phgenomicsФармакогенетика и фармакогеномикаPharmacogenetics and Pharmacogenomics2588-05272686-8849LLC "Izdatelstvo OKI"10.37489/2588-0527-2020-1-42-56phgenomics-188Research ArticleСИСТЕМАТИЧЕСКИЙ ОБЗОРSYSTEMATIC REVIEWНовые возможности фармакогенетического подхода к персонализированной терапии тамоксифеном (обновлённый систематический обзор)New opportunities of pharmacogenetics approach to personalized tamoxifen therapy (updated systematic review)https://orcid.org/0000-0002-2373-2250СавельеваМ. И.SavelyevaM. I.

Савельева Марина Ивановна - д. м. н., профессор кафедры клинической фармакологии и терапии им. Б.Е.Вотчала SPIN-код: 2434-6458

Москва

Savelyeva Marina I. - Doctor of Medical Sciences, Professor of the Department of clinical pharmacology and therapy by B.E.Votchal

SPIN-код: 2434-6458

Moscow

marinasavelyeva@mail.ruhttps://orcid.org/0000-0002-0995-1801ПоддубнаяИ. В.PoddubnayaI. V.

Поддубная Ирина Владимировна - д. м. н., профессор, академик РАН, заведующая кафедрой онкологии, проректор по учебной работе и международному сотрудничеству

SPIN-код:1146-9889

Москва

Poddubnaya Irina V. - Doctor of Medical Sciences, Professor, Academician of Russian Academy of Sciences, Head of the Oncology Department, ViceRector for Academic Affairs and International Cooperation

SPIN code: 1146-9889

Moscow

ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииРоссияRussian Medical Academy of Continuous Professional EducationRussian Federation202028122020014256Copyright © Савельева М.И., Поддубная И.В., 20202020Савельева М.И., Поддубная И.В.Savelyeva M.I., Poddubnaya I.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacogenetics-pharmacogenomics.ru/jour/article/view/188

Тамоксифен, селективный модулятор эстрогеновых рецепторов (ER), в настоящее время применяется для лечения ER(+) рака молочной железы, снижая риск прогрессирования и рецидива болезни. Однако наблюдаются значительные различия в индивидуальном ответе на лечение, что заставляет искать способы и средства персонализированного подбора терапии этим препаратом. Тамоксифен метаболизируется ферментами системы цитохрома Р450. В результате образуются два наиболее активных метаболита тамоксифена: эндоксифен и 4-гидрокси-тамоксифен, от концентрации которых во многом зависит эффективность лечения. Полиморфизмы генов, кодирующих ферменты метаболизма тамоксифена, могут непосредственно оказывать влияние на фармакокинетику и фармакодинамику этого препарата, а поэтому фармакогенетический подход способен стать основой для персонализированной терапии рака молочной железы. В обновлённом систематическом обзоре мы проанализируем информацию, которая имеется на данный момент о потенциале определения CYP2D6, CYP2С19, CYP3A4/5, CYP2B6 для прогнозирования индивидуального ответа на лечение тамоксифеном.

Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used in the treatment of ER(+) breast cancer and substantially decreases the risks of recurrence and disease progression. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is metabolized by cytochrome P450, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. The effectiveness and success of treatment depends largely on concentrations of the active tamoxifen metabolites in blood plasma. Polymorphisms in the genes encoding these enzymes are proposed to influence on pharmacokinetics and pharmacodynamics of tamoxifen. Therefore, pharmacogenetic approach may form the basis of personalized treatment of breast cancer. In the updated systematic review, we analyze all current data about the potential use of genotyping of CYP2D6, CYP2С19, CYP3A4/5, CYP2B6 to predict an individual response on tamoxifen treatment.

