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The article discusses modern approaches in the treatment of HER2-positive breast cancer (BC) with brain metastases (BM).The patients are subject to multidisciplinary, comprehensive and biologically – oriented treatment, with the involvement of a neurosurgeon and a radiation therapist to make a decision considering local treatment of BM, as well as a clinical oncologist to choose systemic drug therapy. Local treatment of HER2+ BC with BM patients includes surgical treatment and/or radiotherapy. Use of targeted anti-HER2 therapy changes “biology” of the disease from aggressive to indolent.In the prospective KAMILLA trial, clinically significant antitumor activity of trastuzumab emtansine was found for the first time both in patients with HER2+ BC with BM, who were previously treated with radiotherapy, and without radiotherapy in the anamnesis, which suggests the validity of further use of trastuzumab emtansine in this category of patients.The antitumor activity of trastuzumab emtansine in patients with HER2+ BC with BM was also confirmed in preclinical models. Despite the similar drug distribution in the tissues, trastuzumab emtansine, in contrast to trastuzumab, significantly slowed the growth of metastases, causing the induction of apoptosis in HER2+ BC models with BM in mice.

Breast cancer is the most common malignancy in females. More than 1.7 million of cases are detected annually worldwide. The incidence of breast cancer in Russia has increased by 64 % over the last 20 years. There was a 1.43-fold increase in the prevalence of breast cancer (from 297 to 457cases per 100,000) between 2005 and 2017. A total of59,538 new cases were registered in the Russian Federation in 2012. In Russia, breast cancer is the most common malignancy among women aged 40—85years and the second most common cancer among women aged 15—39 (after cervical cancer). The disease is primarily detected in women aged between 40 and 54 years (29.5 %). More than 66,000 of new cases of breast cancer are registered in the Russian Federation annually. In 2017, there were 70,293 new cases of breast cancer; of them, 49,134 patients (69.9 %) hade stage I—II breast cancer. There was a 0.02 % increase in the proportion of new cases of stage I—II breast cancer in 2016—2017. For this reason, it is important to study in depth the markers of breast cancer used in everyday practice in order to personalize the treatment of patients with breast cancer.

Breast cancer, being the most common type of malignant diseases, remains a significant challenge for both clinicians and fundamental researchers. The implementation of screening mammography, as well as adjuvant and neoadjuvant systemic therapy has made a significant progress in tackling the disease. The studies aimed at the assessment of novel biomarkers of breast cancer, alternative to standard ones, are becoming increasingly relevant. A number of new markers, such as p53, CK5/6, SMA, p63, PHH3, E-cadherin, EGFR, FOXA1, androgen receptors, TILs etc., have demonstrated their high predictive and/or prognostic value in multiple studies. New findings suggest that evaluation of novel biomarkers in breast cancer requires further thorough analysis.Recent studies have identified the role of biomarkers in choosing an optimal treatment strategy for breast cancer, estimated the prognostic value of biomarkers associated with tumor proliferative activity (including cyclin D1, G1-cyclin-dependent kinases 4 and 6, and cyclin-dependent kinases 8/19), specified the role of phospho-histone H3 (which is a proliferation marker that can be used to determine tumor grade), and evaluated the prognostic value of androgen receptors and other biomarkers. Multiple studies have also analyzed the expression of various biomarkers and their impact on overall and relapse-free survival.

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.

The review considers information about the efficacy and safety of Ixabepilone as a monotherapy and as a component of combination therapy for advanced breast cancer. Successful treatment of metastatic breast cancer is often confounded by resistance to chemotherapy, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially important. A therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer and “intensivelytreated” variant. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease.

