Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment

作者：Marcath Lauren A; Deal Allison M; Van Wieren Emily; Danko William; Walko Christine M; Ibrahim Joseph G; Weck Karen E; Jones David R; Desta Zeruesenay; McLeod Howard L; Carey Lisa A; Irvin William J Jr; Hertz Daniel L

来源：Pharmacogenetics and Genomics, 2017, 27(11): 402-409.

DOI：10.1097/FPC.0000000000000311

• CYP2C9
• CYP2D6
• endoxifen
• pharmacogenomics
• season
• tamoxifen

Objectives Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations.
Patients and methods Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates.
Results In univariate analysis, higher activity of CYP2C8 (regression beta=0.22, P=0.020) and CYP2C9 (beta=0.20, P=0.04), lower body weight (beta=-0.014, P < 0.0001), and endoxifen measurement during winter (each beta < -0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R-2 by 1.3%.
Conclusion Our results further support a minor contribution of CYP2C9 genetic variability toward steady-state endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes.

• 出版日期2017-11