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<div><p>Introduction</p><p>Breast cancer (BC) presents diverse malignancies with varying biological and clinical behaviors, driven by an interplay between cancer cells and tumor microenvironment. Deciphering these interactions is crucial for personalized diagnostics and treatment. This study explores the prognostic impact of tumor proliferation and immune response patterns, assessed by computational pathology indicators, on breast cancer-specific survival (BCSS) models in estrogen receptor-positive HER2-negative (ER+HER2–) and triple-negative BC (TNBC) patients.</p><p>Materials and methods</p><p>Whole-slide images of tumor surgical excision samples from 252 ER+HER2– patients and 63 TNBC patients stained for estrogen and progesterone receptors, Ki67, HER2, and CD8 were analyzed. Digital image analysis (DIA) was performed for tumor tissue segmentation and quantification of immunohistochemistry (IHC) markers; the DIA outputs were subsampled by hexagonal grids to assess the spatial distributions of Ki67-positive tumor cells and CD8-positive (CD8+) cell infiltrates, expressed as Ki67-entropy and CD8-immunogradient indicators, respectively. Prognostic models for BCSS were generated using multivariable Cox regression analysis, integrating clinicopathological and computational IHC indicators.</p><p>Results</p><p>In the ER+HER2– BC, multivariable Cox regression revealed that high CD8+ density within the tumor interface zone (IZ) (HR: 0.26, <i>p</i> = 0.0056), low immunodrop indicator of CD8+ density (HR: 2.93, <i>p</i> = 0.0051), and low Ki67-entropy (HR: 5.95, <i>p</i> = 0.0.0061) were independent predictors of better BCSS, while lymph node involvement predicted worse BCSS (HR: 3.30, <i>p</i> = 0.0013). In TNBC, increased CD8+ density in the IZ stroma (HR: 0.19, <i>p</i> = 0.0119) and Ki67-entropy (HR: 3.31, <i>p</i> = 0.0250) were independent predictors of worse BCSS. Combining these independent indicators enhanced prognostic stratification in both BC subtypes.</p><p>Conclusions</p><p>Computational biomarkers, representing spatial properties of the tumor proliferation and immune cell infiltrates, provided independent prognostic information beyond conventional IHC markers in BC. Integrating Ki67-entropy and CD8-immunogradient indicators into prognostic models can improve patient stratification with regard to BCSS.</p></div>