Impacts of Inflammatory Microenvironment on the Development of Cancer Relapse after Combined Treatment

Abstract

The purpose of the work was to study the impact of certain elements of the inflammatory microenvironment of the tumor on the development of cancer relapse of main localizations with the amplification of ERBB2 after combined treatment. Materials and methods. 80 patients, who had been treated for the period from 2016 to 2021 in National Cancer Institute, Kyiv, Ukraine. They were 42-78 (average 60) years old, ECOG 0-2, female. All patients histologically proved adenocarcinoma GIII-GIV. Everyone was studied for the level of chitinase-like proteins, cryoglobulins, tumor-associated macrophages in the preoperative (with the first identified disease for the first time, prior to the beginning of the neoadjuvant chemotherapy) and in the postoperative period. 1st block: with a confirmed mutation of HER-2/neu gene (amplification ERBB2 (3+)): a) inflammatory breast cancer (primary-edema form) – 10 people, b) diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophagus cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. 2nd block: without a confirmed mutation of HER-2/neu gene: a) inflammatory breast cancer (primary edema form) – 10 people; b) a diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophageal cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. Results and discussion. In patients with infiltrative breast cancer, diffuse-infiltrative stomach cancer, and diffuse-infiltrative esophagus cancer, and diffuse-infiltrative colorectal cancer there was a tendency to an increase in the expression of YKL-39 with the ERBB2 amplification during inflammatory tumor infiltration in the stroma. High expression of Stabilin-1 (2.1±0.70, n = 22) was found compared to patient tumors that did not reveal the amplification of ERBB2 (1.46±0.67, n = 13, p = 0.015). In most patients with amplification ERBB2, the cryoglobulin content was average (298.6±2.5 mg/l; 1.3±0.08%) – 20 (50%), which corresponds to cryoglobulinemia type II; with conditioned cryoglobulinemia (79.4±1.01 mg/l) in 10 (25%); high content (477.3±48 mg/l; 3.4±0.2%) was recorded in 10 (25%), which indicates the type III of cryoglobulinemia [the hazard ratio (HR) = 0.71, 95%, сonfidence interval (CI): 0.22-0.83, p = 0.005] Conclusion. Amplification of ERBB2 and macrophages surroundings markers CD68, M2 subpopulation RS1 (Stabilin-1), chitinase-like proteins YKL-39 and SI-CLP independently identified subgroups of patients with inflammatory breast cancer, diffuse stomach and diffuse esophageal, diffuse colorectal cancer with a bad forecast. In patients with the presence of the amplification of ERBB2 in the inflammatory tumor infiltrate, in the stroma, the higher expression of the chitinase-like protein YKL-39 and M2-polarization RS1 of the marker Stabilin-1, was detected compared to the patient's tumors without amplifying ERBB2. This study shows an important role of quantitative values associated with the tumor phenotype and macrophages in tumor progression, depending on the presence of ERBB2 gain. In patients with cryoglobulinemia with inflammatory cancer the secondary immunodeficiency is developed. This is determined by anomalies in the cell and humoral immune system, and leads to the development of postoperative inflammatory complications and relapses