Assessing immunohistochemistry biomarkers in the spatial context of the microenvironment of hormone receptor-positive ductal breast carcinoma by digital image analysis

Cancer biology studies have revealed that dysregulated immune responses and interactions between cells in the tumor microenvironment (TME) affect tumor progression and therapeutic resistance. Assessment of tumor-infiltrating lymphocytes (TIL) in TME has been shown prognostic value in various tumors, including HER2-positive and triple-negative breast cancer; however, contradicting evidence is obtained in hormone receptor-positive invasive ductal breast carcinoma (HRBC). TIL assessment based on digital image analysis (DIA) of immunohistochemistry (IHC) slides enables better precision and, importantly, quantification of the spatial distribution of TIL within TME compartments. In this dissertation, based on DIA and hexagonal grid subsampling, quantitative and spatial methodologies of breast cancer tissue analytics, including the immune response and tumor heterogeneity indicators, were developed and tested. It was established that the density of CD8+ cells in the tumor compartment and CD8+ gradient reflecting the directional density profile of immune cells (immunogradient) from stroma to tumor aspect across statistically established interface zone were independent indicators of favorable prognosis in HRBC. In addition, prognostic modeling, based exclusively on the DIA of IHC images, was achieved in HRBC patients, based on three independent features of HRBC – intratumoral heterogeneity of progesterone receptor expression and proliferation rate as well as tissue immune response