phgenomicsФармакогенетика и фармакогеномикаPharmacogenetics and Pharmacogenomics2588-05272686-8849LLC "Izdatelstvo OKI"10.37489/2588-0527-2022-1-63-73phgenomics-246Research ArticleОЦЕНКА ТЕХНОЛОГИЙ ЗДРАВООХРАНЕНИЯHEALTH TECHNOLOGY ASSESSMENTПрогностическое моделирование нежелательных лекарственных реакций тамоксифена при раке молочной железы (результаты когортного исследования)Predictive modeling of adverse events of tamoxifen therapy for breast cancer (results of a cohort study)https://orcid.org/0000-0002-6968-862XГолубенкоЕ. О.GolubenkoE. O.

врач акушер-гинеколог

Москва

obstetrician-gynecologist

Moscow

kate.golubenko@yandex.ruhttps://orcid.org/0000-0002-2373-2250СавельеваМ. И.SavelyevaM. I.

д. м. н., профессор кафедры терапии ИНПО им. профессора Е. Н. Дормидонтова

Ярославль

Dr. Sci. (Med.), professor of the Department of Therapy

Yaroslavl

marinasavelyeva@mail.ruhttps://orcid.org/0000-0001-5166-7903СозаеваЖ. А.SozaevaZ. A.

м. н. с. НИИ молекулярной и персонализированной медицины

Москва

Junior Research of the Institute of Molecular and PersonalizedMedicine

Moscow

zhannet.sozaeva@yandex.ruhttps://orcid.org/0000-0002-0995-1801ПоддубнаяА. В.PoddubnayaI. V.

д. м. н., профессор, академик РАН, зав. каф. онкологии, проректор по учебной работе и международному сотрудничеству

Москва

Dr. Sci. (Med.), Professor, Academician of the RAS, Head of the Department. Oncology, Vice-Rector for Academic Affairs and International Cooperation

Moscow

ivprectorat@inbox.ruhttps://orcid.org/0000-0003-1104-4415КореннаяВ. В.KorennayaV. V.

к. м. н., доцент кафедры акушерства и гинекологии

Москва

PhD, Cand. Sci. (Med.), Associate Professor of the Department of Obstetrics and Gynecology

Moscow

drkorennaya@mail.ruЦентр иммунологии и репродукцииРоссияCenter for Immunology and ReproductionRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Ярославский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияFederal State Budgetary Educational Institution of Higher Education “Yaroslavl State Medical University” of the Ministry of Healthcare of the Russian FederationRussian FederationФедеральное государственное бюджетное образовательное учреждение дополнительного профессионального образования «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской ФедерацииРоссияFederal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of Continuous Professional Education” of the Ministry of Healthcare of the Russian FederationRussian Federation202227022023016373Copyright © Голубенко Е.О., Савельева М.И., Созаева Ж.А., Поддубная А.В., Коренная В.В., 20232023Голубенко Е.О., Савельева М.И., Созаева Ж.А., Поддубная А.В., Коренная В.В.Golubenko E.O., Savelyeva M.I., Sozaeva Z.A., Poddubnaya I.V., Korennaya V.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.pharmacogenetics-pharmacogenomics.ru/jour/article/view/246

Актуальность. Эндокринная терапия — стандартный метод лечения женщин с ER-положительным раком молочной железы (РМЖ). Примерно у 30 % пациентов с РМЖ будет рецидив заболевания в течение 15 лет после лечения, что указывает на широкую вариабельность клинического ответа на лечение тамоксифеном. В статье представлены результаты проспективного фармакогенетического когортного исследования, проводившегося в 2018–2019 годах. Цель. Провести анализ нежелательных лекарственных реакций тамоксифена в адъювантном режиме у пациенток с РМЖ во взаимосвязи с носительством генетических полиморфизмов генов, кодирующих ферменты цитохромной системы Р450 и белки-транспортёры лекарственных средств, и построение на их основе прогностических моделей. Материалы и методы. В исследовании участвовали 120 женщин с РМЖ, прошедшие генетическое тестирование на полиморфизмы генов ферментов цитохрома P450 (CYP) и транспортёров Р-гликопротеина (Pg). Критерии включения: гистологически подтверждённый диагноз РМЖ, приём тамоксифена в рекомендуемых дозах, установление диагноза не ранее 2007 года, получение информированного добровольного согласия на участие в исследовании. Аллельные варианты определялись с помощью метода полимеразной цепной реакции в режиме реального времени в Научно-исследовательском институте молекулярной и персонализированной медицины ФГБОУ ДПО РМАНПО Минздрава России. Результаты. В результате ассоциативного анализа показана связь генетических полиморфизмов CYP2D6, CYP3A5, CYP2C9 и ABCB1 с развитием нежелательных лекарственных реакций (НЛР) тамоксифена, свидетельствующая об их клинической значимости. Проведённый комплексный ассоциативный анализ позволил с использованием математического моделирования построить прогностические модели риска развития таких НЛР при приёме ТАМ, как приливы, диспепсия, боли в костях и астения. Полученные регрессионные модели были статистически значимы (p < 0,001) и продемонстрировали высокую диагностическую эффективность, что позволяет имплементировать их в клиническую практику. Заключение. Таким образом, модели, включающие как генетические, так и негенетические детерминанты, могут способствовать дальнейшему улучшению предсказания индивидуального ответа на тамоксифен у пациенток с РМЖ.

Relevance. Endocrine therapy is the standard treatment for women with ER-positive breast cancer. The clinical response to Tamoxifen is variable. Approximately 30 % of patients with breast cancer will have a recurrence of the disease within 15 years after treatment, despite ongoing endocrine therapy. This article presents the results of a prospective pharmacogenetic cohort study. The study was conducted in 2018–2019. Aim. To analyze adverse drug reactions to Tamoxifen in the adjuvant regimen in breast cancer patients in relation to the carriage of genetic polymorphisms of genes encoding cytochrome P450 enzymes and drug transporter proteins and to build predictive models based on them. A comparative analysis of the relationship between genetic and non-genetic determinants with adverse events on tamoxifen therapy allowed us to build predictive models of their development. Materials and Methods. The study involved 120 women with pre- and postmenopausal breast cancer who underwent genetic testing for CYP and Pg enzyme gene polymorphisms. Entry criteria: a histologically confirmed diagnosis of breast cancer, taking Tamoxifen at the recommended doses, establishing a diagnosis not earlier than 2007, and obtaining informed voluntary consent to participate in the study. Allelic variants were determined using real-time polymerase chain reaction in the Research Institute for Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation. Results. An associative analysis showed their association with the development of adverse drug reactions (ADR) to Tamoxifen, indicating the clinical significance of different genetic polymorphisms of CYP2D6, CYP3A5, CYP2C9 and ABCB1. The complex associative analysis performed using mathematical modeling made it possible to build predictive risk models for the development of such ADR, such as hot flashes, dyspepsia, bone pain, and asthenia. The resulting regression models were statistically significant (p < 0,001) and demonstrated high diagnostic efficiency. This allows them to be implemented in clinical practice. Conclusion. Thus, models that include both genetic and non-genetic determinants of response may further improve the prediction of individual response to tamoxifen

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