Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Tamoxifen is metabolized to active metabolites, 4‐hydroxytamoxifen and endoxifen, by multiple cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A4/5, CYP2C9/19, CYP1A2 and CYP2B6.• The steady‐state plasma concentrations of tamoxifen and its metabolites can be affected by variations in the activity of these enzymes.• Although CYP2D6*4 and *10 have been shown to influence the plasma concentration of endoxifen in Caucasian and Korean patients respectively, there is still a paucity of data on CYP2D6 pharmacogenetics in other Orientals such as Chinese, Malays and Indians.WHAT THIS STUDY ADDS• Pharmacogenetic analyses of a comprehensive panel of CYP2D6 polymorphisms (*2, *2A, *3, *4, *5, *6, *7, *8, *9, *10, *12, *14, *17, *29, *41 and *xN) were performed in three distinct Asian ethnic groups and breast cancer patients with CYP2D6*5 and *10 found to be highly prevalent.• Both CYP2D6*5 and *10 were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen concentrations as well as a lower rate of metabolic conversion of N‐desmethyltamoxifen to endoxifen.• Polymorphisms present in CYP3A5, CYP2C9 and CYP2C19 were not found to be significantly associated with plasma concentrations of analytes suggesting that these enzymes may be playing minor roles in the metabolic pathway of tamoxifen compared with CYP2D6.AIM To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients.METHODS A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n= 76 each) were recruited. The steady‐state plasma concentrations of tamoxifen and its metabolites were quantified using high‐performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing.RESULTS The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N‐desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4‐ to 2.6‐fold higher endoxifen concentrations and 1.9‐ to 2.1‐fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8‐ to 2.6‐times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19.CONCLUSIONS The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.

Priority pharmacogenetics for the African continent: focus on CYP450

“…These duplications are less frequent in populations of Bantu/Niger-Congo origin, such as the Yoruba in Nigeria (4%), Gabonese (4%) and Ghanaians (1.6%) [49,64,65]. The notion that CYP2D6*2xN is an Afro-Asiatic specific allele is further supported by the fact that these alleles also occur commonly in Saudi-Arabia (20%), and to a lesser extent in African-Americans, Europeans and Asians (<2.5%) [41,66,67].…”

“…In Caucasian populations, the frequency of these alleles ranges from 8% to over 20% [40]. However, in Asians, the same alleles are mostly absent or present at frequencies of not more than 3% [41,42]. A similar range in distribution of allelic frequencies is observed across the African continent, but with the noteworthy finding that populations in northern Africa appear to harbor CYP2C9*2 and *3 alleles at higher frequencies with a mean of 11.8%, whereas the mean allelic frequency in sub-Saharan Africa is 0.6% [8], similar to that in African-Americans [42,43].…”

“…CYP2D6*10 is reported to be present in 11-70% of Asian populations [41,60], while it is seldom higher than 10% in populations of African origin [8,59]. CYP2D6*17 and CYP2D6*29, among others, are accepted as being African-specific alleles, and are present at frequencies of up to 34% and 29%, respectively .…”

The Risk of Recurrence in Breast Cancer Patients Treated with Tamoxifen: Polymorphisms of CYP2D6 and ABCB1

“…This variation causes variability in patients' outcomes because CYP2D6 had been reported to biotransform tamoxifen into several active metabolites. Studies on the pharmacokinetics of tamoxifen demonstrated significantly lower steady-state plasma and serum concentrations of 4-hydroxy-Ndesmethyltamoxifen and 4-hydroxytamoxifen in CYP2D6*10/ *10 than other genotypes (4,9,10).…”

Genetic Variants of CYP2D6 Gene and Cancer Risk: A HuGE Systematic Review and Meta-analysis

“…According to the inclusion criteria, 43 studies (Agúndez et al, 1994;Wundrack et al, 1994;Agúndez et al, 1996;Ladona et al1996;Legrand et al, 1996;London et al, 1997;Agúndez et al, 1998;Febbo et al, 1998; González et al, 1998; Hu et Shaw et al, 1998;Krajinovic et al, 1999;Lemos et al, 1999;Topić et al, 2000;Butler et al, 2001;Liu et al, 2002;Sobti et al, 2003;Chen et al, 2004;Fukatsu et al, 2004;Li et al, 2004;Gajecka et al, 2005;Gomes et al, 2005;Guo et al, 2005;Liang et al, 2005;Mochizuki et al, 2005;Sobti et al, 2005;Aydin-Sayitoglu et al, 2006;Bonanni et al, 2006;Li et al, 2006;Lemos et al, 2007;Chen et al, 2008;Khedhaier et al, 2008;Majumdar et al, 2008;Ouerhani et al, 2008 ;Torresan et al, 2008;Yan et al, 2008;Altayli et al, 2009;Gutman et al, 2009;Lim et al, 2011;Luo et al, 2011;Zhou et al, 2011) appeared to have met the inclusion criteria and were subjected to further examination. The flow chart of study selection is shown...…”