| Abstract [eng] |
Human epidermal growth factor receptor 2 (HER2) is an important predictive and prognostic biomarker in invasive breast cancer (BC). The heterogeneity of HER2, at both protein expression and gene amplification levels, is one of the main reasons of inaccurate assessment of HER2 status and non-effective response to therapy. The presence of tumor infiltrating lymphocytes and their distribution in the tumor microenvironment are associated with prognostic value in BC; however, the data are conflicting in different BC subtypes. In this dissertation, automated fluorescence in situ hybridization analysis algorithms were applied to investigate HER2 gene expression heterogeneity in HER2 borderline (by immunohistochemistry, IHC) BC patients. Novel quantifiable measures of HER2 intratumoral heterogeneity (ITH), based on HER2 signal variance in BC cells were developed. The ITH of HER2 protein and other BC IHC biomarkers expression and its prognostic value was investigated using digital image analysis with subsequent hexagonal grid analytics. We established the independent prognostic indicators, representing ITH of HER2 and ER IHC expression, that supplemented the clinical and pathological parameters of BC and outperformed other quantitative indicators used for the assessment of the IHC biomarkers. Indicators of CD8+ lymphocyte distribution in the tumor microenvironment and their prognostic value were explored: in HER2 non-amplified tumors, antitumor immune response, assessed by the CD8+ interface zone Immunogradient indicators, provided prognostic stratification independent and superior to other pathology and IHC variables. |
