Comprehensive Assessment Of The Effect Of Genetic Polymorphisms In Drug Metabolizing Enzymes And Transporters On Tamoxifen Activation To Endoxifen

Background: Tamoxifen is the most commonly prescribed hormonal drug for estrogen receptor positive breast cancer treatment. Tamoxifen itself has weak anti-estrogenic activity, but is bioactivated to the more potent inhibitor endoxifen. Recent data suggest inferior efficacy of tamoxifen treatment in patients who have low systemic endoxifen concentration. Genetic variability in drug metabolizing enzymes and transporters, particularly CYP2D6, are known to effect serum endoxifen concentration. The association of CYP2D6 genotype and endoxifen concentration is well established; however, there is a paucity of data regarding the effects of genetic variants in other drug metabolizing enzymes and transporters on endoxifen concentrations. The objective of our study was to comprehensively screen known, functionally consequential polymorphisms and copy number variations in genes of interest to detect additional pharmacogenetic predictors of endoxifen concentration during tamoxifen treatment. Methods: This analysis includes patients prospectively enrolled on the Lineberger Comprehensive Cancer Center 0801 trial. Patients had received tamoxifen for a minimum of 4 months prior to enrollment and were not concurrently taking strong or moderate CYP2D6 inhibitors. Samples were collected at enrollment for measurement of steady state endoxifen level and collection of germline DNA. Genotyping was performed for CYP2D6 using the Amplichip® CYP450 test (Roche Diagnostics) and for other candidate genes (CYP2C9, CYP3A4, CYP3A5, ABCB1, SLCO1B1, SULT1A1, SULT1A2, and UGT2B7) using the iPLEX® ADME PGx Pro Panel (Agena Bioscience). Activity phenotype for each gene was inferred from genotype data based on known activity of variant alleles or copy numbers. Metabolite concentrations were measured via LC/MS-MS assay at Indiana University and square root transformed prior to analysis to improve normality. Linear regression models were used to evaluate the association of each gene individually with endoxifen concentration, assuming an additive pharmacogenetic effect, after adjustment for CYP2D6 phenotype (EM/UM, IM or PM). Results: 304 Patients with steady-state endoxifen concentration and successful genotyping were included in the analysis. After transformation and adjustment, endoxifen concentration was significantly associated with carrying low-activity CYP2C9 variant alleles (*2, *3, *5, *6, *8, *11, *12) (p=0.016). Predicted endoxifen concentration based on CYP2C9 and CYP2D6 genotype can be found in. Phenotype activity of other enzymes and transporters was not associated with endoxifen concentration (all pu003e0.05). Conclusions: Polymorphisms in CYP2C9 and CYP2D6, but not other enzymes or transporters, contribute to variation in endoxifen exposure. If endoxifen exposure is validated to predict tamoxifen efficacy, personalized tamoxifen dosing algorithms should include CYP2C9, in addition to CYP2D6 and clinical factors, to improve efficacy and minimize side effects. Citation Format: Hertz DL, Danko W, Deal A, Walko CM, Flockhart DA, McLeod HL, Ibrahim JG, Irvin Jr WJ. Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-06.