Spatial-Immune Multi-omics Refines Prognostication in Early-Stage Estrogen Receptor-Positive Breast Cancer

Despite a strong 5–10 year prognosis, in ER ⁺ HER2 ⁻ breast cancer relapses are common beyond 10 years. Genomic assays employed to determine recurrence risk at diagnosis are still ambiguous for a significant proportion of patients with Intermediate risk (i.e. Oncotype Dx Recurrence Score (RS) 16–25). We demonstrate that macrophage and T-helper cells facilitate and impede cytotoxic T-cells, are associated with extracellular matrix remodelling and M2-like (SPP1) genes, and cytotoxicity (GZMA, GZMB, PRF1), checkpoints (LAG3, PD-1, PD-L2), and exhaustion (TOX) genes respectively, consistent with restrained T-cell activation. High cytotoxic T-cell density was associated with poorer 15-year iDFS in the High RS (p = 0.017, FDR < 0.1). Critically, in the randomised Intermediate RS, a treatment-biomarker interaction indicated chemotherapy inferiority at higher stromal CD8 density (ΔLR-χ ² : 7.36, p = 0.007), which was validated orthogonally on whole-resection specimens from the same cohort (ΔLR-χ ² : 7.48, p = 0.006). Using the candidate biomarker suggested a potential treatment change for up to 50% of the Intermediate RS.