Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment
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.
In univariate analysis, higher activity of CYP2C8 (regression β=0.22, P=0.020) and CYP2C9 (β=0.20, P=0.04), lower body weight (β=−0.014, P<0.0001), and endoxifen measurement during winter (each β<−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%.
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.
Document Type: Research Article
Affiliations: 1: Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan 2: UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 3: DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida 4: Department of Clinical Pharmacology, Indiana University, Indianapolis, Indiana 5: UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, Bon Secours Cancer Institute, Richmond, Virginia, USA
Publication date: November 1, 2017