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, 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, 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) npj Breast Cancer, volume 11, issue 1
(Article)
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
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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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Keywords: Oncology, Radiology Nuclear Medicine and imaging, Pharmacology (medical)
ISSN: 1526-8209
Publisher: Elsevier
Note: Publisher Copyright: © The Author(s) 2025.
(Peer reviewed)
