  - https://inrepo02.dkfz.de/record/298978
ER  -