oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2017-16-6-73-85oncotomsk-644Research ArticleОБЗОРЫREVIEWSCYP2D6-ГЕНОТИПИРОВАНИЕ В ОЦЕНКЕ ЭФФЕКТИВНОСТИ ТЕРАПИИ ТАМОКСИФЕНОМ У БОЛЬНЫХ ГОРМОНОПОЗИТИВНЫМ РАКОМ МОЛОЧНОЙ ЖЕЛЕЗЫCYP2D6-GENOTYPING IN THE ASSESSMENT OF THE EFFECTIVENESS OF THERAPY WITH TAMOXIFEN IN PATIENTS WITH ADVANCED HORMONE RECEPTOR-POSITIVE BREAST CANCERЛюбченкоЛ. Н.LyubchenkoL. N.

доктор медицинских наук, заведующая лабораторией клинической онкогенетики

SPIN-код: 9589-9057

MD, PhD, DSc, Head of Clinical Genetic Laboratory, Oncology Research Institute

SPIN-код: 9589-9057

clingen@mail.ruФилипповаМ. Г.FilippovaM. G.

кандидат медицинских наук, старший научный сотрудник лаборатории клинической онкогенетики

SPIN-код: 1927-6110

PhD, Senior Researcher, Clinical Genetic Laboratory, Oncology Research Institute

SPIN-код: 1927-6110

fimargarita@yandex.ruМехтиеваН. И.MekhtievaN. I.

кандидат медицинских наук, отделение сосудистой и реконструктивной хирургии

MD, PhD, Department of General Oncology (surgery department № 1), Oncology Research Institute

ШендриковаТ. А.ShendrikovaT. A.

аспирант

Postgraduate, Oncology Research Institute

shendrikova.tatyana@gmail.comСемьянихинаА. В.SemaynikhinaA. V.

врач-онколог лаборатории клинической онкогенетики

SPIN-код: 1751-7909

MD, Physician, Clinical Genetic Laboratory, Oncology Research Institute

SPIN-код: 1751-7909

alexandra_silina@mail.ruСнеговойА. В.SnegovoyA. V.

доктор медицинских наук, заведующий отделением амбулаторной химиотерапии (дневной стационар)

SPIN-код: 8398-2396

MD, PhD, DSc, Head of Department of Outpatient Chemotherapy, Oncology Research Institute

SPIN-код: 8398-2396

 

drsneg@gmail.comФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, г. МоскваРоссияN.N. Blokhin Medical Research Center of Oncology, MoscowRussian Federation2017241220171667385Copyright © Любченко Л.Н., Филиппова М.Г., Мехтиева Н.И., Шендрикова Т.А., Семьянихина А.В., Снеговой А.В., 20172017Любченко Л.Н., Филиппова М.Г., Мехтиева Н.И., Шендрикова Т.А., Семьянихина А.В., Снеговой А.В.Lyubchenko L.N., Filippova M.G., Mekhtieva N.I., Shendrikova T.A., Semaynikhina A.V., Snegovoy A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/644

Тамоксифен является препаратом выбора при эндокринотерапии гормоноположительного рака молочной железы у женщин в репродуктивном периоде. Метаболическая активность тамоксифена в организме определяется активностью фермента CYP2D6, кодируемого одноименным геном: под действием фермента тамоксифен переходит в метаболически активную форму – эндоксифен. Фармакогенетическое тестирование гена CYP2D6 у пациентов с гормоноположительным раком молочной железы поможет прогнозировать эффективность терапии и оценить риск развития побочных эффектов в целях улучшения отдаленных результатов лечения.

 

Tamoxifen is a drug of choice for endocrine therapy of hormone receptor- positive breast cancer in women of reproductive age. The metabolic activity of tamoxifen is determined by the activity of the CYP2D6 enzyme encoded by the CYP2D6 gene: under the action of the enzyme, tamoxifen converts into the metabolically active form called endoxifen. Pharmacogenetic testing of the CYP2D6 gene in patients with hormone-positive breast cancer can help to predict response to therapy and assess the risk of side effects with the aim of improving long-term treatment outcomes.

