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

Journal article

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: Hoppe, R; Winter, S; Lo, W; Michailidou, K; Bolla, MK

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: npj Breast Cancer
• Volume: 11
• Issue: 1
• Article number: 18
• Publication date: 2025-02-19
• Acceptance date: 2025-02-04
• DOI: 10.1038/s41523-025-00733-y
• EISSN: 2374-4677
• ISSN: 2374-4677
• Language: English