Impact of CYP2D6 polymorphisms on adverse events in patients with breast cancer treated with tamoxifen: Insights from an early dose escalation trial in CYP2D6 poor metabolizers.

Abstract

547 Background: Tamoxifen is widely used in treating hormone receptor-positive breast cancer. It is primarily metabolized by the CYP2D6 enzyme to yield active metabolites. However, CYP2D6 polymorphisms have been associated with a differential response to tamoxifen. In a clinical trial involving an early dose escalation of tamoxifen in poor metabolizers, we found endoxifen concentration levels similar to those of patients with extensive phenotype, and no long-term survival differences among CYP2D6 phenotypes. However, the impact of that dose escalation on side effect incidence was not addressed. Methods: In this study, we analyzed the incidence of specific side effects - osteoarticular pain, hot flashes, asthenia, and uterine alterations - in 86 breast cancer patients, differentiated by their CYP2D6 phenotype estimated according to the Clinical Pharmacogenetics Implementation Consortium. In poor metabolizers, the tamoxifen standard dose of 20 mg/day was escalated to 40 mg/day and 60 mg/day for 4 months each, and then treated with 20 mg/day until completing the treatment. Kaplan-Meier analysis and Cox proportional hazards regression model were employed to assess the relationship between the CYP2D6 phenotype and the incidence of these side effects. Results: The median follow-up time was 139.5 months. The analyses revealed that only uterine changes showed significant differences between CYP2D6 phenotypes, with a lower incidence in extensive metabolizers (P-value < 0.001 in Kaplan-Meier; HR in Cox of 0.195, 95% CI 0.073 - 0.521, P = 0.001). This finding persisted after adjustment for the covariates tumor grade, size, nodal status, chemotherapy, and radiotherapy in multivariate Cox regression (HR 0.098, 95% CI 0.020 - 0.466, P = 0.004). Selection of a subgroup through Propensity Score Matching (21 vs 21) corroborated these results. The spectrum of uterine changes and pathologies included endometrial hyperplasia, polyps, adenocarcinoma, myometrial or endometrial thickening, and the presence of multiple myomas. Conclusions: Our study indicates that an early increase in tamoxifen dose in poor metabolizer patients according to CYP2D6 polymorphisms may significantly affect the incidence of uterine changes, but not the incidence of osteoarticular pain, hot flashes, or asthenia. Clinical trial information: 2007-002942-40/ES .