 

рак молочной железыгормонотерапиятамоксифенфармакогенетическое тестированиеген CYP2D6tamoxifenpharmacogenetics testingCYP2D6 genehormonotherapybreast cancerReferencesДавыдов М.И., Аксель Е.М. Статистика злокачественных новообразований в России и странах СНГ в 2012 г. М., 2014. 226.Davydov M.I., Axel E.M. Statistics of malignant neoplasms in Russia and CIS countries in 2012. Moscow, 2014. 226. [in Russian]Goldhirsch A., Wood W.C., Gelber R.D., Coates A.S., Thürlimann B., Senn H.J.; 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer Ann Oncol. 2007 Jul; 18 (7): 1133–44.Goldhirsch A., Wood W.C., Gelber R.D., Coates A.S., Thürlimann B., Senn H.J.; 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer Ann Oncol. 2007 Jul; 18 (7): 1133–44.Davies C., Pan H., Godwin J., Gray R., Arriagada R., Raina V., Abraham M., Medeiros Alencar V.H., Badran A., Bonfill X., Bradbury J., Clarke M., Collins R., Davis S.R., Delmestri A., Forbes J.F., Haddad P., Hou M.F., Inbar M., Khaled H., Kielanowska J., Kwan W.H., Mathew B.S., Mittra I., Müller B., Nicolucci A., Peralta O., Pernas F., Petruzelka L., Pienkowski T., Radhika R., Rajan B., Rubach M.T., Tort S., Urrútia G., Val-entini M., Wang Y., Peto R.; 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 randomized trial. Lancet. 2013; 381 (9869): 805–16. doi: 10.1016/S0140-6736(12)61963-1.Davies C., Pan H., Godwin J., Gray R., Arriagada R., Raina V., Abraham M., Medeiros Alencar V.H., Badran A., Bonfill X., Bradbury J., Clarke M., Collins R., Davis S.R., Delmestri A., Forbes J.F., Haddad P., Hou M.F., Inbar M., Khaled H., Kielanowska J., Kwan W.H., Mathew B.S., Mittra I., Müller B., Nicolucci A., Peralta O., Pernas F., Petruzelka L., Pienkowski T., Radhika R., Rajan B., Rubach M.T., Tort S., Urrútia G., Val-entini M., Wang Y., Peto R.; 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 randomized trial. Lancet. 2013; 381 (9869): 805–16. doi: 10.1016/S0140-6736(12)61963-1.Gray R.G., Rea D., Handley K., Bowden S.J., Perry P., Earl H.M., Poole C.J., Bates T., Chetiyawardana S., Dewar S.A., Fernando I.N., Grieve R., Nicoll J., Rayter Z., Robinson A., Salman A., Yarnold J., Bathers S., Mar-shall A., Lee M. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol. 2013; 31 (18S): 5.Gray R.G., Rea D., Handley K., Bowden S.J., Perry P., Earl H.M., Poole C.J., Bates T., Chetiyawardana S., Dewar S.A., Fernando I.N., Grieve R., Nicoll J., Rayter Z., Robinson A., Salman A., Yarnold J., Bathers S., Marshall A., Lee M. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol. 2013; 31 (18S): 5.Lim Y.C., Desta Z., Flockhart D.A., Skaar T.C. Endoxifen (4-hydroxy-N-desmethyltamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxytamoxifen. Cancer Chemother Pharmacol. 2005; 55 (5): 471–8. doi: 10.1007/s00280-004-0926-7.Lim Y.C., Desta Z., Flockhart D.A., Skaar T.C. Endoxifen (4-hydroxy-N-desmethyltamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxytamoxifen. Cancer Chemother Pharmacol. 2005; 55 (5): 471–8. doi: 10.1007/s00280-004-0926-7.Crewe H.K., Ellis S.W., Lennard M.S., Tucker G.T. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol. 1997; 53 (2): 171–8.Crewe H.K., Ellis S.W., Lennard M.S., Tucker G.T. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol. 1997; 53 (2): 171–8.Murdter T.E., Schroth W., Bacchus-Gerybadze L., Winter S., Heinkele G., Simon W., Fasching P.A., Fehm T.; German Tamoxifen and AI Clinicians Group, Eichelbaum M., Schwab M., Brauch H. 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 May; 89 (5): 708–17. doi: 10.1038/clpt.2011.27.Murdter T.E., Schroth W., Bacchus-Gerybadze L., Winter S., Heinkele G., Simon W., Fasching P.A., Fehm T.; German Tamoxifen and AI Clinicians Group, Eichelbaum M., Schwab M., Brauch H. 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 May; 89 (5): 708–17. doi: 10.1038/clpt.2011.27.Wu X., Hawse J.R., Subramaniam M., Goetz M.P., Ingle J.N., Spels-berg T.C. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. 2009; 69 (5): 1722–7. doi: 10.1158/0008-5472.CAN-08-3933.Wu X., Hawse J.R., Subramaniam M., Goetz M.P., Ingle J.N., Spels-berg T.C. