Search

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.

Achieving a pathologic complete response as a result of neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial showed a significant survival improvement with capecitabine treatment of patients with residual invasive disease following neoadjuvant chemotherapy, and the KATHERINE trial demonstrated a significant benefit of trastuzumabemtansine (TDM1) in patients with HER2-positive breast cancer who did not achieve a pathologic complete response, so we have a lot of interesting alternatives of post-neoadjuvant treatments for high-risk patients. The discovery of molecular markers of resistance to endocrinotherapy (cyclin-dependent kinases (CDK 4/6), ER mutation (ESR1), mTOR signaling pathway, co-expression of ER+/HER2+) and inhibitors to them expanded the possibilities of endocrinotherapy not only in advanced and metastatic breast cancer, but also in residual ER+ tumors. The pCR rates in hormone receptor-positive breast cancer after neoadjuvant chemotherapy are around 10%, which is much lower than the values observed in HER2-positive and triple negative subtypes, so new strategies are needed to improve pCR rates in this subgroup, even though the adjuvant endocrine therapy impacts significantly the outcomes of this patients. The cyclin-dependent kinases (CDKs) are serine–threonine kinases that regulate cell cycle progression from the G1 to the S-phase during mitosis. CDKs activity can be abnormally increased or dysregulated in breast cancer, leading to a constant stimulus for cell proliferation and survival, which is a known mechanism of resistance to endocrine treatment. The CDK inhibitors act on CDKs and block their activity, thereby restoring the cell cycle regulation. In studies with metastatic hormone receptor-positive breast cancer patients, the combination of a CDKis with first or second-line endocrine therapy showed significant improvements in progression-free survival and response rates. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our understanding of the biology of residual disease and also the mechanisms involved in treatment resistance.

Immunotherapy has already become an important component of the standard treatment of patients with advanced cancer. Most treatment methods include monoclonal antibodies (mAbs) that block immune checkpoints, in particular, the programmed cell death 1 (PD-1) receptor and its ligand 1 (PD-L1) or are directed against T-lymphocyte-associated protein 4 (CTLA-4). The future prospects for immuno-oncology will be to determine whether these agents can be more effective if administered in a postoperative adjuvant or in a neoadjuvant regimen prior to surgical treatment. Vaccine therapy has shown promising results, and this therapy is especially attractive due to absence of pronounced toxicity.

Since 1990-s the efficiency of treatment of patients with metastatic/advanced breast cancer (MBC) was started to evaluate not only by overall survival but also by quality of life which is characterized by physical, social, mental and emotional condition of the patient. As there are no standards of system treatment for MBC after anthracyclines and taxanes, choice of further tactics was based on separate randomized trials and own intuition of the oncologist until recently. Eribulin mesylate (eribulin) became the first chemotherapy agent, confirmed to be effective in two large randomized trials: in first of them a significant increase of overall survival and the preservation of quality of life were shown in population of patients with MBC progressing after treatment including anthracycline antibiotics and taxanes. In second trial advantage of the drug was registered in patients with triple negative and luminal B HER2-negative MBC subtypes.

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.