Pharmacogenomic diversity of tamoxifen metabolites and estrogen receptor genes in Hispanics and non-Hispanic whites with breast cancer

Abstract

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.

Development of a high‐performance liquid chromatography method with fluorescence detection for the routine quantification of tamoxifen, endoxifen and 4‐hydroxytamoxifen in plasma from breast cancer patients

“…The concentration range for each compound observed here agrees with previous reports (Dezentjé et al, ; Hertz et al, ; Lee et al, ; Lorizio et al, ; Rangel et al, ). In addition, sample reconstitution in the least possible amount of diluent allowed quantification of tamoxifen and its metabolites within the linear intervals in plasma samples (see below).…”

“…1, Internal standard (100 ng/mL); 2, E-endoxifen (20 ng/mL); 3, Z-endoxifen (20 ng/mL); 4, 4-hydroxytamoxyfen (20 ng/mL); 5, Z-tamoxifen (250 ng/mL) FIGURE 2 Representative chromatogram of the lowest concentration from the standard curve. 1, E-Endoxifen (3 ng/mL); 2, Z-endoxifen (3 ng/ mL); 3, 4-hydroxytamoxyfen (3 ng/mL); 4, Z-tamoxifen (50 ng/mL) The concentration range for each compound observed here agrees with previous reports (Dezentjé et al, 2015;Hertz et al, 2015;Lee et al, 2003;Lorizio et al, 2012;Rangel et al, 2014). In addition, sample reconstitution in the least possible amount of diluent allowed quantification of tamoxifen and its metabolites within the linear intervals in plasma samples (see below).…”

“…Quantification of tamoxifen and its metabolites has been proposed as the gold standard for accurate measurement of therapeutic plasma concentrations (Hennig et al, 2015;Lorizio et al, 2012;Rangel et al, 2014;Saladores et al, 2015). Studies testing this approach have shown dose escalation quantified via endoxifen levels to be an effective strategy for improving tamoxifen's anti-estrogenic treatment (Dezentjé et al, 2015;Martinez de Dueñas et al, 2014).…”

Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity

“…This is not the case with all pharmacogenetic associations, as evidenced by the inferior performance of genetically guided warfarin dosing strategies in AfricanAmerican patients [32], which has been attributed to racial differences in the effect of clinical and genetic factors [33]. Interestingly, greater endoxifen concentrations have been reported for Hispanic patients in comparison with nonHispanic white patients [34]. This could be partially attributable to the lower frequency of CYP2D6 low-activity alleles found in the Hispanic cohort; however, within the CYP2D6 EM group, Hispanic patients had greater endoxifen concentrations.…”

The fluctuating incidence, improved survival of patients with breast cancer, and disparities by age, race, and socioeconomic status by decade, 1981–2010

“… 31 Recently, the genetic evidence explaining incidence and survival disparity were explored, implying a biological difference between whites and blacks. 33 – 36 Our data demonstrated that black breast cancer patients displayed more advanced tumors at the time of diagnosis. Furthermore, race-specific survival disparity can be partially attributed to the different SES distribution between them, specifically a bigger proportion of whites belong to low-poverty group.…”