Introduction . In the last ten years, it became obvious that on the molecular level breast cancer is a group of heterogenous tumors. The current objective of routine clinical practice of treatment prescription includes accurate disease prognosis for every individual patient and conviction that the risk of breast cancer recurrence after adjuvant hormone therapy without adjuvant chemotherapy doesn’t increase. The study objective is to evaluate how clinical use of risk associated with cell density can in practice improve prognosis of recurrence risk in patients with breast cancer after standard clinical and pathomorphological examinations. Materials and methods . The article analyzes therapy results using data from the cumulative cancer registry of breast cancer diagnosis and treatment of the N.N. Petrov National Medical Research Oncology Center in 2000–2009. The database includes information on diagnosis, treatment, and survival of 5106 patients with breast cancer. Archived material (from 2000 to 2009) from paraffin blocks of the “targeted group” for methods of molecular and genetic profiling was poured into recipient blocks, stained with corresponding antibodies such as widely used ER, PR, HER2/neu, Ki-67 markers as well as poorly studied markers: cell density, р53, CK5/6, CK14, CD4/CD8, p63, EGFR, FOXP3, AR, FOX1. Results . The study of 1118 patients with stage T1–2N0M0 breast cancer has shown that analysis of risk associated with cell density allows to predict disease outcome. Correlation between the marker and the grade of histological malignancy is more rare than for Ki-67 determined in this patient group. As a result, determination of cell density is an additional method to increase objectivity and accuracy of breast cancer prognosis. Conclusions . Automated cell density analysis for breast cancer is almost fully operator-independent which increases accuracy and objectivity of the results. Cell density in breast cancer lower than 3000 cells/mm 2 is a favorable prognostic factor.

Introduction. Triple-negative breast cancer (BC) is very aggressive form of breast malignancies with high levels of dissemination, frequent ecurrence and poor survival rate, as compared to other breast cancer subtypes. Aim of the study – development and introduction of optimized treatment strategy of patients with triple-negative breast cancer into the clinical practice of City Clinical Oncological Dispensary. Materials and methods . The study included 201 patients (21–90 years, mean age 52 years) who were treated in the first department of St. Petersburg City Clinical Oncological Dispensary from 2005 to 2011. Stage IА–IIIC invasive breast cancer with triple-negative phenotype according to immunohistochemical study of the tumor material was verified in all the patients before beginning of the treatment. Standard chemotherapy by FAC, CMF and taxane-containing regimen was used as neoadjuvant chemotherapy. The degree of therapeutic pathomorphism was evaluated according to Miller-Payne (2003) classification, which was designed taking into account an overall survival rate of patients, depending on the degree of pathologic tumor regression. Results. We performed evaluation of 3-year relapse-free survival, depending on the degree of pathomorphological regression and histological degree of malignancy. There is a clear dependence of the 3-year relapse-free survival on the degree of histological differentiation of the tumor. We noted an inverse correlation between high degree of histological malignancy with a short relapse-free period. The disease progressed in patients who have a high degree of histological malignancy. Conclusion . The highest efficiency was achieved in patients receiving chemotherapy with the addition of taxanes. It is advantageous to include taxane-containing chemotherapy regimens in the treatment of patients with a high degree of histological malignancy.

Brain metastases are detectable in 25–35 % of patients with progressive HER-2-positve breast cancer. Even after spreading metastases into the brain, chemotherapy in combination with anti-HER- 2 therapy improves survival due to better control of the systemic disease. The paper presents the results of investigations substantiating the use of anti-HER-2 targeting agents, as well as the innovative agent T-DM1 to treat brain metastases.

As is known, the HER-2-expressing biological subtype of breast cancer (BC) is characterized by an aggressive course and has a poor prognosis in the absence of specific treatment. Before the emergence of trastuzumab, 5-year overall survival in patients with the disseminated forms of BC was 20 % (median survival, 16–29 months), out of whom only 2–5 % were long-term survivors. Addition of trastuzumab, a humanized monoclonal antibody that binds selectively to HER-2 receptor on the surface of tumor cells, to first-line chemotherapy for HER-2-positive metastatic BC caused a considerable enhancement of therapeutic efficiency. When trastuzumab is incorporated into chemotherapy for metastatic BC, median progression-free survival and overall survival were 7.4 and 25.1 months (4.6 and 20.3 months without trastuzumab), respectively. Kadcyla® (T-DM1), an antibody-drug conjugate, represents a new approach to treating HER-2-positive metastatic BC. T-DM1 is characterized by the innovative and selective mechanism of action on the HER-2-positive tumor cells. Through this mechanism, T-DM1 leads to a double antitumor effect: a trastuzumab-mediated anti-HER-2 effect and a cytotoxic effect due to the selective transport of the potent antimitotic agent DM1 into the cytoplasm. This mechanism of action enhances the efficiency of antitumor therapy and reduces toxicity. Kadcyla® has been approved in the Russian Federation, as well as by the European Medicines Agency and the United States Food and Drug Administration as monotherapy in HER-2-positive inoperable locally advanced or metastatic BC patients previously treated with taxanes and / or trastuzumab.

General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists)