Influence of CYP2D6 and its polymorphic forms on the metabolism of tamoxifen in therapy of luminal forms of breast cancer

Abstract

Annotation. Tamoxifen belongs to the group of selective estrogen receptor modulators (SERM) and is metabolized by the detoxification system of xenobiotics, and the phenomenon of metabolic activation can be observed at the first stage. CYP2D6 also directly participates in this process, the analysis of polymorphic forms of which can influence the prediction of the effectiveness and toxicity of tamoxifen in the treatment of luminal forms of breast cancer, which is of great importance considering the duration of therapy with this drug. The aim – to analyze scientific literature data on the effect of CYP2D6 and its polymorphs on the metabolism of tamoxifen in the treatment of luminal forms of breast cancer. A retrospective analysis of the literature of scientific databases Scopus, Web of Science, PubMed., MedLines for 2013-2023 was carried out. It is established that CYP2D6 can be considered a predictor of treatment effectiveness only in patients with breast cancer (ER+) who are postmenopausal and receive 20 mg of tamoxifen per day for 5 years and do not have hepatotoxic conditions and CYP2D6 inhibition phenomena, which determines the expediency of genotyping CYP2D6 polymorphic variants in such a group. Long-term therapy with tamoxifen can be complicated by the development of secondary endometrial cancer. Undesirable effects of tamoxifen may also depend on the activity of CYP2D6. Thus, in slow metabolizers, for example, carriers of CYP2D6*3/*4 and CYP2D6*6/*6, a statistically significant increase in the frequency of cases of endometrial hyperplasia was observed. In addition, polymorphisms of other enzymes of the biotransformation system of xenobiotics that participate in both the activation and deactivation of tamoxifen and its metabolites, both the first (CYP3A4, CYP3A5, CYP2B6, CYP2C9, CYP2C19 and CYP2D6) and the second phase (SULT and UGT), remain a promising direction for study. The study of the consequences of the phenomena of iatrogenic cholestasis and drug interactions at the level of CYP2D6, which may affect the metabolism of tamoxifen, also requires a detailed study, taking into account the intensive pharmacotherapy of BC.