Возможности фармакогенетического подхода к персонализированной терапии рака молочной железы тамоксифеном: описание клинических случаев

Савельева М.И., Дудина И.А., Захаренкова Ю.С. и др. Возможности фармакогенетического подхода к персонализированной терапии рака молочной железы тамоксифеном: описание клинических случаев. Современная Онкология. 2019; 21 (1): 24–30. DOI: 10.26442/18151434.2019.1.190248

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Savelyeva M.I., Dudina I.A., Zaharenkova J.S. et al. Opportunities of the pharmacogenetic approach to personalized tamoxifen breast cancer therapy: case reports. Journal of Modern Oncology. 2019; 21 (1): 24–30. DOI: 10.26442/18151434.2019.1.190248

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Аннотация

Тамоксифен – селективный модулятор эстрогеновых рецепторов (ER), препарат выбора при эндокринотерапии ER-позитивного рака молочной железы (РМЖ) у женщин в пременопаузе, а также в постклимактерическом периоде. Тамоксифен является пролекарством и метаболизируется в более активные формы при участии ферментов цитохрома P450 (CYP): CYP2D6, CYP3A4, CYP3A5, CYP2C9 и CYP2C19. Гены CYP являются полиморфными, поэтому среди пациенток наблюдаются различия в метаболизме тамоксифена, способствующие изменению концентрации метаболитов в сыворотке и, возможно, влияющие на эффективность терапии РМЖ. В данной статье представлены два клинических случая, описывающих пациенток c люминальным A РМЖ, с похожими прогностическими характеристиками, но имеющих разную переносимость терапии тамоксифеном. Было проведено анкетирование, затем у пациенток были взяты образцы буккального эпителия для генетического анализа мутаций генов CYP2D6*4, CYP3A5*3, CYP3A4*17, CYP2C9*2,3, CYP2C19*2,3 и ABCB1 методом полимеразной цепной реакции в реальном времени. У пациентки А. идентифицированы клинически значимые мутации генов CYP2D6(*1/*4), CYP3A5(*3/*3) и CYP2С9(*2/*3), у пациентки Б. ни один из изучаемых полиморфизмов обнаружен не был.
В течение 1 мес после начала эндокринотерапии тамоксифеном пациентка Б. отметила появление ярко выраженных побочных эффектов (боли в костях разной локализации, слабость, головокружения, умеренные приливы, ночная потливость и др.), которые значительно снижали качество жизни, что потребовало через 3 мес смены препарата. Пациентка А. принимает тамоксифен в течение 19 мес, изменения общего состояния не отмечает. В данной статье также представлен анализ мировой литературы о клинической значимости различных генетических вариантов CYP2D6, CYP3A5, CYP2C9, выдвинута гипотеза о роли этих полиморфизмов в возможности развития побочных эффектов при терапии тамоксифеном и описаны возможные пути преодоления проблемы резистентности. Важно, что с привлечением генетического исследования в рутинную клиническую практику появится возможность более эффективного назначения лекарственных препаратов, в том числе и тамоксифена, а при оценке противопоказаний речь будет идти не только о наличии/отсутствии клинических предикторов, но и об оценке фармакогенетического профиля пациента.

Ключевые слова: рак молочной железы, тамоксифен, фармакогенетика, цитохромы, полиморфизм.

