Abstract
BackgroundTamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy.MethodsBlood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.ResultsIn nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r2 = 0.23; p < 10−16) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10−16) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10−43).ConclusionsThe majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1575-4) contains supplementary material, which is available to authorized users.
Highlights
Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes
We have indicated an association between lower (E/Z)-4-OH-NDM-Tam-gluc levels (r2 = 0.23; p < 10−16) and an increasing degree of CYP2D6 functional impairment
Consistent with other reports [12, 31], both NDM-Tam and 4′-OH-NDM-Tam were inversely correlated with the number of CYP2D6 deficient alleles. Both active metabolites tended to decrease in proportion to the degree of CYP2D6 deficiency, with the strongest correlation being observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM
Summary
The most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The drug is primarily metabolized to N-desmethyl-tamoxifen (NDMTam), the most abundant metabolite in patients’ plasma, and 4-hydroxy-tamoxifen (4-OH-Tam), which are further converted to the secondary metabolite 4-hydroxyN-desmethyl-tamoxifen (4-OH-NDM-Tam; endoxifen) [4] Both endoxifen and 4-OH-Tam exhibit 30- to 100fold higher anti-estrogenic potency than NDM-Tam or tamoxifen itself, with respect to their affinity for ER and suppression of estrogen-dependent breast cancer MCF7 cells proliferation, and are considered as the active tamoxifen metabolites responsible for the overall therapeutic drug activity [5,6,7]. (Z)-isomers of endoxifen and 4-OH-Tam were found to exert the strongest ER inhibition among tamoxifen metabolites, with half maximal inhibitory concentration (IC50) values of 3 nmol/l and 7 nmol/l, respectively [2]
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