Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer
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 753 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.
Hoppe, Reiner
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Winter, Stefan
9d062111-898a-4344-bda2-3f74c55639b8
Lo, Wing-Yee
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Eccles, Diana
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Tapper, William
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19 February 2025
Hoppe, Reiner
7f2e8119-e115-430b-a6b1-8d871560afd8
Winter, Stefan
9d062111-898a-4344-bda2-3f74c55639b8
Lo, Wing-Yee
f95ac706-be9a-4069-984c-a66a53ab4420
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Hoppe, Reiner, Winter, Stefan and Lo, Wing-Yee
,
et al
(2025)
Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.
npj Breast Cancer, 11 (1), [18].
(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 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.
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Accepted/In Press date: 4 February 2025
Published date: 19 February 2025
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Local EPrints ID: 499541
URI: http://eprints.soton.ac.uk/id/eprint/499541
PURE UUID: 7b24bf20-0320-41d1-b655-d01c1e5d0f3f
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Date deposited: 25 Mar 2025 18:03
Last modified: 22 Aug 2025 01:44
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Author:
Reiner Hoppe
Author:
Stefan Winter
Author:
Wing-Yee Lo
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