Prevalence of <em>CYP2D6*2</em>, <em>CYP2D6*4</em>, <em>CYP2D6*10</em>, and <em>CYP3A5*3</em> in Thai breast cancer patients undergoing tamoxifen treatment

Abstract

BackgroundTamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment.Patients and methodsIn total, 134 Thai breast cancer patients were randomly invited to join the Thai Tamoxifen Project. Their blood samples were collected and extracted for individual DNA. The alleles and genotypes were determined by real-time polymerase chain reaction with TaqMan® Drug Metabolism Genotyping Assays.ResultsThe patients were aged from 27.0 years to 82.0 years with a body mass index range from 15.4 to 40.0, with the majority (103/134) in the early stage (stages 0–II) of breast cancer. The median duration of TAM administration was 17.2 months (interquartile range 16.1 months). Most (53%) of the patients were premenopausal with an estrogen receptor (ER) and progesterone receptor (PR) status of ER+/PR+ (71.7%), ER+/PR− (26.9%), ER−/PR+ (0.7%), and ER−/PR− (0.7%). The allele frequencies of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP3A5*1, and CYP3A5*3 were 72.9%, 3.2%, 1.1%, 22.8%, 37.3%, and 62.7%, respectively, while the genotype frequencies of CYP2D6*1/*1, CYP2D6*1/*2, CYP2D6*2/*2, CYP2D6*4/*4, CYP2D6*1/*10, CYP2D6*2/*10, CYP2D6*4/*10, CYP2D6*10/*10, CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 were 9.7%, 2.2%, 3.7%, 1.5%, 15.7%, 9.7%, 3.7%, 53.7%, 13.4%, 47.8%, and 38.8%, respectively.ConclusionThe majority (97.8%) of Thai breast cancer patients undergoing TAM treatment carry at least one incomplete functional allele, including 20.9% of the patients who carry only incomplete functional alleles for both the CYP2D6 and CYP3A5 genes. This research indicates the high prevalence of these defective alleles that are involved in TAM-metabolic pathways that might further affect TAM treatment.

Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

“…The demographic data of the patients have been described in previous research 18. In brief, these patients demonstrated stage 0–IV breast cancer.…”

“…Early researches suggested that CYP2D6*10/*10 patients had shorter disease-free survival than heterozygous CYP2D6*10 ( p =0.046)17 and lower END concentrations than those patients with CYP2D6*1/*10 and CYP2D6*1/*1 ( p =0.045)19 among Thai breast cancer patients; however, the result was not completely generalized to target population because of the limited sample size 19. Furthermore, the associations between CYP3A5 polymorphisms and levels of TAM and its metabolites have never been explored in Thai breast cancer patients, even though a high prevalence of CYP3A5 incomplete allele ( CYP3A5*3 ) has been suggested in a previous study 18. The purpose of the present study was to determine the associations of CYP2D6 and CYP3A5 polymorphisms and the concentrations of TAM and its metabolites in large numbers of Thai breast cancer patients undergoing TAM treatment.…”

“…A total of 134 Thai breast cancer patients undergoing TAM treatment were recruited from the Thai Tamoxifen Project 18,20. In brief, the patients took 20 mg of TAM once daily for at least 2 months to ensure a steady-state concentration and visited the outpatient clinic at King Chulalongkorn Memorial Hospital between February and March 2015.…”

“…A sample size calculation was performed using G*Power version 3.1 program21 using the priori method22 with type-I errors 0.05 (two-tailed) and type-II errors 0.2. Ten milliliters of whole blood was drawn from each patient by a professional nurse and stored in a Vacutainer ® (K 2 EDTA [di-potassium salts of ethylene-diaminetetraacetic acid]; 10 mL) tube (BD, Franklin Lakes, NJ, USA) 18. The DNA extraction for assessing CYP2D6 and CYP3A5 polymorphisms and the determination of the polymorphisms have been described in previous research 18…”

“…The genetic data were described as genotypes ( CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP3A5*1 and CYP3A5*3 ) and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]). The phenotypes were classified using a conventional method which is described in a previous report 18. Briefly, the genotypes were firstly divided into two groups (complete and incomplete alleles).…”