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

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 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n≥90,000 cases) and retrieved 2,789 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=8,857), 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.

Description

Funder: Robert Bosch Stiftung (Robert Bosch Foundation); doi: https://doi.org/10.13039/501100001646

Funder: Acción Estratégica de Salud del Instituto, de Salud Carlos III, (FIS PI12/02125/Cofinanciado), Acción Estratégica de Salud del Instituto, de Salud Carlos III, (FEDER PI17/00918/Cofinanciado, FEDER), Acción Estratégica de Salud del Instituto, de Salud Carlos III, (FIS Intrasalud PI13/01136), Programa Grupos Emergentes, Cancer, Genetics Unit, Instituto de Investigacion, Biomedica Galicia Sur. Xerencia de, Xestion Integrada de Vigo-SERGAS,, Instituto de Salud Carlos III, (10CSA012E), Consellería de Industria Programa, Sectorial de Investigación Aplicada,, PEME I + D e I + D Suma del Plan, Gallego de Investigación, Desarrollo e, Innovación Tecnológica de la Consellería, de Industria de la Xunta de Galicia, (EC11-192)

Funder: Dutch Cancer Society (DDHK 2004-3124) Dutch Cancer Society (DDHK 2009-4318)

Funder: NCI/NIH, (U01CA164920)

Funder: Finnish Cancer Foundation, the Academy of Finland, (250083), (122715), (251314)

Funder: Genome Canada and the Canadian, Institutes of Health Research, (GPH-129344) Genome Québec, (PSRSIIRI-701)

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): HEALTH-F2-2009-223175

Funder: NIH, (R35CA253187), (R01CA192393), (R01CA116167), (R01CA176785) NIH Specialized Program of Research, Excellence (SPORE), (P50CA116201)

Funder: University Hospital Erlangen, (UISGE-005/2018)

Funder: Dutch Cancer Society, (NKI 2007-3839) Dutch Cancer Society, (NKI 2009 4363)

Funder: NIH, (U19 GM61388) NIH, (P50CA116201) NIH, (U10CA77202) NIH, (R01CA196648)

Journal Title

npj Breast Cancer

Journal ISSN

2374-4677
2374-4677

Volume Title

11

Publisher

Springer Science and Business Media LLC

Publisher DOI

https://doi.org/10.1038/s41523-025-00733-y

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by-nc-nd/4.0/

Sponsorship

Canadian Institutes of Health Research (CIHR) (via Universit� Laval) (CRN-87521 IC089832)
Cancer Research Uk (None)
Cancer Research Uk (None)

We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This work was supported by Cancer Research UK grant: PPRPGM-Nov20\100002 and by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312) [*]. *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Additional funding for BCAC is provided by the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health, the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation. The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer Research UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for iCOGS came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. Detailed acknowledgements of individual studies with funding information are provided in Supplementary Note 1 in the Supplementary Information.

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