Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1

Abstract

Tamoxifen is metabolically activated to 4-hydroxytamoxifen and endoxifen by cytochrome P450 (CYP). CYP phenotypes have been correlated to tamoxifen outcomes, but few have considered drug interactions or combinations of genes. Fewer still have considered ABCB1, which encodes P-glycoprotein and transports active tamoxifen metabolites. We compared the concentrations of tamoxifen and metabolites in 116 breast cancer patients with predicted phenotypes for CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and ABCB1 genotypes. A significant correlation between CYP2D6 phenotypes and tamoxifen metabolites was seen, strongest for endoxifen (P < .0001). Statistical fit of the data improved when using gene activity scores adjusted for known drug interactions. Concentration of tamoxifen was significantly higher (P = .02) for patients taking a CYP2C19 inhibitor. No significant relationships were found for other genes unless patients were subgrouped according to CYP2D6 phenotypes or ABCB1 genotypes. Lower concentrations of endoxifen and endoxifen/4-hydroxytamoxifen ratios were seen with impaired CYP2C9 (P = .05 and P = .03, respectively) if patients had the same CYP2D6 phenotype and were not taking a CYP2D6 or CYP2C19 inhibitor. Lower concentrations of 4-hydroxytamoxifen were seen for impaired CYP2C19 when ABCB1 SNP3435 was nonvariant (P = .04). With 3 impaired CYP phenotypes, endoxifen concentrations were lower than if only CYP2D6 was impaired (P = .05). When CYP2D6 was impaired, ABCB1 3435 CC (rs1045642) was associated with significantly higher endoxifen (P = .03). Thus, impairment in CYP2C9, CYP2C19, or ABCB1 contributes to a lower steady-state endoxifen concentration at the dose studied. These studies represent an improved way of examining relationships between pharmacogenetics, drug concentrations, and clinical outcomes and warrants study in larger populations.

Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment

“…*4 and *11) and concomitant inhibitor treatment (i.e. fluoxetine and omeprazole), confirming that patients with diminished CYP2C9 activity have lower endoxifen concentrations[17]. Our results are in line with these previous findings, though we did not have information on CYP2C9 inhibitor co-administration.…”

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics

“…Since the publication of our metaanalysis, using the same search criteria through November 2017 (D. P. Cronin-Fenton et al, 2013), over 20 additional published studies have investigated the impact of CYP2D6 genetic polymorphisms on breast cancer prognosis. (Argalacsova, Slanar, Bakhouche, & Pertuzelka, 2017;Chamnanphon et al, 2013;De Ameida Melo et al, 2016;Dezentje et al, 2013;Dezentje et al, 2015;Goetz et al, 2017;Hertz et al, 2017;Johansson et al, 2016;Lei et al, 2016;Marcath et al, 2017;Markkula, Hjertberg, Rose, Ingvar, & Jernstrom, 2014;Martins, Vidal, Souza, Brusaca, & Brito, 2014;Mwinyi et al, 2014;Powers et al, 2016;Sanchez-Spitman et al, 2017;Sensorn et al, 2013;Zhang et al, 2015) Most suggest little evidence of an association of the CYP2D6 *4 or *10 variant with recurrence and mortality in tamoxifen-treated breast cancer patients. Here, we provide some highlight some of these studies.…”

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People

“…Genetic variation in CYP3A4 , CYP3A5 , and CYP2C9 may also influence tamoxifen metabolism, although their role in endoxifen formation is less certain . Previous research has focused largely on genotype‐phenotype associations in common CYP3A4 ( *1B , *1G , and *22 ), CYP3A5 ( *3 ), and CYP2C9 ( *2 and *3 ) alleles.…”

“…We observed strong associations with CYP2D6 variation, but we only detected modest associations with variation in other CYP genes, in contrast with what others have observed particularly in the case of CYP2C9 . One of the limitations of our study is the small cohort size and we may have low power to detect associations for less common variants in these genes.…”