Journal Article

DKFZ-2025-00398

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.

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.DKFZ* ; Nbcs Collaborators ; Dörk, T. ; Eccles, D. M. ; Figueroa, J. D. ; Gago-Dominguez, M. ; García-Sáenz, J. A. ; Gündert, M.DKFZ* ; Hack, C. C. ; Hamann, U.DKFZ* ; Han, S. ; Hooning, M. J. ; Huebner, H. ; Abctb Investigators ; 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.DKFZ*

2025
Nature Publ. Group London

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Please use a persistent id in citations: doi:10.1038/s41523-025-00733-y

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.

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Contributing Institute(s):

1. Epidemiologie von Krebs (C020)
2. DKTK Koordinierungsstelle Tübingen (TU01)
3. Molekulare Epidemiologie (C080)
4. Molekulargenetik des Mammakarzinoms (B072)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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