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res. 2009; 69 (5): 1722–7. doi: 10.1158/0008-5472.CAN-08-3933.de Vries Schultink A.H., Zwart W., Linn S.C., Beijnen J.H., Huitema A.D. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinet. 2015 Aug; 54 (8): 797–810. doi: 10.1007/s40262-015-0273-3.de Vries Schultink A.H., Zwart W., Linn S.C., Beijnen J.H., Huite-ma A.D. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinet. 2015 Aug; 54 (8): 797–810. doi: 10.1007/s40262-015-0273-3.Mwinyi J., Vokinger K., Jetter A., Breitenstein U., Hiller C., Kullak-Ublick G.A., Trojan A. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol. 2014; 73 (6): 1181–8. doi: 10.1007/ s00280-014-2453-5.Mwinyi J., Vokinger K., Jetter A., Breitenstein U., Hiller C., Kullak-Ublick G.A., Trojan A. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol. 2014; 73 (6): 1181–8. doi: 10.1007/ s00280-014-2453-5.Gonzalez F.J., Mackenzie P.I., Kimura S., Nebert D.W. Isolation and characterization of mouse full-length cDNA and genomic clones of 3-methylcholanthrene-inducible cytochrome P1-450 and P3-450. Gene. 1984 Sep; 29 (3): 281–92.Gonzalez F.J., Mackenzie P.I., Kimura S., Nebert D.W. Isolation and characterization of mouse full-length cDNA and genomic clones of 3-methylcholanthrene-inducible cytochrome P1-450 and P3-450. Gene. 1984 Sep; 29 (3): 281–92.Nebert D.W., Nelson D.R., Coon M.J., Estabrook R.W., Feyereisen R., Fujii-Kuriyama Y., Gonzalez F.J., Guengerich F.P., Gunsalus I.C., John-son E.F. The P450 gene superfamily: recommended nomenclature. DNA. 1987; 6 (1): 1–11. doi: 10.1089/dna.1987.6.1.Nebert D.W., Nelson D.R., Coon M.J., Estabrook R.W., Feyereisen R., Fujii-Kuriyama Y., Gonzalez F.J., Guengerich F.P., Gunsalus I.C., John-son E.F. The P450 gene superfamily: recommended nomenclature. DNA. 1987; 6 (1): 1–11. doi: 10.1089/dna.1987.6.1.Nelson D.R. Cytochrome P450 gene superfamily. [Cited 2002 July 10]. Avaliable from: drnelson.utmem.edu/cytochromeP450.html.Nelson D.R. Cytochrome P450 gene superfamily. [Cited 2002 July 10]. Avaliable from: drnelson.utmem.edu/cytochromeP450.html.Phillips K.A., Veenstra D.L., Oren E., Lee J.K., Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001; 286 (18): 2270–9.Phillips K.A., Veenstra D.L., Oren E., Lee J.K., Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001; 286 (18): 2270–9.Andersson T., Flockhart D.A., Goldstein D.B., Huang S.M., Kroetz D.L., Milos P.M., Ratain M.J., Thummel K. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther. 2005 Dec; 78 (6): 559–81. doi: 10.1016/j.clpt.2005.08.013.Andersson T., Flockhart D.A., Goldstein D.B., Huang S.M., Kroetz D.L., Milos P.M., Ratain M.J., Thummel K. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther. 2005 Dec; 78 (6): 559–81. doi: 10.1016/j.clpt.2005.08.013.Franceschi M., Scarcelli C., Niro V., Seripa D., Pazienza A.M., Pepe G., Colusso A.M., Pacilli L., Pilotto A. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf. 2008; 31 (6): 545–56.Franceschi M., Scarcelli C., Niro V., Seripa D., Pazienza A.M., Pepe G., Colusso A.M., Pacilli L., Pilotto A. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf. 2008; 31 (6): 545–56.Lazarou J., Pomeranz B.H., Corey P.N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998; 279 (15): 1200–5.Lazarou J., Pomeranz B.H., Corey P.N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998; 279 (15): 1200–5.Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2001; 3 (2): 229–43. doi: 10.1023/B:BREA.0000025406.31193.e8.Bradford L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2001; 3 (2): 229–43. doi: 10.1023/B:BREA.0000025406.31193.e8.Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics. 2005; 5 (1): 6–13. doi: 10.1038/ sj.tpj.6500285.Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics. 2005; 5 (1): 6–13. doi: 10.1038/ sj.tpj.6500285.Zanger U.M., Raimundo S., Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan; 369 (1): 23–37.Zanger U.M., Raimundo S., Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan; 369 (1): 23–37.Goetz M.P., Rae J.M., Suman V.J., Safgren S.L., Ames M.M., Vis-scher D.W., Reynolds C., Couch F.J., Lingle W.L., Flockhart D.A., Desta Z., Perez E.A., Ingle J.N. