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Materials and methods. The effect of melatonin (MLT) and metformin (MTF) on the efficacy of neoadjuvant hormone therapy with toremifene was investigated in 54 patients with estrogen receptor-positive, locally advanced breast cancer (ER + BC). The average age of women was 67 years. The patients had no diabetes mellitus. The first group of patients (n = 19) received toremifene 120 mg per day, the second group (n = 16) - toremifene in combination with MLT 3 mg orally every night, the third group (n = 19) - toremifene in combination with MTF 850 mg twice daily. Randomization was performed - 1: 1: 1. The duration of therapy in all study groups was 4 months. After the end of treatment, all patients were undergone surgery. Further adjuvant treatment depended on the results of the postoperative pathomorphological conclusion. The primary endpoint was a decrease in the Ki-67% level (a surrogate marker for the effectiveness of hormone therapy), the secondary endpoints were the objective response, a pathological response in the tumor and lymph nodes, and the quality of life.
Results. In all patients (n = 54), the frequency of decrease Ki-67 level and the frequency of objective response were 57% and 50%, respectively. At the same time, the incidence of Ki-67% level decrease in the «toremifene» group was 42%, in the «toremifene+MLT» group - 56%, in the «toremifene+MTF» group - 74%. Multifactor analysis showed that the addition of MTF to toremifene increases the chances of reducing Ki-67 compared with control 4.2 times (RR 4.23 [95% CI 1,04417,139], p = 0.043). It is important that only in the patients of the «toremifene+MTF» group a significant correlation was found between the Ki-67 index decrease in the tumor and the BMI value above the norm (p = 0.015). A complete pathomorphological response in the tumor and lymph nodes was not achieved in any patient. The objective response in the study groups was 31.6%, 86.7% and 47.3%, respectively. The addition of MLT to hormone therapy with toremifene significantly increased the frequency of the objective response from 31.6% to 86.7% (x2 = 10.32, p = 0.001). The inclusion into neoadjuvant hormone therapy with toremifene of MLT or MTF did not reduce the quality of life of patients, while in 50% of patients in the «toremifene+MLT» group there was an improvement in sleep.
References
Анисимов В.Н., Физиологические функции эпифиза // Рос. Физиол. ж. им. И.М. Сеченова. - 1997. - Т. 83. - № 8. - С. 1-13.
Берштейн Л.М. Антидиабетический бигуанид метформин и онкологическая заболеваемость // Сахарный диабет. - 2010. - № 3. - С. 45-48.
Берштейн Л.М. Неоднозначность данных об эффективности метформина как средства, снижающего массу тела и предотвращающего опухолевый рост: причины и следствия // Ожирение и метаболизм. - 2012. - №2.
Гржибовский А.М., Иванов С.В., Горбатова М.А. Сравнение количественных данных двух парных выборок с использованием программного обеспечения Statistica и SPSS: параметрические и непараметрические критерии // Наука и здравоохранение. - 2016. - № 3. - С. 5-25.
Гржибовский А.М., Иванов С.В., Горбатова М.А. Анализ номинальных и ранговых переменных данных с использованием программного обеспечения Statistica и SPSS // Наука и здравоохранение. - 2016. - № 6. - С. 5-39.
Мусатов С.А., Розенфельд С.В., Того У.Ф., и др. Влияние мелатонина на мутагенность и противоопухолевый эффект цитостатиков у мышей // Вопр. онкол. - 1997. - № 6. - С. 623-626.
Наследов А. SPSS 19: профессиональный статистический анализ данных. - СПб.: Питер, 2011. - 400 с.
Осипов М.А., Анисимов В.Н., Попович И.Г, Семиглазова Т.Ю. Мелатонин усиливает противоопухолевый эффект доксорубицина на модели перевиваемой опухоли Эрлиха у самок мышей SHR // Вопр. Онкологии. - 2016. - Т. 62. - № 1. - С. 146-149.
Осипов М.А., Семиглазова Т.Ю., Попович И.Г. и др. Влияние метформина, мелатонина и их комбинаций с паклитакселом на рост перевиваемой HER2 положительной опухоли молочной железы у самок мышей FBV/N // Вопросы онкологии. - 2017. - Т. 63. - № 4. - С. 650-654.
Осипов М.А., Семиглазова Т.Ю., Криворотько П.В. и др. Метформин в лечении рака молочной железы // Злокачественные опухоли. - 2017. - № 2. - С. 7682.
Попович И.Г., Панченко А.В., Тындык М.Л. и др. Влияние противоопухолевых препаратов и их комбинаций с мелатонином на рост перевиваемой опухоли молочной железы с инкорпорированным геном HER 2/ neu у самок мышей FBV // Материалы VII съезда онкологов и радиологов СНГ и Евразии. - Казань, 2014. - С. 116.
Семиглазов В.Ф., Криворотько П.В., Семиглазова Т.Ю. и др. Рекомендации по лечению рака молочной железы. - М.: Мегаполис, 2017. - 168 с.
Семиглазов В.Ф., Семиглазов В.В., Дашян Г.А. и др. Неоадъювантная эндокринотерапия пациентов с эстроген-рецептор-положительным раком молочной железы // Сибирский онкологический журнал. - 2018. - Т. 17. - № 3. - С. 11-19.
