title: Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.
abstract: Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.
authors.affiliation: Division of Biostatistics/Clinical Pharmacology, Indiana University, School of Medicine, 410 W. 10th St., HITS 3000, Indianapolis, IN 46202; e-mail: lali@iupui.edu.
authors.forename: Silvana
authors.initials: S
authors.lastname: Borges
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Azzouz
authors.initials: A
authors.lastname: Faouzi
authors.forename: Jason D
authors.initials: JD
authors.lastname: Robarge
authors.forename: Sanosh
authors.initials: S
authors.lastname: Philips
authors.forename: Santosh
authors.initials: S
authors.lastname: Philip
authors.forename: Anne
authors.initials: A
authors.lastname: Nguyen
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Daniel
authors.initials: D
authors.lastname: Hayes
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Lang
authors.initials: L
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012042:Registries; D013629:Tamoxifen / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6