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23 (36): 9312–8. doi: 10.1200/JCO.2005.03.3266.Goetz M.P., Rae J.M., Suman V.J., Safgren S.L., Ames M.M., Visscher D.W., Reynolds C., Couch F.J., Lingle W.L., Flockhart D.A., Desta Z., Perez E.A., Ingle J.N. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23 (36): 9312–8. doi: 10.1200/JCO.2005.03.3266.Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. [Cited 2014 Dec 28, 2014]. Available from: www.cypalleles.ki.se/cyp2d6.htm.Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. [Cited 2014 Dec 28, 2014]. Available from: www.cypalleles.ki.se/cyp2d6.htm.Gaikovitch E.A., Cascorbi I., Mrozikiewicz P.M., Brockmöller J., Frötschl R., Köpke K., Gerloff T., Chernov J.N., Roots I. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol. 2003; 59 (4): 303–12. doi: 10.1111/j.1472-8206.2007.00510.x.Gaikovitch E.A., Cascorbi I., Mrozikiewicz P.M., Brockmöller J., Frötschl R., Köpke K., Gerloff T., Chernov J.N., Roots I. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol. 2003; 59 (4): 303–12. doi: 10.1111/j.1472-8206.2007.00510.x.McGraw J., Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012 Mar; 8 (3): 371–82. doi: 10.1517/17425255.2012.657626.McGraw J., Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012 Mar; 8 (3): 371–82. doi: 10.1517/17425255.2012.657626.Eichelbaum M., Ingelman-Sundberg M., Evans W.E. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006; 57: 119–37. doi: 10.1146/annurev.med.56.082103.104724.Eichelbaum M., Ingelman-Sundberg M., Evans W.E. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006; 57: 119–37. doi: 10.1146/annurev.med.56.082103.104724.Evans W.E., Relling M.V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999; 286 (5439): 487–91.Evans W.E., Relling M.V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999; 286 (5439): 487–91.Rimoin D.L., Connor J.M., Pyeritz R.E., Korf B.R. Emery and rimoin’s principles and practice of medical genetics. Edinburgh: Harcourt Brace, 2002. 590–631.Rimoin D.L., Connor J.M., Pyeritz R.E., Korf B.R. Emery and rimoin’s principles and practice of medical genetics. Edinburgh: Harcourt Brace, 2002. 590–631.Crewe H.K., Notley L.M., Wunsch R.M., Lennard M., Gillam M.J. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 40 -hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metabolism Dispos. 2002; 30 (8): 869–74.Crewe H.K., Notley L.M., Wunsch R.M., Lennard M., Gillam M.J. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 40 -hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metabolism Dispos. 2002; 30 (8): 869–74.Desta Z., Ward B.A., Soukhova N.V., Flockhart D.A. 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): 1062–75. doi: 10.1124/ jpet.104.065607.Desta Z., Ward B.A., Soukhova N.V., Flockhart D.A. 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): 1062–75. doi: 10.1124/ jpet.104.065607.Maximov P.Y., McDaniel R.E., Fernandes D.J., Korostyshevskiy V.R., Bhatta P., Mürdter T.E., Flockhart D.A., Jordan V.C. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes. Br J Pharmacol. 2014; 171 (24): 5624–35. doi: 10.1111/bph.12864.Maximov P.Y., McDaniel R.E., Fernandes D.J., Korostyshevskiy V.R., Bhatta P., Mürdter T.E., Flockhart D.A., Jordan V.C. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes. Br J Pharmacol. 2014; 171 (24): 5624–35. doi: 10.1111/bph.12864.Johnson M.D., Zuo H., Lee K.H., Trebley J.P., Rae J.M., Weatherman R.V., Desta Z., Flockhart D.A., Skaar T.C. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85 (2): 151–9.Johnson M.D., Zuo H., Lee K.H., Trebley J.P., Rae J.M., Weatherman R.V., Desta Z., Flockhart D.A., Skaar T.C. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004; 85 (2): 151–9.Кольман Я., Рём К.Г. Наглядная биохимия. М.: Мир, 2000. 470.Kohlmann I., Rem K.G. Visible biochemistry. Moscow, 2000. 470. [in Russian]Сычев Д.А., Миронова Н.