Genetic variation in CYP19A1 and response to exemestane: Survival in early breast cancer in the Dutch TEAM trial.

Abstract

10518 Background: In patients with endocrine-sensitive breast cancer treated with adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a recurrence and who will benefit from AI’s. Variations in the aromatase gene (CYP19A1) are associated with altered estrogen levels and altered aromatase activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 gene on survival in a prospective cohort of breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and who were treated with five years of exemestane were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. A significant association with worse RFS was found with two SNPs: rs7176005 and rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous variant types respectively. These SNPs, as well as a third SNP, rs6493497, were also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). Conclusions: Germline variations in the CYP19A1 gene are related to a worse outcome in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. The relation between RFS and SNP’s in CYP19A1. [Table: see text]