Pharmacogenomic diversity of tamoxifen metabolites and estrogen receptor genes in Hispanics and non-Hispanic whites with breast cancer.
Ethnic differences in patient genetics and breast cancer (BC) biology contribute to ethnic disparities in cancer presentation and patient outcome. We prospectively evaluated SNPs within phase I and phase II tamoxifen (TAM) metabolizing enzymes, and the estrogen receptor gene (ESR1), aiming to identify potential pharmacogenomic ethnicity patterns in an ER-positive BC cohort constituted of Hispanic and Non-Hispanic White (NHW) women in South Texas. Plasma concentrations of TAM/metabolites were measured using HPLC. CYP2C9, CYP2D6 and SULT1A1 genotypes were determined by DNA sequencing/Pyrosequencing technology. ESR1 PvuII and XbaI SNPs were genotyped using Applied Biosystems Taqman Allelic Discrimination Assay. Hispanics had higher levels of TAM, 4-hydroxytamoxifen, and endoxifen than NHWs. There was a higher prevalence of CYP2D6 EM within Hispanics than NHWs, which corresponded to higher endoxifen levels, but no differences were verified with regard to CYP2C9 and SULT1A1. We found a higher incidence of the wild type forms of the ESR1 in Hispanics than NHWs. The performance status, the disease stage at diagnosis, and the use of aromatase inhibitors might have overcome the overall favorable pharmacogenomics profile of Hispanics when compared to NHWs in relation to TAM therapy responsiveness. Our data strongly point to ethnical peculiarities related to pharmacogenomics and demographic features of TAM treated Hispanics and NHWs. In the era of pharmacogenomics and its ultimate goal of individualized, efficacious and safe therapy, cancer studies focused on the Hispanic population are warranted because this is the fastest growing major demographic group, and an understudied segment in the U.S.
Department of Pharmaceutical Sciences, Biotechnology Program/RENORBIO, Health Sciences Center, Universidade Federal do Espirito Santo, Av. Marechal Campos, 1468, Maruipe, Vitoria, ES, 29040-090, Brazil.
Leticia B A
LB
Rangel
Jodi L
JL
Taraba
Christopher R
CR
Frei
Lon
L
Smith
Gladys
G
Rodriguez
John G
JG
Kuhn
D000368:Aged; D000483:Alleles; D015239:Arylsulfotransferase / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005838:Genotype; D006630:Hispanic or Latino; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; C016601:afimoxifene; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human