تأثير تعدد الأشكال الجيني ل CYP3A4 و ABCB1 على فعالية عقار تاموكسيفين لدى النساء العراقيات المصابات بسرطان الثدي

Submitted to the Council of College of Pharmacy/ University of Kerbala as Partial Fulfillment of the Requirements for the Master Degree of Science in Pharmacology and Toxicology

Abstract

Breast cancer is the most common type of cancer affecting women. Tamoxifen is a selective estrogen receptor modulator considered the cornerstone in the treatment of hormonal receptor positive breast cancer. Tamoxifen is a prodrug and converted to the more active metabolites by many metabolizing enzymes. Pharmacogenomics has a critical impact on the interindividual variability that affect treatment response, and it is important to study the polymorphic genes included in tamoxifen kinetics. Therefore, the genetic polymorphisms of tamoxifen’s important metabolizing enzyme CYP3A4 and tamoxifen with its metabolites efflux transporter ABCB1 might have potential impact on therapeutic outcome of tamoxifen.
The study aims to: detect the CYP3A4*22 G>A (rs35599367) and ABCB1 C3435T (rs1045642) genetic polymorphisms among breast cancer Iraqi women included in this study and to investigate the influence of these genes’ variants on tamoxifen efficacy.
Patients and methods: This is an observational cross-sectional study conducted at Imam Al-Hussein Medical City and Imam AL-Hassan AL-Mujtaba Teaching Hospital /Oncology Center in Kerbala along with laboratories of College of Pharmacy / University of Kerbela carried out between November 2022 to April 2023. One hundred female patients with breast cancer that were estrogen-receptor and / or progesterone-receptor positive were selected. Patients aged 45- and above, being on tamoxifen 20 mg daily dose for at least four months were enrolled in this study. The study also included one hundred healthy women provides a critical comparison group for biochemical analysis (Estradiol level, Tumor marker CA15.3, Calcium and lipid profiles).
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Five milliliters of venous blood were drawn from each patient after they are signed written informed consent to measure biochemical parameters such as estradiol, CA15.3, calcium, and lipid profile in addition to genetic analysis. The Amplification Refractory Mutation System and Allele Specific Polymerase Chain Reactions were used for the detection CYP3A4*22 G>A (rs35599367) and ABCB1 C3435T (rs1045642) respectively.
Results: The obtained findings demonstrated that there were different genetic variants of CYP3A4*22 G>A (rs35599367) and ABCB1 C3435T (rs1045642). For rs35599367 G>A, the wild homogenous (GG) the most common genotype followed by homogenous mutant (AA) and the (GA) heterogeneous genotypes are less common with 39%, 35% and 26% frequencies respectively. But for rs1045642 C>T, the mutant homogenous (TT) is the most frequent genotype while, the heterogeneous (CT) and wild homogenous (CC) genotypes are less with 43%, 29% and 28% frequencies respectively. The levels of estradiol, calcium, and low-density lipoprotein in the serum showed insignificant, while, level of serum tumor marker CA15.3 show significant association between the studied two single nucleotide polymorphisms of CYP3A4 and ABCB1 genes with p-value less than 0.05. Furthermore, the present study found that hot flash side effect occurs at high incidence about 82% and low recurrence rate of 5%.
Conclusion: The present study concluded that there be a correlation between genetic variation in CYP3A4*22 and ABCB1 genes and the variability in the response to tamoxifen therapy among Iraqi women with breast cancer in which the wild GG genotype of CYP3A4*22 rs35599367 and the mutant TT genotype of ABCB1 rs1045542 are good responder groups with severe hot flashes occurrence.