CYP2D6 genotype and outcome in tamoxifen treated early breast cancer

Background and purpose: The clinical significance of individual CYP2D6 activity for the outcome of tamoxifen treatment in early breast cancer is unclear. Our previous investigation in patients diagnosed over the period 1998-2000 indicated an association between reduced CYP2D6 activity and poor outcome in premenopausal women. The aim of this study was to investigate the association between CYP2D6 genotype and clinical outcome in a larger tamoxifen treated cohort. Patients/material and methods: Swedish breast cancer patients who initiated adjuvant tamoxifen treatment over the period 2006-2014 constituted the full study cohort. Clinical information was collected from medical records. Data on endocrine treatment, use of CYP2D6 inhibitors was retrieved from the Swedish Prescribed Drug Register. CYP2D6 was genotyped and translated into predicted metabolic activity. The association between CYP2D6 activity and clinical outcome was analyzed using Cox regression, controlling for potential confounding variables. Subgroup analyses were performed based on menopausal status, tamoxifen treatment for at least 1 year and as single endocrine treatment, HER2-status and tamoxifen monotherapy. Results: A total of 1,103 patients were included. A total of 761 patients received tamoxifen as monotherapy. A total of 42% were premenopausal. Median follow-up was 11.4 years. No significant association was found between CYP2D6 activity and recurrence (adjusted hazard ratio [aHR] 1.18, 95% CI 0.92; 1.52) or breast cancer mortality (aHR 1.41, 95%CI 0.93; 2.13) in the full cohort, or in the subgroup with tamoxifen monotherapy (aHR 1.39, CI 0.99; 1.96 and 1.88, CI 0.98; 3.60 respectively). Interpretation: No association was noted between reduced CYP2D6 activity and poorer outcome in this early breast cancer cohort, with patients generally at lower risk of recurrence, reflecting the role of adjuvant tamoxifen in current clinical practice.