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

Hoppe R, Winter S, Lo WY, Michailidou K, Bolla MK, Keeman R, Wang Q, Dennis J, Lush M, Kalari KR, Goetz MP, Wang L, Cairns J, Weinshilboum R, Shepherd L, Chen BE, Häberle L, Rübner M, Beckmann M, He W, Larson NL, Armasu SM, Schroth W, Chowbay B, Khor CC, Abubakar M, Antoniou AC, Brüning T, Castelao JE, Chang-Claude J, NBCS Collaborators , Dörk T, Eccles DM, Figueroa JD, Gago-Dominguez M, García-Sáenz JA, Gündert M, Hack C, Hamann U, Han S, Hooning MJ, Hübner H, ABCTB Investigators , John EM, Ko YD, Kristensen VN, Linn S, Margolin S, Mavroudis D, Nevanlinna H, Neven P, Obi N, Park-Simon TW, Pylkäs K, Rashid MU, Romero A, Saloustros E, Sawyer EJ, Tapper WJ, Tomlinson I, Wendt C, Winqvist R, Dunning AM, Simard J, Hall P, Pharoah PD, Schwab M, Couch FJ, Czene K, Fasching P, Easton DF, Schmidt MK, Ingle JN, Brauch H (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 11

Article Number: 18

Journal Issue: 1

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.

Authors with CRIS profile

Involved external institutions

Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) The University of Melbourne Australia (AU) Cyprus Institute of Neurology and Genetics Cyprus (CY) University of Cambridge United Kingdom (GB) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Mayo Clinic United States (USA) (US) Mayo Clinic College of Medicine and Science (MCCMS) United States (USA) (US) Queen's University Canada (CA) Karolinska Institute Sweden (SE) National Cancer Institute (NCI) United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Oulun Yliopisto / University of Oulo Finland (FI) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Hospital Universitario Puerta de Hierro - Majadahonda Spain (ES) General University Hospital of Larissa Greece (GR) King’s College London United Kingdom (GB) University of Southampton United Kingdom (GB) University of Oxford United Kingdom (GB) CHU de Québec-Université Laval Canada (CA) Cedars-Sinai Medical Center United States (USA) (US) National Cancer Centre Singapore (NCCS) Singapore (SG) Genome Institute of Singapore Singapore (SG) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung, Institut der Ruhr-Universität Bochum (IPA) Germany (DE) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Hospital Clínico San Carlos Spain (ES) Erasmus University Medical Center (MC) Netherlands (NL) University of Sydney (USYD) Australia (AU) Stanford University United States (USA) (US) Johanniter GmbH Germany (DE) Södersjukhuset Sweden (SE) University General Hospital of Heraklion Greece (GR) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) Finland (FI) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE)

How to cite

APA:

Hoppe, R., Winter, S., Lo, W.Y., Michailidou, K., Bolla, M.K., Keeman, R.,... Brauch, H. (2025). Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer. npj Breast Cancer, 11(1). https://doi.org/10.1038/s41523-025-00733-y

MLA:

Hoppe, Reiner, et al. "Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer." npj Breast Cancer 11.1 (2025).

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