Минимизация риска повышения эстрадиола на фоне ингибиторов ароматазы в адъювантной терапии рака молочной железы у пациенток в пременопаузе. Результаты пилотного исследования


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Минимизация риска повышения эстрадиола на фоне ингибиторов ароматазы в адъювантной терапии рака молочной железы у пациенток в пременопаузе. Результаты пилотного исследования

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Минимизация риска повышения эстрадиола на фоне ингибиторов ароматазы в адъювантной терапии рака молочной железы у пациенток в пременопаузе. Результаты пилотного исследования

Журнал "Медицинский совет. Онкология" №19, 2018

DOI: https://doi.org/10.21518/2079-701X-2018-19-76-84

И.Б. Кононенко1, А.В. Снеговой1, Л.В. Манзюк1, Е.И. Коваленко1, В.Ю. Сельчук2 1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва 2 ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава России, Москва

Ингибиторы ароматазы (ИА) в комбинации с агонистами гонадотропин-рилизинг-гормона (аГнРГ) признаны эффективным подходом в адъювантной эндокринотерапии рака молочной железы (РМЖ) у пациенток в периоде пременопаузы с наличием неблагоприятных факторов прогноза. Однако доказан риск неоптимальной супрессии яичников, обусловленный механизмом действия ингибиторов ароматазы. И хотя на сегодня недостаточно научного обоснования для интерпретации этого результата, внедрение в клинические рекомендации ингибиторов ароматазы у молодых женщин диктует необходимость поиска тактики снижения риска опосредованного повышения эстрадиола (E2) на фоне такой терапии. Настороженность возникает в тех случаях, когда к моменту назначения ингибиторов ароматазы уровень Е2 в сыворотке крови превышает границу менопаузы. Цель исследования. Минимизация риска повышения эстрадиола на фоне ингибиторов ароматазы в комбинации с аГнРГ в адъювантной терапии рака молочной железы у пациенток в пременопаузе. Материал и методы. Изучено 47 пациенток ≤ 50 лет с ГР+ HER2- РМЖ I-III стадии и регулярным менструальным циклом до начала нео-/адъювантной химиотерапии. Оценка уровня E2 и ФСГ проводилась на этапе до химиотерапии и непосредственно перед назначением адъювантной эндокринотерапии. После завершения химиотерапии лишь у 7 из 47 женщин сохранялся менструальный цикл – пациентки без клинической и биохимической супрессии овариальной функции (СОФ). Цитостатическая аменорея наступила в 86% случаев (n = 40), из которых в 23 случаях (58%) это состояние не сочеталось с биохимическим ответом половых гормонов, т.е. отсутствовала биохимическая СОФ. Таким образом, в группу изучения вошли 30 пациенток, которым предполагалась терапия ингибиторами ароматазы + аналоги ГнРГ, и к моменту назначения адъювантной эндокринотерапии у них не наступила клиническая или биохимическая менопауза. С целью снижения риска опосредованного повышения эстрадиола пациенткам назначали введение аналога ГнРГ (Бусерелин-депо) до начала терапии ингибиторами ароматазы. Результаты и выводы. После химиотерапии у 73% женщин зарегистрировано снижение уровня эстрадиола, сопровождающееся физиологическим повышением уровня ФСГ. Введение Бусерелина-депо привело к достоверному снижению медианы ФСГ (p<0,01) у 90% пациентов и прогрессивному снижению уровня Е2, что позволило 97% пациенткам назначить ингибиторы ароматазы и продолжение аГнРГ. Таким образом, полученные результаты на основании динамической оценки гормонов (Е2, ФСГ) подтверждают возможность достижения супрессии овариальной функции, предшествующего назначению ИА, что может рассматриваться в качестве рациональной тактики адъювантной эндокринотерапии у пациенток репродуктивного возраста.

Tactics for minimizing risk of increasing estradiol against the background of aromatase inhibitors in combination with gonadotropin releasing hormone agonists in adjuvant therapy for breast cancer in premenopausal patients. Pilot study results

I.B. Kononenko1, A.V. Snegovoi1, L.V. Manzyuk1, E.I. Kovalenko1, V.Yu. Selchuk2 1 Blokhin Russian Cancer Research Centre, Federal State Budgetary Institution of the Ministry of Health of Russia, Moscow 2 Yevdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of Russia, Moscow

Aromatase inhibitor (AI) combined with Gonadotropin-releasing hormone agonist (GnRH-a) have been recognized as an effective approach to adjuvant endocrinotherapy for breast cancer (BC) in premenopausal patients with adverse predictive factors. However, the risk of non-optimal suppression of the ovaries due to the mechanism of action of aromatase inhibitors has been proven. Recently published SOFT-EST studies showed that the blood estradiol (E2) level in 37% of patients was above the level that was permissible for the purpose of this group of drugs. And although today there is no enough scientific justification to interpret this result, the introduction of aromatase inhibitors in adjuvant therapy in young women requires the search for tactics to reduce the risk of mediated increase in estradiol against the background of such therapy. Alertness occurs when the E2 serum level exceeds the menopause limit by the time the aromatase inhibitors are prescribed. Objective of the study. Determine the tactics for minimizing the risk of increasing estradiol against the background of aromatase inhibitors in combination with GnRH-a in adjuvant therapy for breast cancer in premenopausal patients. Material and methods. 47 patients of ≤ 50 years old with GR + HER2- Stages I-III Breast Cancer and a regular menstrual cycle before the start of neo-/adjuvant chemotherapy were studied. E2 and FSH levels were assessed at the stage prior to chemotherapy and immediately prior to administering adjuvant endocrinotherapy. After the completion of chemotherapy, only 7 out of 47 women had the menstrual cycle - patients without clinical and biochemical suppression of ovarian function (SOF). 86% of cases had cytostatic amenorrhea (n = 40), of which 23 cases (58%) showed that this condition was not combined with the biochemical response of sex hormones, i.e. there was no biochemical SOF. Thus, the study group included 30 patients, who were supposed to be treated with aromatase inhibitors + GnRH analogues, and had no clinical or biochemical menopause by the time adjuvant endocrinotherapy was prescribed. In order to reduce the risk of mediated increase in estradiol, even with pharmaceutical “switching off” ovarian function, the patients were prescribed the GnRH analogue (Buserelin Depot) before starting aromatase inhibitors therapy. Results and conclusion. A progressive decrease in E2 level was determined after each subsequent administration of Buserelin Depot. The median values remained low only after the third injection. Following the chemotherapy, a decrease in estradiol was accompanied by a physiological increase in the FSH levels in 73% of women. The administration of Buserelin Depot led to a significant decrease in FSH median (p <0.01) in 90% of patients. Aromatase inhibitors and continuing GnRH-a were prescribed to 97% of patients. The results indicate that the achievement of ovarian function suppression prior to the administration of IA, can be considered as a reliable tactics for adjuvant endocrinotherapy in patients of reproductive age. The dynamic assessment of reproductive hormones (E2, FSH) is recognized useful when choosing or correcting therapy in such patients.

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