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Tamoxifen is the selective modulator of estrogen receptors. Nowadays, it is widely used for treatment of premenopausal women with ER(+) breast cancer likewise for postmenopausal women with treatment contraindications to aromatase inhibitors. Tamoxifen is a prodrug which is metabolized by cytochrome P450 (CYP): CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19 to active metabolites. There is high variability in the CYP genes therefore differences in tamoxifen metabolism, tamoxifen individual response and efficacy are observed among patients. This article presents two clinical case reports. Both patients have breast cancer luminal A subtype, similar prognosis and are administered tamoxifen but they have diverse clinical effects. Patients responded to the survey questionnaire, then samples of buccal epithelium were taken for genetic analysis of CYP2D6*4, CYP3A5*3, CYP3A4*17, CYP2C9*2,3, CYP2C19*2,3, ABCB1 gene mutations by use of real time PCR. In patient A samples were detected significant mutations in CYP2D6 (*1/*4), CYP3A5 (*3/*3) и CYP2С9 (*2/*3), but there were no mutations detected in patient B. It is interesting that patient B has had prominent tamoxifen adverse effects, such as flushes, ostealgia, faintness, after 1 month of tamoxifen therapy. Patient A has taken tamoxifen for 19 months without any adverse effects. Also there is a review in this article about clinical value of different CYP2D6, CYP3A5, CYP2C9 polymorphisms. Additionally, we make a suggestion about the role of polymorphisms in tamoxifen adverse effects and the way of solution for problems of tamoxifen resistance. We suppose that routine genetic study before tamoxifen administration would help to predict individual intolerance and increase the efficacy of treatment.

Key words: breast cancer, tamoxifen, pharmacogenetics, cytochrome, polymorphism.

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Список литературы

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[Savel'eva M.I., Panchenko Iu.S., Urvantseva I.A. et al. Perspektivy farmakogeneticheskogo podkhoda k personalizirovannoi terapii tamoksifenom. World J Personalized Med 2017; 1 (1): 27–35. DOI: 10.14341/WJPM9274 (in Russian).]
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21. Tucker 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.2004.08.027
22. 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): 30–9. DOI: 10.1093/jnci/ dji005
23. Khan BA, Robinson R, Fohner AE et al. Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People. Clin Transl Sci 2018; 11 (3): 312–21. DOI: [10.1111/cts.12542]
24. Goetz MP, Rae JM, Suman VJ et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot fl ashes. J Clin Oncol 2005; 23 (36): 9312–8. DOI: 10.1200/JCO.2005.03.3266
25. 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): 5187–93. DOI: 10.1200/JCO.2007.12.2705
26. Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. http://www.cypalleles.ki.se/cyp2d6.htm
27. Teft 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: 95–105. DOI: 10.1007/s10549-013-2511-4
28. Saladores P, Mürdter T, Eccles D et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J 2014; 1: 84–94.
29. Mwinyi 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: 1181–8. DOI: 10.1007/s00280-014-2453-5
30. Hudis CA, Barlow WE, Costantino JP et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007; 25: 2127–32. DOI: 10.1200/JCO.2006.10.3523

