Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. Issue 11 (November 2017)

• Record Type: Journal Article
• Authors: A. Marcath, Lauren; 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.; Hertz, Daniel L.
• Is Part Of: Pharmaocogenetics and genomics. Volume 27:Issue 11(2017:Nov.)
• Publication Date: 2017-11
• Subjects: CYP2C9 -- CYP2D6 -- endoxifen -- pharmacogenomics -- season -- tamoxifen; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000311
• Languages: English
• ISSNs: 1744-6872

Abstract

Abstract : 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 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%. 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. Abstract : Supplemental Digital Content is available in the text.