Spatial Structure of Tumor and Immune Cells Shape Outcomes in ER⁺HER2⁻ and Triple-Negative Breast Cancer

Immune infiltration is prognostic in triple-negative breast cancer (TNBC), but its role in ER⁺/HER2⁻ disease remains unclear, and conventional scoring may overlook spatial context. We analyzed tumors from 1,037 women ≤50 years in the Young Boost Trial (NCT00212121), integrating centralized pathology review, deep learning–based spatial profiling of whole-slide H&E, and multiplex immunophenotyping. In TNBC, stromal tumor-infiltrating lymphocytes (sTILs) were robustly prognostic, independent of clinicopathologic features, confirming immune burden as the dominant signal. By contrast, in ER⁺/HER2⁻ cancers, sTILs were protective only in low-grade tumors and lost significance when architectural features were considered. Instead, grade, lymphovascular invasion, central sclerosis, and spatial separation of lymphocytes and tumor cells carried stronger independent prognostic value. These findings highlight subtype-specific prognostic biology: in TNBC, immune density alone captures outcome, whereas in ER⁺/HER2⁻ disease, the interplay between immune infiltrates and tumor architecture governs prognostic associations.