А. Фармакогенетическое тестирование по CYP2D6 и CYP2C19: значение для персонализации применения лекарственных средств в клинической практике. Лаборатория. 2012; 4: 11–3.Sychev D.A., Mironova N.A. Pharmacogenetic testing for CYP2D6 and CYP2C19: a value for personalizing the use of drugs in clinical practice. Laboratory 2012; 4: 11–3. [in Russian]Zhou S.F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009; 48 (12): 761–804. doi: 10.2165/11318030-000000000-00000.Zhou S.F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009; 48 (12): 761–804. doi: 10.2165/11318030-000000000-00000.Borges S., Desta Z., Li L., Skaar T.C., Ward B.A., Nguyen A., Jin Y., Storniolo A.M., Nikoloff D.M., Wu L., Hillman G., Hayes D.F., Stearns V., Flockhart D.A. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol. 2006; 80(1): 61–74. doi: 10.1016/j. clpt.2006.03.013.Borges S., Desta Z., Li L., Skaar T.C., Ward B.A., Nguyen A., Jin Y., Storniolo A.M., Nikoloff D.M., Wu L., Hillman G., Hayes D.F., Stearns V., Flockhart D.A. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol. 2006; 80(1): 61–74. doi: 10.1016/j. clpt.2006.03.013.Lim H.S., Ju Lee H., Seok Lee K., Sook Lee E., Jang I.J., Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007; 25 (25): 3837–45. doi: 10.1200/JCO.2007.11.4850.Lim H.S., Ju Lee H., Seok Lee K., Sook Lee E., Jang I.J., Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007; 25 (25): 3837–45. doi: 10.1200/JCO.2007.11.4850.Madlensky L., Natarajan L., Tchu S., Pu M., Mortimer J., Flatt S.W., Nikoloff D.M., Hillman G., Fontecha M.R., Lawrence H.J., Parker B.A. Wu A.H., Pierce J.P. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89 (5): 718–25. doi: 10.1038/clpt.2011.32.Madlensky L., Natarajan L., Tchu S., Pu M., Mortimer J., Flatt S.W., Nikoloff D.M., Hillman G., Fontecha M.R., Lawrence H.J., Parker B.A. Wu A.H., Pierce J.P. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011; 89 (5): 718–25. doi: 10.1038/clpt.2011.32.Schroth W., Goetz M.P., Hamann U., Fasching P.A., Schmidt M., Winter S., Fritz P., Simon W., Suman V.J., Ames M.M., Safgren S.L., Kuffel M.J., Ulmer H.U., Boländer J., Strick R., Beckmann M.W., Koelbl H., Weinshilboum R.M., Ingle J.N., Eichelbaum M., Schwab M., Brauch H. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009; 302 (13): 1429–36. doi: 10.1001/jama.2009.1420.Schroth W., Goetz M.P., Hamann U., Fasching P.A., Schmidt M., Winter S., Fritz P., Simon W., Suman V.J., Ames M.M., Safgren S.L., Kuffel M.J., Ulmer H.U., Boländer J., Strick R., Beckmann M.W., Koelbl H., Weinshilboum R.M., Ingle J.N., Eichelbaum M., Schwab M., Brauch H. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009; 302 (13): 1429–36. doi: 10.1001/jama.2009.1420.Regan M.M., Leyland-Jones B., Bouzyk M., Pagani O., Tang W., Kammler R., Dell’orto P., Biasi M.O., Thürlimann B., Lyng M.B., Ditzel H.J., Neven P., Debled M., Maibach R., Price K.N., Gelber R.D., Coates A.S., Goldhirsch A., Rae J.M., Viale G.; Breast International Group (BIG) 1-98 Collaborative Group. 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 Mar 21; 104 (6): 441–51. doi: 10.1093/jnci/djs125.Regan M.M., Leyland-Jones B., Bouzyk M., Pagani O., Tang W., Kammler R., Dell’orto P., Biasi M.O., Thürlimann B., Lyng M.B., Ditzel H.J., Neven P., Debled M., Maibach R., Price K.N., Gelber R.D., Coates A.S., Goldhirsch A., Rae J.M., Viale G.; Breast International Group (BIG) 1-98 Collaborative Group. 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 Mar 21; 104 (6): 441–51. doi: 10.1093/jnci/djs125.Rae J.M., Drury S., Hayes D.F., Stearns V., Thibert J.N., Hay-nes B.P., Salter J., Sestak I., Cuzick J., Dowsett M.; ATAC trialists. CYP2-D6and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104 (6): 452–60. doi: 10.1093/jnci/djs126.Rae J.M., Drury S., Hayes D.F., Stearns V., Thibert J.N., Hay-nes B.P., Salter J., Sestak I., Cuzick J., Dowsett M.; ATAC trialists. CYP2-D6and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104 (6): 452–60. doi: 10.1093/jnci/djs126.Nakamura Y., Ratain M.J., Cox N.J., McLeod H.L., Kroetz D.L., Flockhart D.A. 