тамоксифенCYP2D6CYP2С19CYP3A4/5CYP2B6рак молочной железыфармакогеномикафармакогенетикаtamoxifenCYP2D6CYP2С19CYP3A4/5CYP2B6breast cancerpharmacogenomicspharmacogenomicsReferencesEarly Breast Cancer Trialists’ Collaborative G. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. The Lancet. 2005;365(9472): 1687–1717. DOI: 10.1016/S0140-6736(05)66544-0Early Breast Cancer Trialists’ Collaborative G. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. The Lancet. 2005;365(9472): 1687–1717. DOI: 10.1016/S0140-6736(05)66544-0Early Breast Cancer Trialists’ Collaborative G, Davies C, Godwin J, et al. 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. DOI: 10.1016/S0140-6736(11)60993-8Early Breast Cancer Trialists’ Collaborative G, Davies C, Godwin J, et al. 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. DOI: 10.1016/S0140-6736(11)60993-8Massarweh S, Schiff R. Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res. 2007;13(7):1950-1954. DOI: 10.1158/1078-0432.CCR-06-2540Massarweh S, Schiff R. Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res. 2007;13(7):1950-1954. DOI: 10.1158/1078-0432.CCR-06-2540Burstein HJ, Griggs JJ, Prestrud AA, Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. 2010;6(5):243–246. DOI: 10.1200/JOP.000082Burstein HJ, Griggs JJ, Prestrud AA, Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. 2010;6(5):243–246. DOI: 10.1200/JOP.000082Schiavon G, Smith IE. Endocrine therapy for advanced/metastatic breast cancer. Hematol Oncol Clin North Am. 2013;27(4):715–736, viii. DOI: 10.1016/j.hoc.2013.05.004Schiavon G, Smith IE. Endocrine therapy for advanced/metastatic breast cancer. Hematol Oncol Clin North Am. 2013;27(4):715–736, viii. DOI: 10.1016/j.hoc.2013.05.004Jones ME, van Leeuwen FE, Hoogendoorn WE et al. Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: pooled results from three countries. Breast Cancer Res. 2012 Jun 12;14(3):R91.Jones ME, van Leeuwen FE, Hoogendoorn WE et al. Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: pooled results from three countries. Breast Cancer Res. 2012 Jun 12;14(3):R91.Bardia A, Stearns V. Personalized tamoxifen: a step closer but miles to go. Clin Cancer Res. 2010;16(17):4308–4310. DOI: 10.1158/1078-0432.CCR-10-1506Bardia A, Stearns V. Personalized tamoxifen: a step closer but miles to go. Clin Cancer Res. 2010;16(17):4308–4310. DOI: 10.1158/1078-0432.CCR-10-1506Binkhorst L, Mathijssen RH, Jager A, van Gelder T. Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping. Cancer Treat Rev. 2015;41(3):289–299. DOI: 10.1016/j.ctrv.2015.01.002Binkhorst L, Mathijssen RH, Jager A, van Gelder T. Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping. Cancer Treat Rev. 2015;41(3):289–299. DOI: 10.1016/j.ctrv.2015.01.002Desta Z, Ward BA, Soukhova NV, Flockhart DA. 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. DOI: 10.1124/jpet.104.065607Desta Z, Ward BA, Soukhova NV, Flockhart DA. 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. DOI: 10.1124/jpet.104.065607Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxyN-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55(5):471–478. DOI: 10.1007/s00280-004-0926-7Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxyN-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55(5):471–478. DOI: 10.1007/s00280-004-0926-7Johnson 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. DOI: 10.1023/B:BREA.0000025406.31193.e8Johnson 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. DOI: 10.1023/B:BREA.0000025406.31193.e8Singh MS, Michael M. Role of xenobiotic metabolic enzymes in cancer epidemiology. Methods Mol Biol. 2009;472:243–264. DOI: 10.1007/978-1-60327-492-0_10Singh MS, Michael M. Role of xenobiotic metabolic enzymes in cancer epidemiology. Methods Mol Biol. 2009;472:243–264. DOI: 10.1007/978-1-60327-492-0_10Singh MS, Francis PA, Michael M. Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. Breast. 2011;20(2):111–118. DOI: 10.1016/j.breast.2010.11.003Singh MS, Francis PA, Michael M. Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. Breast. 2011;20(2):111–118. DOI: 10.1016/j.breast.2010.11.003Boocock DJ, Brown K, Gibbs AH, et al. Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis. 2002;23(11):1897–1901.Boocock DJ, Brown K, Gibbs AH, et al. Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis. 2002;23(11):1897–1901.Crewe HK, Notley LM, Wunsch RM, et al. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4’-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002;30(8):869–874.Crewe HK, Notley LM, Wunsch RM, et al. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4’-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002;30(8):869–874.Coller JK, Krebsfaenger N, Klein K, et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002;54(2):157– 167. PMC1874408Coller JK, Krebsfaenger N, Klein K, et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002;54(2):157– 167. PMC1874408Gaedigk A, Blum M, Gaedigk R, et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet. 1991;48(5):943–950.Gaedigk A, Blum M, Gaedigk R, et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet. 1991;48(5):943–950.de Vries Schultink AH, Zwart W, Linn SC, et al. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen. Clin Pharmacokinet. 2015;54(8):797–810. DOI: 10.1007/s40262-015-0273-3de Vries Schultink AH, Zwart W, Linn SC, et al. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen. Clin Pharmacokinet. 2015;54(8):797–810. DOI: 10.1007/s40262-015-0273-3Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at: http://www.cypalleles.ki.se/cyp2d6.htm. Accessed 23.04.2017Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at: http://www.cypalleles.ki.se/cyp2d6.htm. Accessed 23.04.2017Del Re M, Citi V, Crucitta S, et al. Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel? Pharmacol Res. 2016;107:398–406. DOI: 10.1016/j.phrs.2016.03.025Del Re M, Citi V, Crucitta S, et al. Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel? Pharmacol Res. 2016;107:398–406. DOI: 10.1016/j.phrs.2016.03.025Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci. 2007;96(9):2224–2231. DOI: 10.1002/jps.20892Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci. 2007;96(9):2224–2231. DOI: 10.1002/jps.20892Mürdter TE, Schroth W, Bacchus-Gerybadze L, et al. 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. DOI: 10.1038/clpt.2011.27Mürdter TE, Schroth W, Bacchus-Gerybadze L, et al. 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. DOI: 10.1038/clpt.2011.27Borges 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. DOI: 10.1016/j.clpt.2006.03.013Borges 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. DOI: 10.1016/j.clpt.2006.03.013Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007;25(25):3837–3845. DOI: 10.1200/JCO.2007.11.4850Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007;25(25):3837–3845. DOI: 10.1200/JCO.2007.11.4850Gjerde J, Hauglid M, Breilid H, et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol. 2008;19(1):56–61. DOI: 10.1093/annonc/mdm434Gjerde J, Hauglid M, Breilid H, et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol. 2008;19(1):56–61. DOI: 10.1093/annonc/mdm434Madlensky L, Natarajan L, Tchu S, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89(5):718–725. DOI: 10.1038/clpt.2011.32Madlensky L, Natarajan L, Tchu S, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89(5):718–725. DOI: 10.1038/clpt.2011.32Martinez de Duenas 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. DOI: 10.1016/j.breast.2014.02.008Martinez de Duenas 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. DOI: 10.1016/j.breast.2014.02.008Irvin Jr 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. DOI: 10.1200/JCO.2010.31.4427Irvin Jr 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. DOI: 10.1200/JCO.2010.31.4427Jin 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. DOI: 10.1093/jnci/dji005Jin 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. DOI: 10.1093/jnci/dji005Goetz 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. DOI: 10.1200/JCO.2005.03.3266Goetz 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. DOI: 10.1200/JCO.2005.03.3266Wegman P, Elingarami S, Carstensen J, et al. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007;9(1):R7. DOI: 10.1186/bcr1640Wegman P, Elingarami S, Carstensen J, et al. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007;9(1):R7. DOI: 10.1186/bcr1640Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005;7(3):R284–290. DOI: 10.1186/bcr993Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005;7(3):R284–290. DOI: 10.1186/bcr993Channahon M, Pechatanan K, Sirachainan E, et al. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen. Pharmgenomics Pers Med. 2013;6:37–48. DOI: 10.2147/PGPM.S42330Channahon M, Pechatanan K, Sirachainan E, et al. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen. Pharmgenomics Pers Med. 2013;6:37–48. DOI: 10.2147/PGPM.S42330Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci. 2008;99(5):995–999. DOI: 10.1111/j.1349-7006.2008.00780.xKiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci. 2008;99(5):995–999. DOI: 10.1111/j.1349-7006.2008.00780.xKiyotani K, Mushiroda T, Imamura CK, et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol. 2010;28(8):1287– 1293. DOI: 10.1200/JCO.2009.25.7246Kiyotani K, Mushiroda T, Imamura CK, et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol. 2010;28(8):1287– 1293. DOI: 10.1200/JCO.2009.25.7246Saladores 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. DOI: 10.1038/tpj.2014.34Saladores 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. DOI: 10.1038/tpj.2014.34Schroth 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. DOI: 10.1200/JCO.2007.12.2705Schroth 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. DOI: 10.1200/JCO.2007.12.2705Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008;19(8):1423–1429. DOI: 10.1093/annonc/mdn155Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008;19(8):1423–1429. DOI: 10.1093/annonc/mdn155Regan MM, Leyland-Jones B, Bouzyk M, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012;104(6):441–451. DOI: 10.1093/jnci/djs125Regan MM, Leyland-Jones B, Bouzyk M, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012;104(6):441–451. DOI: 10.1093/jnci/djs125Rae JM, Drury S, Hayes DF, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012;104(6):452–460. DOI: 10.1093/jnci/djs126Rae JM, Drury S, Hayes DF, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012;104(6):452–460. DOI: 10.1093/jnci/djs126Dezentje VO, van Schaik RH, Vletter-Bogaartz JM, et al. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial. Breast Cancer Res Treat. 2013;140(2):363–373. DOI: 10.1007/s10549-013-2619-6Dezentje VO, van Schaik RH, Vletter-Bogaartz JM, et al. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial. Breast Cancer Res Treat. 2013;140(2):363–373. DOI: 10.1007/s10549-013-2619-6Stanton V, Jr. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst. 2012;104(16):1265–1266; author reply 1266-1268. DOI: 10.1093/jnci/djs305Stanton V, Jr. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst. 2012;104(16):1265–1266; author reply 1266-1268. DOI: 10.1093/jnci/djs305Goetz MP, Suman VJ, Hoskin TL, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013;19(2):500–507. DOI: 10.1158/1078-0432.CCR-12-2153Goetz MP, Suman VJ, Hoskin TL, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013;19(2):500–507. DOI: 10.1158/1078-0432.CCR-12-2153Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302(13):1429–1436. DOI: 10.1001/jama.2009.1420Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302(13):1429–1436. DOI: 10.1001/jama.2009.1420Province MA, Goetz MP, Brauch H, et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2014;95(2):216–227. DOI: 10.1038/clpt.2013.186Province MA, Goetz MP, Brauch H, et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2014;95(2):216–227. DOI: 10.1038/clpt.2013.186Berry DA. CYP2D6 genotype and adjuvant tamoxifen. Clin Pharmacol Ther. 2014;96(2):138–140. DOI: 10.1038/clpt.2014.96Berry DA. CYP2D6 genotype and adjuvant tamoxifen. Clin Pharmacol Ther. 2014;96(2):138–140. DOI: 10.1038/clpt.2014.96Yang G, Nowsheen S, Aziz K, Georgakilas AG. