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Are plasma concentrations of tamoxifen active metabolites sufficient to ensure therapeutic efficacy for tamoxifen treated women with breast cancer in Poland?
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Abstract
Tamoxifen is the most commonly used drug for treating those patients with breast cancer who are oestrogen receptor positive. The main active metabolite of tamoxifen is (Z)-endoxifen whose therapeutic efficacy depends on its plasma concentration. A therapeutically effective threshold level has indeed been defined for (Z)-endoxifen above which the breast cancer relapse rate is significantly reduced. Such steady-state concentrations are conditional on gene polymorphism, principally cytochrome P450 2D6 (CYP2D6), that modulates the activity of the encoded enzymes that convert tamoxifen to its active metabolites. This drug’s metabolism however may become significantly altered when other medication is concomitantly taken, such as selective serotonin reuptake inhibitors, which inhibit CYP2D6. A recent study have demonstrated that the majority of tamoxifen treated women with breast cancer in Poland, may not in fact attain the therapeutic threshold levels of (Z)-endoxifen. In such cases, personalising optimal treatment should be based on direct monitoring of steady-state plasma concentrations of tamoxifen and its metabolites, which can thereby significantly improve therapeutic efficacy.
Abstract
Tamoxifen is the most commonly used drug for treating those patients with breast cancer who are oestrogen receptor positive. The main active metabolite of tamoxifen is (Z)-endoxifen whose therapeutic efficacy depends on its plasma concentration. A therapeutically effective threshold level has indeed been defined for (Z)-endoxifen above which the breast cancer relapse rate is significantly reduced. Such steady-state concentrations are conditional on gene polymorphism, principally cytochrome P450 2D6 (CYP2D6), that modulates the activity of the encoded enzymes that convert tamoxifen to its active metabolites. This drug’s metabolism however may become significantly altered when other medication is concomitantly taken, such as selective serotonin reuptake inhibitors, which inhibit CYP2D6. A recent study have demonstrated that the majority of tamoxifen treated women with breast cancer in Poland, may not in fact attain the therapeutic threshold levels of (Z)-endoxifen. In such cases, personalising optimal treatment should be based on direct monitoring of steady-state plasma concentrations of tamoxifen and its metabolites, which can thereby significantly improve therapeutic efficacy.
Keywords
tamoxifen, CYP2D6 genotype, endoxifen concentration, breast cancer
About this articleTitle
Are plasma concentrations of tamoxifen active metabolites sufficient to ensure therapeutic efficacy for tamoxifen treated women with breast cancer in Poland?
Journal
Nowotwory. Journal of Oncology
Issue
Article type
Review paper
Pages
307-311
Published online
2016-12-23
Page views
874
Article views/downloads
1603
DOI
Bibliographic record
Nowotwory. Journal of Oncology 2016;66(4):307-311.
Keywords
tamoxifen
CYP2D6 genotype
endoxifen concentration
breast cancer
Authors
Ewa E. Hennig
References (33)- Veronesi U, Maisonneuve P, Rotmensz N, et al. Italian Tamoxifen Study Group. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007; 99(9): 727–737.
- Davies C, Godwin J, Gray R, et al. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011; 378(9793): 771–784.
- Davies C, Pan H, Godwin J, et al. Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013; 381(9869): 805–816.
- Coezy E, Borgna JL, Rochefort H. Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res. 1982; 42(1): 317–323.
- Johnson MD, Zuo H, Lee KH, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85(2): 151–159.
- Mürdter TE, Schroth W, Bacchus-Gerybadze L, et al. German Tamoxifen and AI Clinicians Group. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 2011; 89(5): 708–717.
- Teunissen SF, Rosing H, Seoane MD, et al. Investigational study of tamoxifen phase I metabolites using chromatographic and spectroscopic analytical techniques. J Pharm Biomed Anal. 2011; 55(3): 518–526.
- Desta Z, Ward BA, Soukhova NV, et al. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004; 310(3): 1062–1075.
- Robertson DW, Katzenellenbogen JA, Long DJ, et al. Tamoxifen antiestrogens. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen. J Steroid Biochem. 1982; 16(1): 1–13.
- Rebsamen MC, Desmeules J, Daali Y, et al. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J. 2009; 9(1): 34–41.
- Sistonen J, Sajantila A, Lao O, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics. 2007; 17(2): 93–101.
- Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003; 95(23): 1758–1764.
- Madlensky L, Natarajan L, Tchu S, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89(5): 718–725.
- Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006; 80(1): 61–74.
- Hennig EE, Piatkowska M, Karczmarski J, et al. 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; 15: 570.
- Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25(33): 5187–5193.
- Binkhorst L, Mathijssen RHJ, Jager A, et al. Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping. Cancer Treat Rev. 2015; 41(3): 289–299.
- de Vries Schultink AHM, Zwart W, Linn SC, et al. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen. Clin Pharmacokinet. 2015; 54(8): 797–810.
- Kiyotani K, Mushiroda T, Zembutsu H, et al. Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies. J Hum Genet. 2013; 58(6): 327–333.
- Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005; 97(1): 30–39.
- Wu X, Hawse JR, Subramaniam M, et al. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. 2009; 69(5): 1722–1727.
- Hawse JR, Subramaniam M, Cicek M, et al. Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens. PLoS One. 2013; 8(1): e54613.
- Gong IY, Teft WA, Ly J, et al. Determination of clinically therapeutic endoxifen concentrations based on efficacy from human MCF7 breast cancer xenografts. Breast Cancer Res Treat. 2013; 139(1): 61–69.
- Saladores P, Mürdter T, Eccles D, et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2015; 15(1): 84–94.
- Love RR, Desta Z, Flockhart D, et al. CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer. Springerplus. 2013; 2(1): 52.
- Jager NGL, Rosing H, Schellens JHM, et al. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care. Breast Cancer Res Treat. 2014; 143(3): 477–483.
- Irvin WJ, Walko CM, Weck KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol. 2011; 29(24): 3232–3239.
- Martinez de Dueñas E, Ochoa Aranda E, Blancas Lopez-Barajas I, et al. Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype. Breast. 2014; 23(4): 400–406.
- Kiyotani K, Mushiroda T, Imamura CK, et al. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat. 2012; 131(1): 137–145.
- Antunes MV, Linden R, Santos TV, et al. Endoxifen levels and its association with CYP2D6 genotype and phenotype: evaluation of a southern Brazilian population under tamoxifen pharmacotherapy. Ther Drug Monit. 2012; 34(4): 422–431.
- van Herk-Sukel MPP, van de Poll-Franse LV, Voogd AC, et al. Half of breast cancer patients discontinue tamoxifen and any endocrine treatment before the end of the recommended treatment period of 5 years: a population-based analysis. Breast Cancer Res Treat. 2010; 122(3): 843–851.
- Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23(36): 9312–9318.
- Dickschen K, Eissing T, Mürdter T, et al. Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling. Springerplus. 2014; 3: 285.