Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen

Background: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultrametabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. Methods: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genoryping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. Results: A highly significant difference was detected (41.2% of difference, 95% CI 6-61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). Conclusions: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.