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther. 2013;139(3):392–404. DOI: 10.1016/j.pharmthera.2013.05.005Yang G, Nowsheen S, Aziz K, Georgakilas AG. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther. 2013;139(3):392–404. DOI: 10.1016/j.pharmthera.2013.05.005Hirsimaki P, Aaltonen A, Mantyla E. Toxicity of antiestrogens. Breast J. 2002;8(2):92–96.Hirsimaki P, Aaltonen A, Mantyla E. Toxicity of antiestrogens. Breast J. 2002;8(2):92–96.Okishiro M, Taguchi T, Jin Kim S, et al. Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer. 2009;115(5):952–961. DOI: 10.1002/cncr.24111Okishiro M, Taguchi T, Jin Kim S, et al. Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer. 2009;115(5):952–961. DOI: 10.1002/cncr.24111Dieudonne AS, Lambrechts D, Claes B, et al. Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users. Breast Cancer Res Treat. 2009;118(3):531–538. DOI: 10.1007/s10549-009-0463-5Dieudonne AS, Lambrechts D, Claes B, et al. Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users. Breast Cancer Res Treat. 2009;118(3):531–538. DOI: 10.1007/s10549-009-0463-5Dieudonne AS, Lambrechts D, Smeets D, et al. The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen. Ann Oncol. 2014;25(1):90–95. DOI: 10.1093/annonc/mdt399Dieudonne AS, Lambrechts D, Smeets D, et al. The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen. Ann Oncol. 2014;25(1):90–95. DOI: 10.1093/annonc/mdt399Gunaldi M, Erkisi M, Afsar CU, et al. Evaluation of endometrial thickness and bone mineral density based on CYP2D6 polymorphisms in Turkish breast cancer patients receiving tamoxifen treatment. Pharmacology. 2014;94(3-4):183–189. DOI: 10.1159/000363304Gunaldi M, Erkisi M, Afsar CU, et al. Evaluation of endometrial thickness and bone mineral density based on CYP2D6 polymorphisms in Turkish breast cancer patients receiving tamoxifen treatment. Pharmacology. 2014;94(3-4):183–189. DOI: 10.1159/000363304Brauch H, Mürdter T, Eichelbaum M, Schwab M. Pharmacogenomics of Tamoxifen Therapy. Clinical Chemistry. 2009;55(10):1770–1782. DOI: 10.1373/clinchem.2008.121756Brauch H, Mürdter T, Eichelbaum M, Schwab M. Pharmacogenomics of Tamoxifen Therapy. Clinical Chemistry. 2009;55(10):1770–1782. DOI: 10.1373/clinchem.2008.121756Jennifer Gjerde, Jürgen Geisler, Steinar Lundgren, et al. Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer. BMC Cancer. 2010;10:313.Jennifer Gjerde, Jürgen Geisler, Steinar Lundgren, et al. Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer. BMC Cancer. 2010;10:313.Mercedes Zafra-Ceres, Tomas de Haro, Esther Farez-Vidal, et al. Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer. Int J Med Sci. 2013;10(7):932–937. DOI:10.7150/ijms.5708Mercedes Zafra-Ceres, Tomas de Haro, Esther Farez-Vidal, et al. Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer. Int J Med Sci. 2013;10(7):932–937. DOI:10.7150/ijms.5708Powers JL, Buys SS, Fletcher D, et al. Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1. J Clin Pharmacol. 2016; 56:1570–1581.Powers JL, Buys SS, Fletcher D, et al. Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1. J Clin Pharmacol. 2016; 56:1570–1581.Lim JS, Chen XA, Singh O, et al. Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol. 2011;71(5):737–750. DOI: 10.1111/j.1365-2125.2011.03905.xLim JS, Chen XA, Singh O, et al. Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol. 2011;71(5):737–750. DOI: 10.1111/j.1365-2125.2011.03905.xLim JS, Sutiman N, Muerdter TE, et al. Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients. Br J Clin Pharmacol. 2016;81(6):1142–1152. DOI: 10.1111/bcp.12886Lim JS, Sutiman N, Muerdter TE, et al. Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients. Br J Clin Pharmacol. 2016;81(6):1142–1152. DOI: 10.1111/bcp.12886Lu WJ, Desta Z, Flockhart DA. Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer. Breast Cancer Res Treat. 2012;131(2):473–481. DOI: 10.1007/s10549-011-1428-zLu WJ, Desta Z, Flockhart DA. Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer. Breast Cancer Res Treat. 2012;131(2):473–481. DOI: 10.1007/s10549-011-1428-zLu WJ, Xu C, Pei Z, Mayhoub AS, Cushman M, Flockhart DA. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast Cancer Res Treat. 2012 May; 133(1):99–109. DOI: 10.1007/s10549-011-1699-4Lu WJ, Xu C, Pei Z, Mayhoub AS, Cushman M, Flockhart DA. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast Cancer Res Treat. 2012 May; 133(1):99–109. DOI: 10.1007/s10549-011-1699-4Lu WJ, Liu J, Lu D, et al. Synthesis of mixed (E,Z)-, (E)-, and (Z)- norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2013; 56(11):4611–4618. DOI: 10.1021/jm400364hLu WJ, Liu J, Lu D, et al. Synthesis of mixed (E,Z)-, (E)-, and (Z)- norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2013; 56(11):4611–4618. DOI: 10.1021/jm400364hWei Lv, Jinzhong Liu, Todd C. Skaar, et al. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities. J Med Chem. 2015;58(6):2623–2648. DOI: 10.1021/jm501218eWei Lv, Jinzhong Liu, Todd C. Skaar, et al. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities. J Med Chem. 2015;58(6):2623–2648. DOI: 10.1021/jm501218eMwinyi J, Vokinger K, Jetter A, et al. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol. 2014;73(6):1181–1188. DOI: 10.1007/s00280-014-2453-5Mwinyi J, Vokinger K, Jetter A, et al. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol. 2014;73(6):1181–1188. DOI: 10.1007/s00280-014-2453-5Moyer AM, Suman VJ, Weinshilboum RM, et al. SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen. Pharmacogenomics. 2011; 12(11):1535–1543. DOI: 10.2217/pgs.11.97Moyer AM, Suman VJ, Weinshilboum RM, et al. SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen. Pharmacogenomics. 2011; 12(11):1535–1543. DOI: 10.2217/pgs.11.97Ruiter R, Bijl MJ, van Schaik RH, et al. CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen. Pharmacogenomics. 2010; 11(10):1367–1375. DOI: 10.2217/pgs.10.112Ruiter R, Bijl MJ, van Schaik RH, et al. CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen. Pharmacogenomics. 2010; 11(10):1367–1375. DOI: 10.2217/pgs.10.112Beelen K, Opdam M, Severson TM, et al. CYP2C19*2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment. Breast Cancer Res Treat. 2013;139(3):649–655. DOI: 10.1007/s10549-013-2568-0Beelen K, Opdam M, Severson TM, et al. CYP2C19*2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment. Breast Cancer Res Treat. 2013;139(3):649–655. DOI: 10.1007/s10549-013-2568-0Schaik RH, Kok M, Sweep FC, et al. The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics. 2011; 12(8):1137–1146. DOI: 10.2217/pgsSchaik RH, Kok M, Sweep FC, et al. The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics. 2011; 12(8):1137–1146. DOI: 10.2217/pgsBai L, He J, He GH, et al. Association of CYP2C19 polymorphisms with survival of breast cancer patients using tamoxifen: results of a metaanalysis. Asian Pac J Cancer Prev. 2014;15(19):8331–8335. DOI: 10.7314/apjcp.2014.15.19.8331Bai L, He J, He GH, et al. Association of CYP2C19 polymorphisms with survival of breast cancer patients using tamoxifen: results of a metaanalysis. Asian Pac J Cancer Prev. 2014;15(19):8331–8335. DOI: 10.7314/apjcp.2014.15.19.8331Justenhoven C, Hamann U, Pierl CB, et al. CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009;115(2):391– 396. DOI: 10.1007/s10549-008-0076-4Justenhoven C, Hamann U, Pierl CB, et al. CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009;115(2):391– 396. DOI: 10.1007/s10549-008-0076-4Jager NG, Rosing H, Linn SC, et al. Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen. Breast Cancer Res Treat. 2012;133(2):793–798. DOI: 10.1007/s10549-012-2000-1Jager NG, Rosing H, Linn SC, et al. Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen. Breast Cancer Res Treat. 2012;133(2):793–798. DOI: 10.1007/s10549-012-2000-1Teft WA, Gong IY, Dingle B, et al. