تواتر الأليل عديم الوظيفة CYP2D6*4 لدى مريضات سرطان ثدي سوريات و تأثيره في استجابتهن للتاموكسيفين

الملخص EN

Cytochrome P450 2D6 (CYP2D6) metabolizes approximately 25% of all prescribed medications, and is the main enzyme responsible for the bioactivation of "tamoxifen" into its highly effective metabolite "endoxifen".

the gene encoding CYP2D6 is highly polymorphic, and the genetic differences contribute to the interindividual and interethnic differences in the drug pharmacokinetics and pharmacodynamics.

CYP2D6*4 (rs3892097) is the most prevalent loss-of-function allele in the middle east.

this study aimed to identify the frequency of CYP2D6*4 allele in a cohort of hormone receptor positive breast cancer patients, and assess its impact on the responsiveness to adjuvant endocrine therapy with tamoxifen.

this case-control observational study encompassed 94 ER+ and/or PR+ breast cancer patients classified according to their responsiveness to tamoxifen into responders (control), who completed relapse-free five years of treatment with tamoxifen (n= 38), and non-responders (case) (n=56), with recurrence before completion the five-year adjuvant hormonal therapy.

disease-free survival (DFS) was used as the primary endpoint.

patients were genotyped based on sequencing of the specific PCR amplification products.

data were analyzed using SPSS statistical software, version 23.

the overall frequency of CYP2D6*4 allele was 6.9% of the study cohort, with only two patients being homozygous (4*/4*).

the estimated median DFS for patients with the CYP2D6*4/*4 genotype was 11 months, compared to a statistically significant longer DFS of 39 months in patients with the extensive and intermediate metabolizer phenotypes (i.e., *1/*1 and *4/*1), (P = 0.037).

our findings support an increased recurrence risk and decreased DFS in breast cancer patients carrying CYP2D6*4/*4.

further investigations are needed to determine the frequencies of other reduced- and null function alleles, and assess their impacts on response to tamoxifen in Syrian patients.