medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/ms2025-253medsovet-9254Research ArticleГОРМОНОТЕРАПИЯHormonotherapyФулвестрант в терапии люминального HER2-негативного метастатического рака молочной железыFulvestrant in the treatment of luminal HER-2-negative metastatic breast cancerhttps://orcid.org/0000-0002-1836-0851КоролеваИ. А.KorolevaI. A.

Королева Ирина Альбертовна, д.м.н., профессор кафедры клинической медицины последипломного образования

443001, Самара, ул. Чапаевская, д. 227

Irina A. Koroleva, Dr. Sci. (Med.), Professor of the Department of Clinical Medicine of Postgraduate Education

227, Chapaevskaya St., Samara, 443001

korolevaia_samara@mail.ruМедицинский университет «Реавиз»РоссияMedical University “Reaviz”Russian Federation2025300720250108392Copyright © Королева И.А., 20252025Королева И.А.Koroleva I.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/9254

Гормонотерапия является эффективным методом лечения люминального HER2-негативного метастатического РМЖ (мРМЖ). Ингибиторы ароматазы и фулвестрант – основные препараты гормонотерапии. Фулвестрант является одновременно конкурентным антагонистом и селективным деградатором рецепторов эстрогена (SERD). В исследовании III фазы FALCON (n = 462), в которое были включены больные мРМЖ в постменопаузе, ранее не получавшие никакой эндокринной терапии, сравнивался фулвестрант с ингибитором ароматазы анастрозолом. Статистически значимое улучшение БРВ было достигнуто при терапии фулвестрантом по сравнению с анастрозолом: 16,6 мес. в группе фулвестранта против 13,8 мес. при применении анастрозола [ОР = 0,797; 95% ДИ: 0,637–0,999; Р = 0,0486]. Подгрупповой анализ показал, что фулвестрант проявил наибольшую эффективность у пациентов без висцеральных метастазов. Во всех исследованиях фулвестрант продемонстрировал хороший профиль токсичности, именно поэтому он изучается как компонент комбинированной гормонотерапии. В исследовании PALOMA-3 комбинация фулвестранта с палбоциклибом (ингибитор CDK4/6) показала медиану ВБП 9,5 мес. по сравнению с монотерапией фулвестрантом – 4,6 мес. (ОР = 0,46, p < 0,0001 В исследовании MONALEESA-3 у пациенток, получавших рибоциклиб с фулвестрантом, медиана ВБП была значимо выше по сравнению с теми, кто принимал плацебо с фулвестрантом: 20,5 мес. и 12,8 мес. соответственно (ОР = 0,593; 95% ДИ: 0,480–0,732; р < 0,001). В исследовании MONARCH-2 комбинация фулвестранта и абемациклиба изучалась во второй линии терапии: медиана ВБП составила 16,4 мес. в группе пациенток, получавших фулвестрант и абемациклиб, и 9,3 мес. – в группе фулвестранта и плацебо (ОР = 0,553; 95% ДИ: 0,449–0,681; p < 0,0001). Исследование SOLAR-1 продемонстрировало эффективность комбинации «фулвестрант + алпелисиб» (ингибитор PI3K) при люминальном HER2-негативном мРМЖ, ассоциированном с мутацией PIK3CA в I и II линиях терапии. Медиана ВБП в группе «фулвестрант + алпелисиб» составила 11 мес. по сравнению с 5,7 мес.  в группе фулвестранта (ОР = 0,65; 95% ДИ: 0,50–0,85; р < 0,001). На основании данных клинических исследований можно говорить о том, что комбинация ингибиторов ароматазы с ингибиторами CDK4/6 является оптимальной первой линией лечения у больных с гормоночувствительными опухолями, т. е. при прогрессировании более 1 года после окончания адъювантной гормонотерапии. В свою очередь, фулвестрант ± ингибиторы CDK4/6 применяются при прогрессировании болезни на фоне адъювантной гормонотерапии в первой линии или в качестве второй линии при прогрессировании на терапии ингибиторами ароматазы по поводу метастатического рака. Комбинация «фулвестрант + алпелисиб» является высокоэффективной во второй линии терапии люминальнго HER2-негативного мРМЖ при наличии мутации PIK3CA.

Hormonal therapy is an effective treatment for luminal HER2-negative metastatic breast cancer (mBC). Aromatase inhibitors and fulvestrant are the mainstays of hormone therapy. Fulvestrant is both a competitive antagonist and a selective estrogen receptor degrader (SERD), this mechanism of action provides complete blocking of the estrogen signaling pathway. In the FALCON phase III study (n = 462), which included postmenopausal MBC patients who had not previously received any endocrine therapy, fulvestrant 500 mg was compared with the aromatase inhibitor anastrozole. Significant improvement in PFS was achieved with fulvestrant therapy compared to anastrozole: 16.6 months in the fulvestrant group versus 13.8 months with anastrozole [OR = 0.797; 95% CI 0.637–0.999; P = 0.0486]. A subgroup analysis showed that patients without visceral metastases can benefit most from taking fulvestrant. In all studies fulvestrant 500 mg has demonstrated a good toxicity profile, so it is being studied as a component of combined endocrine therapy. In the PALOMA-3 study the combination of fulvestrant with palbociclib (CDK4/6 inhibitor) demonstrated a median PFS 9.5 months, compared with monotherapy with fulvestrant – 4.6 months (HR = 0.46, p < 0.0001). In the MONALEESA-3 study, the median PFS in patients receiving ribociclib with fulvestrant was significantly higher compared to those taking placebo with fulvestrant: 20.5 months and 12.8 months, respectively (HR = 0.593; 95% CI: 0.480–0.732; p < 0.001). In the MONARCH-2 study the combination of fulvestrant and abemaciclib was studied in the second line of therapy, the median PFS was 16.4 months in the group of fulvestrant and abemaciclib, and 9.3 months in the group of fulvestrant and placebo (HR = 0.553; 95% CI 0.449–0.681; p < 0.0001). The SOLAR-1 study demonstrated the efficacy of the combination of fulvestrant + alpelisib (PI3K inhibitor) in luminal HER2-negative mBC associated with PIK3CA mutation in the first and second lines of therapy. The median PFS in the fulvestrant + alpelisib group was 11 months compared with 5.7 months in the fulvestrant group (HR = 0.65; 95% CI 0.50–0.85; p < 0.001). Based on clinical research data, the combination of aromatase inhibitors with CDK4/6 inhibitors is the optimal first-line treatment in patients with hormone-sensitive tumors, i.e. with progression more than 1 year after the end of adjuvant hormone therapy. While fulvestrant ± CDK4/6 inhibitors is used for disease progression on the background of adjuvant hormone therapy in the first line or as a second line for progression on aromatase inhibitor therapy for metastatic cancer. The combination fulvestrant + alpelisib is highly effective in the second-line treatment of luminal HER2negative breast cancer in the presence of a PIK3CA mutation.

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