The effect of neoadjuvant chemotherapy on the structural and functional state of tumor cells in the secondary edematous form of breast cancer
Authors: Lukashova O.P. , Bilyy О.М. , Pakhomov V.S. , Shutov S.V. , Slobodianyuk О.V. , Lepekha І.V. , Teslenko І.М. 
Published: October 2022

Background. Secondary edematous form of breast cancer (SЕF BC) is the most aggressive type of BC that is characterized by rapid progression, high levels of metastasis, significant resistance to chemotherapy and radiotherapy. SЕF BC is not just a combination of cancer and local inflammation, but is a rare phenomenon in which the development of the tumor is primary. The processes of edema and inflammation occur because of lymph flow blockage by the formation of emboli from tumor cells (TC), which have elevated levels of E-cadherin, properties of polyploid cells and show signs of stem cells. Trimodal therapy methods are used for the treatment of SЕF BC, the main components of which are neoadjuvant systemic chemotherapy, surgery and adjuvant radiation therapy. However, the results of treatment remain insufficient, possibly due to the fact that the features of SЕF, the role of stem cells and inflammatory factors are not taken into account. Therefore, further research is needed in various fields of oncology, molecular biology, immunology, genetics, morphology, including electron microscopy, which is an important area for establishing the characteristics of both tumor cells and their environment. Purpose. Study of the neoadjuvant polychemotherapy influence on the structural and functional state of tumor cells of different molecular subtypes in the secondary edematous form of breast cancer.

Materials and methods. Tumors of 29 patients with normal breast cancer and 32 patients with SЕF BC were studied. Receptors to estrogen (ER), progesterone (PR) and epidermal human growth factor 2 (HER2) were immunohistochemically determined before systemic neoadjuvant polychemotherapy (PCT). According to the receptor status, tumors were divided into 4 groups: 1 – triple negative («3-neg») tumors, 2 – HER2-positive («HER2») tumors, 3 – hormonally receptor («HP») tumors, 4 – tumorswith co-expression of hormonal receptors and HER2 («HR + HER2»). For polychemotherapy (PCT) the regimen (AСx4–Рx4) was used.The ultrastructure of the tumor cells (TC) was examined using standard electron microscopy methods. In all study groups, the frequency of cases with pronounced therapeutic pathomorphosis (PTPM) was determined, as well as the frequency of tumors with luminal and non-luminal symptoms after treatment. The obtained data were calculated using non-parametric methods with the software package for PC «Biostat» application and using a non-parametric criterion of the most plausible assessment of reliability for small selections (Pmp).

Results. It was found that PCT in patients with conventional BC causes a pronounced therapeutic pathomorphosis (РТPM) of most tumors of the receptor groups «3-neg», «HER2» and «HR+HER2», compared with the group «HR», where no case of РTPM was observed. At SЕF BC the frequency of tumors with the pronounced pathomorphosis in groups with nonluminal subtypes and co-expression of receptors decreases, that for group «3-neg» is reliable. This indicates increased chemoresistance of triple negative tumors. In the group of hormone receptor tumors at SEF, this index increases significantly. Analysis of the ultrastructure of tumors of different molecular subtypes showed that most of the processes of damage and accompanying reactions to the action of PCT are identical for both forms of BC. Thus, in response to chemotherapy, different types of cell death: necrotic, dark cell, apoptotic; processes of cell nucleus damage: presence of dinuclear PCs, cells with micronuclei; disturbance of the microvessels structure: edema and condensation of the endothelial cells cytoplasm and their exfoliation; activation of phagocytosis and immune processes are observed. Only SЕF is characterized by the presence of TCs and emboli in capillaries, as well as a significantly increased frequency of giant polyploid tumor cells. It was also found that after PCT in patients with normal BC preserved tumor cells show mainly luminal signs (72.7–100%). However, in SЕF BC such reaction occurs only for hormone-receptor subtypes and the group with co-expression of receptors, whereas for tumors of three negative and HER2-positive subtypes the frequency of luminal signs is lower than in conventional BC and is 33.3%, p ≤ 0.05 and 66.7%, respectively.

Conclusions. Peculiarities of SЕF BC in contrast to the usual form of BC are significantly reduced sensitivity of 3-negative cancer to chemotherapy and the tendency to chemoresistance of molecular subtypes with the presence of HER2; significant survival after PCT tumors with non-luminal cells characteristic in the group of 3-negative cancer, while in other receptor subtypes most tumors have luminal features; probably increased after chemotherapy the number of tumors with giant polyploid cells. It is possible that the features of SЕF BC are associated with the presence of polyploid TCs resistant to chemotherapy, and both inflammation and chemotherapy may play a role in stimulating their formation.