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 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.

Keywords:

ESTROGEN-RECEPTOR

INDUCED APOPTOSIS

THERAPY

POLYMORPHISMS

ASSOCIATION

ANASTROZOLE

SUPPRESSION

TOXICITY

SURVIVAL

EFFICACY

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

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