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat. 2013;139(1):95–105. DOI: 10.1007/s10549-013-2511-4Teft WA, Gong IY, Dingle B, et al. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat. 2013;139(1):95–105. DOI: 10.1007/s10549-013-2511-4Antunes MV, de Oliveira V, Raymundo S, et al. CYP3A4*22 is related to increased plasma levels of 4-hydroxytamoxifen and partially compensates for reduced CYP2D6 activation of tamoxifen. Pharmacogenomics. 2015;16(6):601–617. DOI: 10.2217/pgs.15.13Antunes MV, de Oliveira V, Raymundo S, et al. CYP3A4*22 is related to increased plasma levels of 4-hydroxytamoxifen and partially compensates for reduced CYP2D6 activation of tamoxifen. Pharmacogenomics. 2015;16(6):601–617. DOI: 10.2217/pgs.15.13Wang D, Guo Y, Wrighton SA, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11(4):274–286. DOI: 10.1038/tpj.2010.28Wang D, Guo Y, Wrighton SA, et al. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11(4):274–286. DOI: 10.1038/tpj.2010.28Thummel KE, Brimer C, Yasuda K, et al. Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. Mol Pharmacol. 2001;60(6):1399-1406. DOI: 10.1124/mol.60.6.1399Thummel KE, Brimer C, Yasuda K, et al. Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. Mol Pharmacol. 2001;60(6):1399-1406. DOI: 10.1124/mol.60.6.1399Thirumaran RK, Lamba JK, Kim RB, et al. Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR polymorphisms and show seasonal variation. Biochem Pharmacol. 2012;84(1):104–112. DOI: 10.1016/j.bcp.2012.03.017Thirumaran RK, Lamba JK, Kim RB, et al. Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR polymorphisms and show seasonal variation. Biochem Pharmacol. 2012;84(1):104–112. DOI: 10.1016/j.bcp.2012.03.017Chu W, Fyles A, Sellers EM, et al. Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use. Carcinogenesis. 2007;28(10):2139–2142. DOI: 10.1093/carcin/bgm087Chu W, Fyles A, Sellers EM, et al. Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use. Carcinogenesis. 2007;28(10):2139–2142. DOI: 10.1093/carcin/bgm087Tucker AN, Tkaczuk KA, Lewis LM, et al. Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005;217(1):61–72. DOI: 10.1016/j.canlet.2004.08.027Tucker AN, Tkaczuk KA, Lewis LM, et al. Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005;217(1):61–72. DOI: 10.1016/j.canlet.2004.08.027Tan SH, Lee SC, Goh BC, Wong J. Pharmacogenetics in Breast Cancer Therapy. Clin Cancer Res. 2008 Dec 15;14(24):8027–8041. DOI: 10.1158/1078-0432.CCR-08-0993Tan SH, Lee SC, Goh BC, Wong J. Pharmacogenetics in Breast Cancer Therapy. Clin Cancer Res. 2008 Dec 15;14(24):8027–8041. DOI: 10.1158/1078-0432.CCR-08-0993Sim SC, Ingelman-Sundberg M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effect. Hum Genomics. 2010 Apr;4(4):278–281. DOI: 10.1186/1479-7364-4-4-278Sim SC, Ingelman-Sundberg M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effect. Hum Genomics. 2010 Apr;4(4):278–281. DOI: 10.1186/1479-7364-4-4-278Fernández-Santander A, Gaibar M, Novillo A, et al. Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients. PLoS One. 2013;8(7):e70183. DOI: 10.1371/journal.pone.0070183Fernández-Santander A, Gaibar M, Novillo A, et al. Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients. PLoS One. 2013;8(7):e70183. DOI: 10.1371/journal.pone.0070183Del Rea M, Micheluccib A, Simi P, Danesi R. Pharmacogenetics of anti-estrogen treatment of breast cancer. Cancer Treat Rev. 2012 Aug; 38(5):442–450. DOI: 10.1016/j.ctrv.2011.08.003Del Rea M, Micheluccib A, Simi P, Danesi R. Pharmacogenetics of anti-estrogen treatment of breast cancer. Cancer Treat Rev. 2012 Aug; 38(5):442–450. DOI: 10.1016/j.ctrv.2011.08.003Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol. 2003 Aug;59(4):303–312. DOI: 10.1007/s00228-003-0606-2Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol. 2003 Aug;59(4):303–312. DOI: 10.1007/s00228-003-0606-2Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels. Available at: www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htmTable of Valid Genomic Biomarkers in the Context of Approved Drug Labels. Available at: www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htmBecquemont L, Alfirevic A, Amstutz U, et al. Pharmacogenomics. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics. 2011 Jan;12(1):113-24. DOI: 10.2217/pgs.10.147Becquemont L, Alfirevic A, Amstutz U, et al. Pharmacogenomics. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics. 2011 Jan;12(1):113-24. DOI: 10.2217/pgs.10.147Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte- an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662–673. DOI: 10.1038/clpt.2011.34Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte- an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662–673. DOI: 10.1038/clpt.2011.34Fleeman N, Martin Saborido C, Payne K, et al. The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. Health Technol Assess. 2011;15(33):1–102. DOI: 10.3310/hta15330Fleeman N, Martin Saborido C, Payne K, et al. The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. Health Technol Assess. 2011;15(33):1–102. DOI: 10.3310/hta15330NCCN Clinical Practice Guidelines in Oncology. Breast cancer version 2.2017 – April 6, 2017. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp#siteNCCN Clinical Practice Guidelines in Oncology. Breast cancer version 2.2017 – April 6, 2017. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp#siteFDA Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at: www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htmFDA Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at: www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htmBinkhorst L, Mathijssen RH, van Herk-Sukel MP, et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013;139(3):923–929. DOI: 10.1007/s10549-013-2585-zBinkhorst L, Mathijssen RH, van Herk-Sukel MP, et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013;139(3):923–929. DOI: 10.1007/s10549-013-2585-zGoetz MP, Sun JX, Suman VJ, et al. Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. J Natl Cancer Inst. 2014;107(2):dju401. DOI: 10.1093/jnci/dju401Goetz MP, Sun JX, Suman VJ, et al. Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. J Natl Cancer Inst. 2014;107(2):dju401. DOI: 10.1093/jnci/dju401Ratain MJ, Nakamura Y, Cox NJ. CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. Clin Pharmacol Ther. 2013;94(2):185-187. DOI: 10.1038/clpt.2013.66Ratain MJ, Nakamura Y, Cox NJ. CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. Clin Pharmacol Ther. 2013;94(2):185-187. DOI: 10.1038/clpt.2013.66Савельева М.И., Урванцева И.А., Игнатова А.К., Панченко Ю.С., Поддубная И.В. Фармакогенетические особенности II фазы биотрансформации тамоксифена: систематический обзор. Фармакогенетика и Фармакогеномика. 2017;(1):10-15. Доступно по: https://www.pharma-cogeneticspharmacogenomics.ru/jour/article/view/34 [Savelyeva MI, Urvantseva IA, Ignatova AK, Panchenko JS, Poddubnaya IV. Pharmacogenetic features of the phase II biotransformation of tamoxifen: a systematic review. Pharmacogenetics and Pharmacogenomics. 2017;(1):10-15. (In Russ.)]Савельева М.И., Урванцева И.А., Игнатова А.К., Панченко Ю.С., Поддубная И.В. Фармакогенетические особенности II фазы биотрансформации тамоксифена: систематический обзор. Фармакогенетика и Фармакогеномика. 2017;(1):10-15. Доступно по: https://www.pharma-cogeneticspharmacogenomics.ru/jour/article/view/34 [Savelyeva MI, Urvantseva IA, Ignatova AK, Panchenko JS, Poddubnaya IV. Pharmacogenetic features of the phase II biotransformation of tamoxifen: a systematic review. Pharmacogenetics and Pharmacogenomics. 2017;(1):10-15. (In Russ.)]Table of Pharmacogenomic Biomarkers in Drug Labeling. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomicbiomarkers-drug-labelingTable of Pharmacogenomic Biomarkers in Drug Labeling. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomicbiomarkers-drug-labeling

The authors declare that there are no conflicts of interest present.