Composite Functional Genetic and Comedication CYP2D6 Activity Score in Predicting Tamoxifen Drug Exposure Among Breast Cancer Patients

Abstract

Background Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. We propose a novel CYP2D6 scoring systems that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Method Training (n=159) and validation (n=81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: one genotype-independent and one genotype-based. Three CYP2D6 gene score systems, and their combination with the inhibitor factors, were compared. These three scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. Results The overall performance of the three gene score systems without consideration of CYP2D6 inhibiting medications in predicting CYP2D6 phenotype was poor both in the training (R2=0.24, 0.22 and 0.18) and the validation set, (R2=0.30, 0.24 and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R2 values in the training and validation data sets are nearly twice as high as the genotype only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41) respectively. Conclusion The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 Activity Score doubled our ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, yet unidentified, factors must be involved in tamoxifen activation.

CYP2D6 Polymorphisms as Predictors of Outcome in Breast Cancer Patients Treated with Tamoxifen: Expanded Polymorphism Coverage Improves Risk Stratification

“…As shown by others, individuals with an EM phenotype based on AmpliChip CYP450 algorithm are characterized by genotypic heterogeneity associated with variation in CYP2D6 activity towards amitriptyline pointing to a functional gene dose effect (30). We did not adapt this concept of semiquantitative gene dose (30,31) for two reasons. First, the gene dose score would define at least six score groups, which, given the moderate sample size in this study, would reduce power for each group, resulting in unreliable survival estimates in outcome analyses.…”

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

“…To determine the effect of the HNF4A SNP on CYP2D6 enzyme activity, the urinary dextromethorphan metabolic ratio was compared after taking into account the CYP2D6 activity score. The CYP2D6 gene score was assigned on the basis of the expected enzyme activity (Gaedigk et al, 2008;Borges et al, 2010). The fully functional CYP2D6 alleles (*1 and *2) were assigned a score of 1, alleles associated with reduced enzyme activity (*10 and *41) were assigned a score of 0.5, and the nonfunctional alleles (*3-*6) were assigned a score of 0.…”

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…The activity of DMEs (phenotype) such as CYP2D6 is significantly altered in EM patients who are comedicated with its inhibitor(s). Integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype to compute a composite CYP2D6 activity score greatly improves the ability to predict the CYP2D6 drug metabolizing phenotype (Borges et al, 2010), and therefore the clinical response. For example, a study in 87 Caucasian patients treated with antidepressant monotherapy with other comedications revealed genotype-phenotype mismatch in 10 (11.4%) of these patients and that the CYP2D6 phenotype, rather than the genotype, could better predict therapeutic response to the CYP2D6 substrate antidepressant (Gressier et al, 2015).…”