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

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

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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