Семиглазова Т.Ю., Осипов М.А., Новик А.В. и др. Перспективы использования мелатонина в клинической онкологии // Злокачественные опухоли. - 2016. - № 4. - С. 21-29.
Anisimov V.N. Metformin for cancer and aging prevention: is it a time to make the long story short? // Oncotar-get. - 2015. - Vol. 6(37). - P 398-407.
Anisimov V.N. The solar clock of aging // Acta Geront. - 1994. - Vol. 45. - P 10-18.
Anisimov V.N., Zavarzina N.Y, Zabezhinski M.A. et al. Melatonin increases both life span and tumor incidence in female CMBA mice // J. Gerontol. Biol. Sci. - 2001. - Vol. 56A. - P. 311-323.
Azatyan S.K., Lubenets N.V., Kosse V.A. et al. Neoadjuvant hormonotherapy with toremifene vs. letrozole of postmenopausal breast cancer patients // Annals of oncol. - 2014. - Vol. 25(4). - P. 111-112.
Berstein L.M., Vasilyev D.A., Iyevleva A.G. et al. Potential and real ‘antineoplastic' and metabolic effect of metformin in diabetic and nondiabetic postmenopausal females // Future Oncol. - 2015. - Vol. 11(5). - P 759-70.
Berstein L.M. Metformin in obesity, cancer and Aging: Addressing controversies // Aging. 2012. - Vol. 4(5). - P. 320-9.
Bodmer M., Meier C., Krähenbühl S. et al. Long-term metformin use is associated with decreased risk of breast cancer // Diabetes Care. - 2010. - Vol. 33. - P. 1304-8.
Bosco J., Antonsen S., S0rensen H. Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark // Cancer Epidemiol. Biomarkers Prev. - 2011. - Vol. 20 (1). - P. 101-11.
Cabrera-Galeana P, Munos-Montano W., Lara-Medina F. et al. Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy // oncologist. - 2018. - Vol. 23(6). - P. 670-678.
Cortazar P., Zhang L., Untch M. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis // Lancet. - 2014. - Vol. 12(384). - P. 164-72.
Hee J., Hyunwook K., Jong L. et al. Use of metformin and survival of diabetic women with breast cancer // Curr. Drug Saf. - 2013. - Vol. 8. - P. 357-63.
Hernan M.A., Hernandez-Diaz S., Robins J.M. A structural approach to selection bias // Epidemiology. - 2004. - Vol. 15 (5). - P. 615-625.
Kim H., Kwon H., Lee J. Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes // Breast Cancer Res. - 2015. - Vol. 17. - P. 64.
Libby G., Donnely L., Donnan P. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes // Diabetes Care. - 2009. - Vol. 32. - P. 1620-1625.
Lissoni P. Is there a role for melatonin in supportive care? // Support. Care Cancer - 2002. - Vol. 10(2). - P. 110-6.
Ilipoulos D., Heather A., Hirsch K. et al., Metformin decreases the doses of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types // Cancer Res. - 2011. - Vol. 71(9). - P. 3196-201.
Inwald E., Klinkhammer-Schalke M., Hofstadtler F., Zeman F., Koller M. et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry // Breast Cancer Res Treat. - 2013. - Vol. 139(2). - P. 539-52.
Robertson J., Dowsett M., Bliss J., Morden J., Wilcox M. Et al. Peri-operative aromatase inhibitor treatment in determining or predicting longterm outcome in early breast cancer - The POETIC* Trial (CRUK/07/015) // Cancer Res - 2018. - Vol. 78(4). - SABCS17-GS1-03. DOI: 10.1158/1538-7445
Scherbakov A., Sorokin V., Tatarskiy V. Jr. et al. The Phenomenon of Acquired Resistance to Metformin in Breast Cancer Cells: The Interaction of Growth Pathways and Estrogen Receptor Signaling // IUBMB Life. - Vol. 68(4). - P. 281-292.
Seely D., Ping Wu., Heidy F. et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review an meta-analysis of randomized trials // Integr. Cancer Ther. - 2012. - Vol. 11(4). - P. 293-303.
Semiglazov V.F., Semiglazov V.V., Ivanov V.I. et al. The relative efficacy of neoadjuvant endocrine therapy versus chemotherapy in postmenopausal women with ER-positive breast cancer // J. Clinical. Oncology. - 2004. - Vol. 23. - P. 7S.
Semiglazov V.F., Semiglazov V.V., Dashyan G.A. et al. Phase II randomized trial of primary endocrine therapy chemotherapy in postmenopausal patients with estrogen receptor positive breast Cancer. Cancer. - 2007. - Vol. 110. - № 2. - P. 244-54.
Semiglazov V.F., Dashyan G.A., Semiglazov V.V. et al. P198 Prognostic values of breast cancer subtypes: from phase 2 randomized trial of neoadjuvant therapy // The Breast. - 2015. - Vol. 24. - S92.
Sonnenblick A., Agbor-Tarh D., Bradbury I. et al. Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial // J. Clin. Oncol. - 2017. - DOI: 10.1200/JCO.2016.69.7722
Spring L., Gupta A., Reynolds K., et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review a meta-analysis // JAMA Oncol. - 2016. - Vol. 02(11). - P. 1477-1486.
Wang Y, Jin B., Ai F. et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials // Cancer Chemother. Pharmacol. - 2012. - Vol. 69(5). - P. 1213 - 1220.
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