Mechanisms of Tumor Resistance in the Microenvironment of Locally Advanced Breast Cancer

The aim of this work was to optimize the algorithm for managing patients withlocally advanced breast cancer, taking into account the problem of developing therapeutic chemoresistance. Material and methods. The first stage included 187 patients with a verified diagnosis of primary locally advanced breast cancer (T3N2,T4N0-3). In the neoadjuvant chemotherapy regimen, all patients were treated according to the AC regimen (doxorubicin 60 mg, cyclophosphamide 600 mg/m2 i), taking into account the immunohistochemical subtype: a) patients with the luminal variant additionally received paclitaxel 175 mg/m2 for a total of up to 4 courses, or paclitaxel 80 mg/m2 weekly for 12 administrations; b) patients with triple-negative cancer received paclitaxel 175 mg/m2 for a total of up to 4 courses,or paclitaxel 80 mg/m2 in combination with carboplatin AUC2 weekly for 12 administrations. The effectiveness of treatment was assessed by calculating the frequency of the overall objective response (OR) and complete pathomorphological tumor regression (pCR). At the second stage, based on the obtained results, patients with luminal and triple-negative breast cancer were divided into groups with a complete therapeutic response (n=10) and resistant course (n=10). The control group consisted of patients with fibroadenoma (n=10).In order to study the characteristics and mechanisms of formation of therapeutic resistance in patients with different histological subtypes of cancer, an assessment of the expression of immunological markers CD4, CD8, CD20, CD68 and angiogenesis markers HIF-1α, VEGF, ANGP2 in breast tissue was carried out using immunohistochemistry. Results. In the case of luminal, Her2/neu-negative, and triple-negative subtypes, it was shown that weekly administration of taxanes in mono regiment either in combination with platinum drugs (after anthracycline therapy) does not statistically significantly improve the rates of partial objective response and the degree of therapeutic pathomorphosis of the tumor. In the tumor tissue of drug-resistant patients, an increase in the number of CD68+cells was noted compared to the tumor tissue of patients with a complete response to therapy (p<0,001) and the control group (p=0,045); as well as a decrease in the number of cytotoxic CD8+cells in relation to patients with non-resistant cancer (p=0,032) and the control (p=0,001). When assessing the expression of angiogenesis markers in the tumor tissue of patients with no response to therapy, an increase in the number of HIF-1α-positively stained cells was recorded compared to tissue samples from the control group of patients (p=0,004); an increase in the degree of VEGF expression compared to the group with non-resistant cancer (p=0,021) and the control group (p<0,001); as well as a slight increase in the degree of ANGP2 expression compared to the control group (p=0,05). These markers are points of application of targeted therapy and immunotherapy. Conclusion. Thus, knowledge about the molecular basis of breast tumor resistance to neoadjuvant chemotherapy allows us to optimize the algorithm for managing patients, improve the quality of medical care, and improve treatment outcomes.