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.

Immuno-oncology is a rapidly developing field in medicine. Drug combination therapies have already been studied in many clinical trials of different types of tumours. In recent years, a checkpoint inhibition therapy with monoclonal antibodies that target cytological T-lymphocytes has been developed. Thus, inhibition of two regulator genes CTLA 4 and PD1 or PD-L1 ligand to it is able to restore mediated T-cell tumour regression in its many localizations. The article considers a number of key fields of immunology and immunotherapy through a specific example of breast cancer (BC): the role of T-lymphocytes, vaccines, biomarkers of immunotherapy. The treatment used by the authors was based on an innovative technology of autologous dendritic cell-based vaccine based on highly immunogenic cancer/testis antigens (CTA) for immunotherapy of malignant tumours. The technology of specific CTA+-activated autologous dendritic cells (DC)-based immunotherapy was chosen as an innovative solution for the treatment of breast cancer patients. The treatment results showed that a clinically significant anti-tumour effect was achieved in 73.7% of patients. Median disease-free survival was 8.3 months (95% Cl 6.5-9.9 months), no grade 3-4 complications were recorded, grade 1-2 complications were observed in 57% of patients. The immunological effect in laboratory tests was recorded in 92% of patients. Thus, autologous DCs loaded with cancer/testis antigens can be considered as palliative dendritic vaccine therapy in patients with metastatic breast cancer who have exhausted standard treatment options. Also, the authors presented the results of immunological studies of the prognostic and predictive significance of the immunological response from the perspective of pathomorphology and general immunology, including tumour-infiltrating T-lymphocytes (TILs, CD3, CD4, CD8), their quantitative ratio and correlation with regulatory genes (PD-1, PD- L1, FOX-P3). The results of overall analysis comprising data of 2,148 patients from 9 centers confirmed the strong prognostic role of stromal tumour-infiltrating lymphocytes (sTILs) in early triple-negative breast cancer.

46М а м м о л о г и я / M a m m o l o g y 1 ' 2 0 1 6 Том 12 / Vol. 12 ОПУХОЛИ ЖЕНСКОЙ РЕПРОДУКТИВНОЙ СИСТЕМЫ TUMORS OF FEMALE REPRODUCTIVE SYSTEM Лечение После рака легких 2-й наиболее частой причиной метастазов в головной мозг (ГМ) является рак мо-лочной железы (РМЖ), метастазирование при кото-ром наблюдается в 10-16 % случаев [1]. Еще у 10 % больных происходит бессимптомное метастазирова-ние, что подтверждается данными аутопсии [2]. В по-следние годы отмечается более частое выявление метастазов в ГМ, что, вероятно, связано с более дли-тельной выживаемостью больных, получающих со-временные эффективные методы лечения, а также с применением более чувствительных методов визу-ализации.Развитие метастазов в ГМ представляет собой сложный процесс, предполагающий инвазию клеток РМЖ в окружающие ткани и сосуды, циркуляцию

More than 70 % of patients with breast cancer have estrogen-receptor-positive tumors (ER+) and are considered hormone- sensitive. That is why a vast majority of patients with early operable  tumors receive adjuvant endocrine therapy. Patients with metastatic  ER+ breast cancer also receive hormone therapy as first-line  treatment. Patients with ER+/PR+ locally advanced breast cancer  including potentially operable cases (cT2N1, cT3N0M0) are still a  subject to neoadjuvant chemotherapy in most of the oncology  centers in Russia and worldwide. More than 10 years ago, several  trials evaluating the efficacy of neoadjuvant endocrine therapy were  conducted in the Petrov Research Institute of Oncology (aromatase  inhibitors vs tamoxifen, neoadjuvant endocrine therapy vs  neoadjuvant chemotherapy, etc.) The primary endpoint was the  evaluation of pathologic complete/partial response to therapy and  the frequency of breast-conserving surgeries following neoadjuvant  treatment. We now represent 10-year long-term follow-up data on  comparison of neoadjuvant chemotherapy with neoadjuvant  endocrine therapy after retrospective determination of IHC- phenotypes of 239 patients with ER+ breast cancer. The study  results show tendency to better 10-year disease-free survival in  patients with luminal-A breast cancer who received endocrine  therapy compared to neoadjuvant chemotherapy (72.8 % vs 53.9  %, respectively, p=0.062) There were no statistically significant  differences in DFS rates among patients with the luminal B breast  cancer subtype (41 % vs 40 %) The discovery of biomarkers of  potential resistance to endocrine therapy (cycline-dependant kinase  activity [cdk 4/6], estrogenreceptor mutation [ESR1], mTOR  signaling pathway activity, co-expression of the ER and HER2neu  [ER+/ HER2neu3+]) and ways to inhibit the activity of the resistance pathways (palbocyclib, everolimus, etc.) have expanded the  armamentarium of endocrine-therapy for not only metastatic and  locally-advanced but also operable cases of ER+ breast cancer.

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