演題抄録

FACO International Workshop

開催概要
開催回
第53回・2015年・京都
 

Association of CYP2C19*2 and associated haplotypes with lower norendoxifen levels in tamoxifen-treated asian breast cancer patients

演題番号 : FWS11-2

[筆頭演者]
Chowbay Balram:1,2,3 
[共同演者]
Joanne Lim Siok Liu:1、Sutiman Natalia:2、Muerdter Thomas E.:6,7、Singh Onkar:1、Raymond Ng Chee Hui:4、Yap Yoon Sim:4、Wong Nan Soon:5、Schroth Werner:6,7、Schwab Matthias:6,8

1:Division of Medical Sciences, Laboratory of Clinical Pharmacology, National Cancer Center Singapore、2:Clinical Pharmacology, Singapore Health Services Pte Ltd、3:Clinical Sciences, Duke-NUS Graduate Medical School、4:Medical Oncology, National Cancer Center Singapore、5:OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre Singapore、6:Clinical Pharmacology, Dr. Margarete Fischer-Bosch Institute、7:University Tubingen Germany、8:Clinical Pharmacology, University Hospital, Tubingen

 

This study aimed to investigate the impact of CYP2C19 functional polymorphisms and their associated haplotypes on the disposition of (Z)-norendoxifen in Asian breast cancer patients. Of the sixty-six CYP2C19 polymorphisms identified in healthy Asians (N=240), 14 SNPs were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17 and these 17 SNPs were further genotyped in tamoxifen-treated Asian breast cancer patients (N=201). Genotypic-phenotypic associations were evaluated using non-parametric tests. Haplotypic effects of the SNPs were explored using regression methods. No significant associations were observed between any of the CYP2C19 functional polymorphisms and their linked SNPs with the plasma concentrations of tamoxifen and three of its main metabolites N-desmethyltamoxifen (NDM), (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. Yet, two other potentially important metabolites, N,N-Didesmethyltamoxifen (NDDM) and (Z)-norendoxifen were genetically associated: the CYP2C19 H2 haplotype, tagged by CYP2C19*2, was significantly correlated with lower plasma levels of (Z)-norendoxifen (P=0.001). Significant associations were also noted between the CYP2C19 H2 haplotype and significantly lower metabolic ratios, MR(Z)-NorEND/NDDM (P<0.0001) and MR(Z)-NorEND/(Z)-END (P=0.001), indicating significantly lower formation rates of (Z)-norendoxifen. These data underscore the relevance of CYP2C19 pharmacogenetics for modulating norendoxifen levels in tamoxifen-treated Asian breast cancer patients.

キーワード

臓器別:乳腺

手法別:トランスレーショナルリサーチ

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