Factors Associated with Plasma Levels of Tamoxifen and its Main Metabolites in Mexican Patients with Breast Cancer

Abstract

Background: Tamoxifen (TAM) is commonly prescribed as adjuvant therapy in women with estrogen receptor-positive breast cancer. Unfortunately, not all patients respond adequately to this drug. This variation in pharmacological response has been associated with different factors, including genetic polymorphisms of enzymes responsible for the metabolism of TAM. Objective: To determine the concentrations of tamoxifen (TAM) and its main metabolites in Mexican women with breast cancer and to evaluate its relationship with genetic, demographic and anthropometric characteristics. Methods: Eighty-four patients with a mean age of 49.3 (± 8.8) years were included in the study. Plasma concentrations of TAM and its metabolites N-desmethyl-tamoxifen (NDT), 4- hydroxy-tamoxifen (4HT) and endoxifen (END) were determined in predose for each patient. CYP2D6 * 4, * 10 and CYP3A5 * 3 genetic polymorphisms were characterized. Demographic, anthropometric, biochemical and clinical data were recorded for each patient. Results: Plasma concentrations of 4HT and END were higher in the extensive metabolizer (EM) phenotype than in the intermediate metabolizer (IM) phenotype (p<0.05). The metabolic ratio (MR) [END+4HT]/[TAM+NDT] was lower in patients with the CYP2D6 IM phenotype than those with the EM phenotype (p= 0.014). Regarding anthropometric factors, a positive correlation was found for 4HT and the END concerning age (R = 0.256 and 0.232, respectively). The body mass index (BMI) presented a statistically significant correlation with the concentrations of NDT (R=-0.351) and 4HT (R=-0.298). Conclusion: CYP2D6 phenotype, age and BMI could help to explain part of the interindividual variability of TAM plasma levels and its metabolites in the Mexican population.