Interrelations entre les gènes CYP450 et la réponse à l'hormonothérapie adjuvante chez la femme en pré-ménopause dans le cancer du sein.

Abstract

Tamoxifen, a selective estrogen receptor modulator acts as an anti-estrogen in ER+ breast cancer. It inhibits competitively the binding of estradiol to their receptors, the efficacy depends on its active metabolites, particularly endoxifen that is metabolized primarily by CYP2D6, CYP3A5, and CYP2C19 enzymes. The variability in the enzyme activity related to genetic polymorphisms that affect plasma concentrations of the metabolites, thus the efficacy and toxicity of the treatment. Nevertheless, contradictory results provided by many studies which do not currently allow predicting the relevance of CYP450 genotyping before prescription of tamoxifen. In our study, we evaluated the correlation between the main metabolites of tamoxifen and the incidence of relapses after 5 years of tamoxifen treatment as adjuvant, in a cohort of premenopausal Algerian patients with ER+ breast cancer. In addition, a molecular study is conducted to test the impact of pharmacogenetics of CYP2D6, CYP2C19 and CYP3A5 on the pharmacokinetics of tamoxifen. The analyzes revealed significant variability in plasma concentrations of tamoxifen and its metabolites in 143 patients that were included in our series. The genotyping of the CYP2D6, CYP2C19 and CYP3A5 genes was established for 100 samples by OpenArray® technique, based on real-time PCR that allows a high throughput genotyping. In this study we also highlighted the role of CYP2D6, thus plasma endoxifen levels under therapeutic threshold (C< 5.9 ng/ml) was observed in homozygous subjects with reduced alleles (red/red), nul alleles (nul/nul) or heterozygous subjects for the altered alleles (red/nul). In the pharmacodynamics study, our results indicate that patients with PM and IM phenotypes for the CYP2D6 gene are more likely to developed relapses during or post treatment with tamoxifen. Our research, the first performed in Algeria, provides crucial results on the influence of genetic factors, mainly CYP2D6 and to a minor degree CYP3A5 and CYP2C19, on non-genetic parameters (age, as well as clinical and pathological parameters such as tumor size, grade and stage), on the pharmacokinetics and pharmacodynamics of tamoxifen in the context of adjuvant treatment of hormone-positive breast cancer, and thus can be provided as support when introducing hormone therapy in ER+ breast cancer protocol. The best strategy to optimize tamoxifen treatment would consist of an adaptation of doses according to the CYP2D6 genotype accompanied by a TDM of endoxifen once the state of equilibrium reached.