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. 2016 Aug 8:8:149-55.
doi: 10.2147/BCTT.S105563. eCollection 2016.

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

Wanaporn Charoenchokthavee  1 , Duangchit Panomvana  1 , Virote Sriuranpong  2 , Nutthada Areepium  1
Affiliations

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

Wanaporn Charoenchokthavee et al. Breast Cancer (Dove Med Press). .

Abstract

Background: Tamoxifen (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 methods: In 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.

Results: The 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.

Conclusion: The 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.

Keywords: CYP450; SNPs; antihormone; oncology; pharmacogenetics; pharmacogenomics.

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Figures

Figure 1
Figure 1
TAM-metabolic pathways and selected CYP450 enzymes. Notes: TAM was metabolized by CYP450 enzyme to its active metabolites: END and 4OHT. END was created via NDMT and 4OHT. Abbreviations: TAM, tamoxifen; CYP450, cytochrome P450; END, endoxifen; 4OHT, 4-hydroxy-tamoxifen; NDMT, N-desmethyl tamoxifen.
Figure 2
Figure 2
A diagram of CYP2D6, CYP3A5 polymorphisms, and breast cancer outcomes from previous research. Abbreviations: TAM, tamoxifen; NDMT, N-desmethyl-tamoxifen; 4OHT, 4-hydroxy-tamoxifen; END, endoxifen; OS, overall survival; PFS, progress-free survival; CB, clinical benefit; IDFS, invasive disease-free survival; DFS, disease-free survival.
Figure 3
Figure 3
Prevalence of combined CYP2D6 and CYP3A5 phenotype in Thai breast cancer patients undergoing TAM treatment (N=134). Notes: Outer arrow line indicates prevalence of combined CYP2D6 and CYP3A5 phenotype. Outer doughnut chart indicates prevalence of CYP2D6 phenotype. Inner doughnut chart indicates prevalence of CYP3A5 phenotype. Abbreviations: TAM, tamoxifen; EM, extensive metabolizer; PM, poor metabolizer; IM, intermediate metabolizer.
See this image and copyright information in PMC

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