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...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 February 2025
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| In: |
npj Breast cancer
Year: 2025, Volume: 11, Pages: 1-15 |
| ISSN: | 2374-4677 |
| DOI: | 10.1038/s41523-025-00733-y |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41523-025-00733-y Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41523-025-00733-y 
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| Author Notes: | Reiner Hoppe, Jenny Chang-Claude, Ute Hamann [und viele weitere] |
| Summary: | 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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| Item Description: | Gesehen am 22.09.2025 |
| Physical Description: | Online Resource |
| ISSN: | 2374-4677 |
| DOI: | 10.1038/s41523-025-00733-y |