Influence of CYP2D6, CYP2C19 and CYP3A5 polymorphisms on plasma levels of tamoxifen metabolites in Algerian women with ER+ breast cancer

Abstract

Abstract Background Tamoxifen, a selective estrogen receptor modulator, is indicated for breast cancer developed in response to estrogen. Findings In the current study we explored the relationship between the different variants of CYP2D6, CYP2C19, CYP3A5 and plasma Endoxifen levels in Algerian patients with ER + breast cancer. We further conducted the relationship between the candidate genes and the recurrences rate. Endoxifen levels differed significantly (p < .005) between carriers of two functional alleles and patients genotyped as CYP2D6*10, CYP2D6*17, CYP2D6*41 or CYP2D6*5/*5. Patients with elevated Endoxifen concentrations were significantly more likely to not report recurrences than patients with reduced or nul alleles. Such nul/nul, red/red, and red/nul diplotypes have been associated with a higher rate of recurrences than other genotypes during treatment. Conclusion Our findings suggest that the CYP2D6 genotype should be considered in tamoxifen-treated women. While quantitatively, CYP2D6 represents only a minor fraction of the total drug metabolizing capacity of the liver, it is polymorphic and, therefore, may alter the balance of metabolism of tamoxifen toward the activation pathways. Breast cancer patients with the CYP2D6 nul/nul or red/nul diplotype may benefit less from Tamoxifen treatment and are more likely to develop recurrences. Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C19 and CYP3A5 did not have a significant impact on the recurrences in this cohort of patients with ER + breast cancer.

Keywords

• Breast cancer
• Tamoxifen
• Endoxifen
• CYP2D6
• Pharmacogenetics