Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

BMC Cancer, Aug 2015

Background 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. 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. Methods Blood 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. Results In 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 (r 2  = 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 ). Conclusions The 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.

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Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

Hennig et al. BMC Cancer Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer Ewa E. Hennig 0 1 3 Magdalena Piatkowska 0 Jakub Karczmarski 0 Krzysztof Goryca 0 Elzbieta Brewczynska 2 Radoslaw Jazwiec 5 Anna Kluska 0 Robert Omiotek 4 Agnieszka Paziewska 1 Michal Dadlez 5 Jerzy Ostrowski 0 1 0 Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland 1 Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education , Warsaw , Poland 2 Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland 3 Cancer Center-Institute , Roentgena 5, 02-781 Warsaw , Poland 4 Department of Internal Medicine and Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland 5 Institute of Biochemistry and Biophysics, Polish Academy of Sciences , Warsaw , Poland Background: 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. 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. Methods: Blood 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. Results: In 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). Conclusions: The 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. Tamoxifen; Breast cancer; CYP2D6; Polymorphism; Genotyping; Metabolite levels; Serum concentration; Mass spectrometry - Background Tamoxifen is a selective estrogen receptor (ER) modulator commonly used for the treatment or prevention of hormone receptor-positive breast cancer, as well as for chemoprevention in women at high risk of developing breast cancer. Five years of tamoxifen treatment after surgery reduces the annual recurrence rate of ER-positive breast cancers by almost half and reduces the mortality rate by a third [1]. However, significant interindividual variability of tamoxifen efficacy is observed and disease recurs in 30–50 % of patients receiving adjuvant therapy [1]. Responsiveness to tamoxifen depends to a considerable degree on genetic variability in the level of patients’ drugmetabolizing enzymes. Tamoxifen is a prodrug extensively metabolized via an enzymatic network predominantly including cytochrome P450 (CYP) isomers. At least 36 phase I tamoxifen metabolites have been recently described [2, 3]. 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 t (...truncated)


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Ewa Hennig, Magdalena Piatkowska, Jakub Karczmarski, Krzysztof Goryca, Elzbieta Brewczynska, Radoslaw Jazwiec, Anna Kluska, Robert Omiotek, Agnieszka Paziewska, Michal Dadlez, Jerzy Ostrowski. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer, BMC Cancer, 2015, pp. 570, 15, DOI: 10.1186/s12885-015-1575-4