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): 1264. doi: 10.1093/jnci/djs304.Nakamura Y., Ratain M.J., Cox N.J., McLeod H.L., Kroetz D.L., Flockhart D.A. 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): 1264. doi: 10.1093/jnci/djs304.Dezentjé V.O., van Schaik R.H., Vletter-Bogaartz J.M., van der Straaten T., Wessels J.A., Kranenbarg E.M., Berns E.M., Seynaeve C., Putter H., van de Velde C.J., Nortier J.W., Gelderblom H., Guchelaar H.J. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvantmultinational (TEAM) trial. Breast Cancer Res Treat. 2013; 140 (2): 363–73. doi: 10.1007/s10549-013-2619-6.Dezentjé V.O., van Schaik R.H., Vletter-Bogaartz J.M., van der Straaten T., Wessels J.A., Kranenbarg E.M., Berns E.M., Seynaeve C., Putter H., van de Velde C.J., Nortier J.W., Gelderblom H., Guchelaar H.J. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvantmultinational (TEAM) trial. Breast Cancer Res Treat. 2013; 140 (2): 363–73. doi: 10.1007/s10549-013-2619-6.Goetz M.P., Suman V.J., Hoskin T.L., Gnant M., Filipits M., Safgren S.L., Kuffel M., Jakesz R., Rudas M., Greil R., Dietze O., Lang A., Offner F., Reynolds C.A., Weinshilboum R.M., Ames M.M., Ingle J.N. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013; 19 (2): 500–7. doi: 10.1158/1078-0432.CCR-12-2153.Goetz M.P., Suman V.J., Hoskin T.L., Gnant M., Filipits M., Safgren S.L., Kuffel M., Jakesz R., Rudas M., Greil R., Dietze O., Lang A., Offner F., Reynolds C.A., Weinshilboum R.M., Ames M.M., Ingle J.N. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013; 19 (2): 500–7. doi: 10.1158/1078-0432.CCR-12-2153.Karle J., Bolbrinker J., Vogl S., Kreutz R., Denkert C., Eucker J., Wischnewsky M., Possinger K., Regierer A.C. Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. Breast Cancer Res Treat. 2013; 139 (2): 553–60. doi: 10.1007/s10549-013-2565-3.Karle J., Bolbrinker J., Vogl S., Kreutz R., Denkert C., Eucker J., Wischnewsky M., Possinger K., Regierer A.C. Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. Breast Cancer Res Treat. 2013; 139 (2): 553–60. doi: 10.1007/s10549-013-2565-3.Zeng Z., Liu Y., Liu Z., You J., Chen Z., Wang J., Peng Q., Xie L., Li R., Li S., Qin X. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis. Cancer Chemother Pharmacol. 2013; 72 (2): 287–303. doi: 10.1007/s00280-013-2195-9.Zeng Z., Liu Y., Liu Z., You J., Chen Z., Wang J., Peng Q., Xie L., Li R., Li S., Qin X. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis. Cancer Chemother Pharmacol. 2013; 72 (2): 287–303. doi: 10.1007/s00280-013-2195-9.Irvin W.J.Jr., Walko C.M., Weck K.E., Ibrahim J.G., Chiu W.K., Dees E.C., Moore S.G., Olajide O.A., Graham M.L., Canale S.T., Raab R.E., Corso S.W., Peppercorn J.M., Anderson S.M., Friedman K.J., Ogburn E.T., Desta Z., Flockhart D.A., McLeod H.L., Evans J.P., Carey L.A. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol. 2011; 29 (24): 3232–9. doi: 10.1200/JCO.2010.31.4427.Irvin W.J.Jr., Walko C.M., Weck K.E., Ibrahim J.G., Chiu W.K., Dees E.C., Moore S.G., Olajide O.A., Graham M.L., Canale S.T., Raab R.E., Corso S.W., Peppercorn J.M., Anderson S.M., Friedman K.J., Ogburn E.T., Desta Z., Flockhart D.A., McLeod H.L., Evans J.P., Carey L.A. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol. 2011; 29 (24): 3232–9. doi: 10.1200/JCO.2010.31.4427.Kiyotani K., Mushiroda T., Imamura C.K., Tanigawara Y., Hosono N., Kubo M., Sasa M., Nakamura Y., Zembutsu H. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat. 2012; 131 (1): 137–45. doi: 10.1007/ s10549-011-1777-7.Kiyotani K., Mushiroda T., Imamura C.K., Tanigawara Y., Hosono N., Kubo M., Sasa M., Nakamura Y., Zembutsu H. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat. 2012; 131 (1): 137–45. doi: 10.1007/ s10549-011-1777-7.Rolla R., Vidali M., Meola S., Pollarolo P., Fanello M.R., Nicolotti C., Saggia C., Forti L., Agostino F.D., Rossi V., Borra G., Stratica F., Alabiso O., Bellomo G. Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen. Clin Lab. 2012; 58 (11–12): 1211–8.Rolla R., Vidali M., Meola S., Pollarolo P., Fanello M.R., Nicolot-ti C., Saggia C., Forti L., Agostino F.D., Rossi V., Borra G., Stratica F., Alabiso O., Bellomo G. Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen. Clin Lab. 2012; 58 (11–12): 1211–8.Barginear M.F., Jaremko M., Peter I., Yu C., Kasai Y., Kemeny M., Raptis G., Desnick R.J. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther. 2011; 90 (4): 605–11. doi: 10.1038/clpt.2011.153.Barginear M.F., Jaremko M., Peter I., Yu C., Kasai Y., Kemeny M., Raptis G., Desnick R.J. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther. 2011; 90 (4): 605–11. doi: 10.1038/clpt.2011.153.Brauch H., Schroth W., Goetz M.P., Mürdter T.E., Winter S., Ingle J.N., Schwab M., Eichelbaum M. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol. 2013; 31 (2): 176–80. doi: 10.1200/JCO.2012.44.6625.Brauch H., Schroth W., Goetz M.P., Mürdter T.E., Winter S., Ingle J.N., Schwab M., Eichelbaum M. Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol. 2013; 31 (2): 176–80. doi: 10.1200/JCO.2012.44.6625.Stingl J.C., Parmar S., Huber-Wechselberger A., Kainz A., Renner W., Seeringer A., Brockmöller J., Langsenlehner U., Krippl P., Haschke-Becher E. Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin. 2010; 26 (11): 2535–42. doi: 10.1185/03007995.2010.518304.Stingl J.C., Parmar S., Huber-Wechselberger A., Kainz A., Renner W., Seeringer A., Brockmöller J., Langsenlehner U., Krippl P., Haschke-Be-cher E. Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin. 2010; 26 (11): 2535–42. doi: 10.1185/03007995.2010.518304.Bijl M.J., van Schaik R.H., Lammers L.A., Hofman A., Vulto A.G., van Gelder T., Stricker B.H., Visser L.E. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat. 2009; 118 (1): 125–30. doi: 10.1007/s10549-008-0272-2.Bijl M.J., van Schaik R.H., Lammers L.A., Hofman A., Vulto A.G., van Gelder T., Stricker B.H., Visser L.E. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat. 2009; 118 (1): 125–30. doi: 10.1007/s10549-008-0272-2.Schroth W., Antoniadou L., Fritz P., Schwab M., Muerdter T., Zanger U.M., Simon W., Eichelbaum M., Brauch H. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25 (33): 5187–93. doi: 10.1200/ JCO.2007.12.2705.Schroth W., Antoniadou L., Fritz P., Schwab M., Muerdter T., Zanger U.M., Simon W., Eichelbaum M., Brauch H. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007; 25 (33): 5187–93. doi: 10.1200/ JCO.2007.12.2705.Martins D.M., Vidal F.C., Souza R.D., Brusaca S.A., Brito L.M. Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival. Braz J Med Biol Res. 2014; 47 (11): 1008–15.Martins D.M., Vidal F.C., Souza R.D., Brusaca S.A., Brito L.M. Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival. Braz J Med Biol Res. 2014; 47 (11): 1008–15.Nowell S.A., Ahn J., Rae J.M., Scheys J.O., Trovato A., Sweeney C., MacLeod S.L., Kadlubar F.F., Ambrosone C.B. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat. 2005; 91 (3): 249–58. doi: 10.1007/s10549-004-7751-x.Nowell S.A., Ahn J., Rae J.M., Scheys J.O., Trovato A., Sweeney C., MacLeod S.L., Kadlubar F.F., Ambrosone C.B. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat. 2005; 91 (3): 249–58. doi: 10.1007/s10549-004-7751-x.Wegman P., Elingarami S., Carstensen J., Stal O., Nordenskjold B., Wingrem S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007; 9 (1): 7. doi: 10.1186/bcr1640.Wegman P., Elingarami S., Carstensen J., Stal O., Nordenskjold B., Wingrem S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007; 9 (1): 7. doi: 10.1186/bcr1640.Fann J.R., Thomas-Rich A.M., Katon W.J., Cowley D., Pepping M., McGregor B.A., Gralow J. Major depression after breast cancer: a review of epidemiology and treatment. Gen Hosp Psychiatry. 2008; 30 (2): 112–26. doi: 10.1016/j.genhosppsych.2007.10.008.Fann J.R., Thomas-Rich A.M., Katon W.J., Cowley D., Pepping M., McGregor B.A., Gralow J. Major depression after breast cancer: a review of epidemiology and treatment. Gen Hosp Psychiatry. 