________________________________________________

1. Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer 2008; 44 (1): 30–8. DOI: 10.1016/j.ejca.2007.11.002
2. Burstein HJ, Prestrud AA, Seidenfeld J et al. American society of clinical oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010; 28 (23): 3784–96. DOI:
10.1200/JCO.2009. 26.3756
3. Goldhirsch A, Ingle JN, Gelber RD et al. Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol 2009; 20 (8): 1319–29. DOI: 10.1093/annonc/mdp322
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, Gray 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): 771–84. DOI: 10.1016/S0140-6736(11)60993-8
[Obshcherossiiskii soiuz obshchestvennykh ob"edinenii "Assotsiatsiia onkologov Rossii'. Klinicheskie rekomendatsii po diagnostike i lecheniiu raka molochnoi zhelezy. M., 2014 (in Russian).]
6. Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodymamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2012; 27 (1): 9–54.
7. Mürdter TE, Schroth W, Bacchus-Gerybadze L et al; 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; 89 (5): 708–17. DOI: 10.1038/clpt.2011.27
8. Dean L. Tamoxifen therapy and CYP2D6 genotype. SourceMedical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–2014 Oct 7.
9. Schroth W, Hamann U, Fasching PA et al. CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification. Clin Cancer Res 2010; 16 (17): 4468–77. DOI: 10.1158/1078-0432.CCR-10-0478
10. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116 (3): 496–526. DOI: 10.1016/j.pharmthera. 2007.09.004
11. De Duenas ME, Aranda OE, Lopez-Barajas BI et al. Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype. Breast 2014; 23 (4): 400–6. DOI: 10.1016/j.breast.2014.02.008
12. Gjerde 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/ mdm434
13. Irvin WJ Jr, 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): 3232–9. DOI: 10.1200/JCO.2010.31.4427
14. Goetz M, 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): 500–7. DOI: 10.1158/1078-0432.CCR-12-2153
15. Schroth 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): 1429–36. DOI: 10.1001/jama.2009.1420
16. Савельева М.И., Панченко Ю.С., Урванцева И.А. и др. Перспективы фармакогенетического подхода к персонализированной терапии тамоксифеном. World J Personalized Med 2017; 1 (1): 27–35. DOI: 10.14341/WJPM9274
[Savel'eva M.I., Panchenko Iu.S., Urvantseva I.A. et al. Perspektivy farmakogeneticheskogo podkhoda k personalizirovannoi terapii tamoksifenom. World J Personalized Med 2017; 1 (1): 27–35. DOI: 10.14341/WJPM9274 (in Russian).]
17. Swen JJ, Nijenhuis M, de Boer A et al. Pharmacogenetics: from bench to byte – an update of guidelines. Clinical Pharmacol Ther 2011;
89 (5): 662–73. DOI: 10.1038/clpt.2011.34
18. Lamba J, Hebert JM, Schuetz EG et al. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics 2012; 22 (7): 555–8. DOI: [10.1097/FPC.0b013e 328351d47f]
19. Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. http://www.cypalleles.ki.se/cyp2d6.htm
20. 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/ s40262-015-0273-3
21. Tucker 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.2004.08.027
22. 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): 30–9. DOI: 10.1093/jnci/ dji005
23. Khan BA, Robinson R, Fohner AE et al. Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People. Clin Transl Sci 2018; 11 (3): 312–21. DOI: [10.1111/cts.12542]
24. Goetz MP, Rae JM, Suman VJ et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot fl ashes. J Clin Oncol 2005; 23 (36): 9312–8. DOI: 10.1200/JCO.2005.03.3266
25. 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): 5187–93. DOI: 10.1200/JCO.2007.12.2705
26. Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. http://www.cypalleles.ki.se/cyp2d6.htm
27. Teft 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: 95–105. DOI: 10.1007/s10549-013-2511-4
28. Saladores P, Mürdter T, Eccles D et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J 2014; 1: 84–94.
29. Mwinyi 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: 1181–8. DOI: 10.1007/s00280-014-2453-5
30. Hudis CA, Barlow WE, Costantino JP et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007; 25: 2127–32. DOI: 10.1200/JCO.2006.10.3523

Авторы

М.И.Савельева*1, И.А.Дудина2, Ю.С.Захаренкова2, А.К.Игнатова2, К.А.Рыжикова1, Ж.А.Созаева1, Д.А.Кудлай3, О.М.Перфильева1, И.В.Поддубная1

1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 1;
3 ФГБУ ГНЦ «Институт иммунологии» ФМБА России. 115478, Россия, Москва, Каширское ш., д. 24, корп. 2
*marinasavelyeva@mail.ru

________________________________________________

Marina I. Savelyeva*1, Irina A. Dudina2, Juliya S. Zaharenkova2, Anna K. Ignatova2, Kristina A. Ryzhikova1, Zhannet A. Sozaeva1, Dmitriy A. Kudlay3, Oksana M. Perfileva1, Irina V. Poddubnaya1

1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 2/1, Barrikadnaia st., Moscow, 125993, Russian Federation;
2 I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 8, b. 1, Trubetskaia st., Moscow, 119991, Russian Federation;
3 Institute of Immunology of FMBA of Russia. 115478, Russian Federation, Moscow, Kashirskoie sh., d. 24, str. 2
*marinasavelyeva@mail.ru

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