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

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.

Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co‐Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer

“…It could also be that these patients had ingested unreported drugs or herbs that inhibit the activity of CYP2D6, thus phenocopying the IM status. Most of the IM (70%) had ENDO concentrations below the putative threshold, similar to a previous study 36 . Such patients may benefit from dose escalation, as reported in other studies, 37,38 in order to reach high concentrations of ENDO.…”

“…Most of the IM (70%) had ENDO concentrations below the putative threshold, similar to a previous study. 36 Such patients may benefit from dose escalation, as reported in other studies, 37,38 in order to reach high concentrations of ENDO.…”

Pharmacogenetics of tamoxifen in breast cancer patients of African descent: Lack of data

“…As a result, it was decided that the study should be excluded from the review 17 . Another study was conducted in an Algerian population; however, since the majority of the study population was classified as “White”, this study was also excluded 18 . This left a total of 15 studies that qualified for final inclusion in the review 19–33 .…”

“… 17 Another study was conducted in an Algerian population; however, since the majority of the study population was classified as “White”, this study was also excluded. 18 This left a total of 15 studies that qualified for final inclusion in the review. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 Among them, the proportion of participants of African descent reported remained unknown for seven studies.…”

Pharmacokinetics of Tamoxifen and Its Major Metabolites and the Effect of the African Ancestry Specific CYP2D6*17 Variant on the Formation of the Active Metabolite, Endoxifen

“…In a study of TAM-treated Algerian breast cancer patients, including those genotyped as CYP2D6*17/*17 . The median ENDO concentration for IMs was 2.4 times lower than that of CYP2D6*1 carriers, clearly showing that the reduced activity variant in the homozygous state results in reduced levels of ENDO compared to the NM and ultra-rapid metabolizer phenotypes [ 52 ].…”