2008; 30 (2): 112–26. doi: 10.1016/j.genhosppsych.2007.10.008.Jeppesen U., Gram L.F., Vistisen K., Loft S., Poulsen H.E., Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol. 1996; 51 (1): 73–8.Jeppesen U., Gram L.F., Vistisen K., Loft S., Poulsen H.E., Brøsen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol. 1996; 51 (1): 73–8.Binkhorst L., Bannink M., de Bruijn P., Ruit J., Droogendijk H., van Alphen R.J., den Boer T.D., Lam M.H., Jager A., van Gelder T., Ma-thijssen R.H. Augmentation of endoxifen exposure in tamoxifen-treated women following SSRI switch. Clin Pharmacokinet. 2016; 55 (2): 249–55. doi: 10.1007/s40262-015-0315-x.Binkhorst L., Bannink M., de Bruijn P., Ruit J., Droogendijk H., van Alphen R.J., den Boer T.D., Lam M.H., Jager A., van Gelder T., Ma-thijssen R.H. Augmentation of endoxifen exposure in tamoxifen-treated women following SSRI switch. Clin Pharmacokinet. 2016; 55 (2): 249–55. doi: 10.1007/s40262-015-0315-x.Borges S., Desta Z., Jin Y., Faouzi A., Robarge J.D., Philips S., Nguyen A., Stearns V., Hayes D., Rae J.M., Skaar T.C., Flockhart D.A., Li L. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010; 50 (4): 450–8. doi: 10.1177/0091270009359182.Borges S., Desta Z., Jin Y., Faouzi A., Robarge J.D., Philips S., Nguyen A., Stearns V., Hayes D., Rae J.M., Skaar T.C., Flockhart D.A., Li L. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010; 50 (4): 450–8. doi: 10.1177/0091270009359182.Jin Y., Desta Z., Stearns V., Ward B., Ho H., Lee K.H., Skaar T., Storniolo A.M., Li L., Araba A., Blanchard R., Nguyen A., Ullmer L., Hayden J., Lemler S., Weinshilboum R.M., Rae J.M., Hayes D.F., Flock-hart D.A. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005; 97 (1): 30–9. doi: 10.1093/jnci/dji005.Jin Y., Desta Z., Stearns V., Ward B., Ho H., Lee K.H., Skaar T., Storniolo A.M., Li L., Araba A., Blanchard R., Nguyen A., Ullmer L., Hayden J., Lemler S., Weinshilboum R.M., Rae J.M., Hayes D.F., Flock-hart D.A. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005; 97 (1): 30–9. doi: 10.1093/jnci/dji005.Stearns V., Johnson M.D., Rae J.M., Morocho A., Novielli A., Bhargava P., Hayes D.F., Desta Z., Flockhart D.A. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003; 95 (23): 1758–64.Stearns V., Johnson M.D., Rae J.M., Morocho A., Novielli A., Bhargava P., Hayes D.F., Desta Z., Flockhart D.A. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003; 95 (23): 1758–64.Chubak J., Buist D.S., Boudreau D.M., Rossing M.A., Lumley T., Weiss N.S. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat. 2008; 112 (1): 123–32. doi: 10.1007/s10549-007-9828-9.Chubak J., Buist D.S., Boudreau D.M., Rossing M.A., Lumley T., Weiss N.S. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat. 2008; 112 (1): 123–32. doi: 10.1007/s10549-007-9828-9.Lehmann D., Nelsen J., Ramanath V., Newman N., Duggan D., Smith A. Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J Clin Pharmacol. 2004; 44 (8): 861–5. doi: 10.1177/0091270004266618.Lehmann D., Nelsen J., Ramanath V., Newman N., Duggan D., Smith A. Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J Clin Pharmacol. 2004; 44 (8): 861–5. doi: 10.1177/0091270004266618.Swen J.J., Nijenhuis M., de Boer A., Grandia L., Maitland-van der Zee A.H., Mulder H., Rongen G.A., van Schaik R.H., Schalekamp T., Touw D.J., van der Weide J., Wilffert B., Deneer V.H., Guchelaar H.J. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011; 89 (5): 662–73. doi: 10.1038/clpt.2011.34Swen J.J., Nijenhuis M., de Boer A., Grandia L., Maitland-van der Zee A.H., Mulder H., Rongen G.A., van Schaik R.H., Schalekamp T., Touw D.J., van der Weide J., Wilffert B., Deneer V.H., Guchelaar H.J. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011; 89 (5): 662–73. doi: 10.1038/clpt.2011.34Tamoxifen background summary Draft. [Cited 2006, Sep 15]. Available from: www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4248-b1-01-fda-tamoxifen background summary final.pdf.Tamoxifen background summary Draft. [Cited 2006, Sep 15]. Available from: www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4248-b1-01-fda-tamoxifen background summary final.pdf.

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