![]() BC has been classified into several biologically distinct subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched (HER2), basal-like, and normal-like by gene expression profiling analysis ( 1, 2), requiring different treatment strategies. The multifaceted nature of the disease leads to diverse clinical outcomes and therapeutic responses. In conclusion, we present novel prognostic models, based on computational ITH and Immunogradient indicators of the IHC biomarkers, in HER2 IHC 2+ BC patients.īreast cancer (BC) is a complex and diverse disease with distinct clinical, pathological, and molecular characteristics. In the HER2-amplified group, CD8 cell density in the tumor aspect of the IZ was the only independent immune response feature to predict better OS ( HR: 0.22, p = 0.0047). Combining these three computational indicators of the CD8 cell spatial distribution within the tumor microenvironment augmented prognostic stratification of the patients. In the non-amplified tumors, three Immunogradient indicators provided the independent prognostic value: CD8 density in the tumor aspect of the IZ and CD8 center of mass were associated with better OS ( HR: 0.23, p = 0.0079 and 0.14, p = 0.0014, respectively), and CD8 density variance along the tumor edge predicted worse OS ( HR: 9.45, p = 0.0002). In the HER2-amplified patients, HER2 MC contrast ( HR: 0.35, p = 0.0367) and CEP17 copy number ( HR: 0.19, p = 0.0035) were independent predictors of better OS along with worse OS predicted by pN status ( HR: 4.75, p = 0.0018). Multiple Cox regression revealed HER2 membrane completeness (HER2 MC) ( HR: 0.18, p = 0.0007), its spatial entropy ( HR: 0.37, p = 0.0341), and ER contrast ( HR: 0.21, p = 0.0449) as independent predictors of better OS, with worse OS predicted by pT status ( HR: 6.04, p = 0.0014) in the HER2 non-amplified patients. DIA outputs were subsampled by HexT for ITH quantification and tumor microenvironment extraction for Immunogradient indicators. Surgical excision samples stained for estrogen receptor (ER), progesterone receptor (PR), Ki67, HER2, and CD8 from 275 patients with HER2 IHC 2+ invasive ductal BC were used in the study. In particular, we assessed the prognostic value of Immunogradient indicators at the tumor–stroma interface zone (IZ) as a feature of antitumor immune response. We aimed to establish prognostic models of overall survival (OS) of these patients, which take into account spatial aspects of ITH and tumor microenvironment by using hexagonal tiling analytics of digital image analysis (DIA). ![]() This leads to difficulties in therapy decisions. 4Department of Breast Surgery and Oncology, National Cancer Institute, Vilnius, Lithuaniaīreast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH).3Faculty of Medicine, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.2Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.1National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania.Gedmante Radziuviene 1,2* Allan Rasmusson 1,3 Renaldas Augulis 1,3 Ruta Barbora Grineviciute 1 Dovile Zilenaite 1,3 Aida Laurinaviciene 1,3 Valerijus Ostapenko 4 Arvydas Laurinavicius 1,3
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