Spatial determinants of pathological complete response and residual disease after neoadjuvant therapy in breast cancer

Pathological complete response (pCR) after neoadjuvant therapy is associated with favorable outcomes in breast cancer, yet differences in response cannot be explained by immune-cell abundance alone. This review examines pCR and residual disease from a spatial perspective. An effective antitumor response requires coordinated immune recruitment, local activation and renewal, movement across tissue boundaries, contact with malignant cells, and maintenance of effector function. Disruption at any stage may preserve resistant tumor regions despite substantial overall immune infiltration. Current evidence indicates that immune-cell positioning, multicellular organization, and the spatial distribution of stromal, vascular, and metabolic constraints can provide information beyond conventional cell-density measurements. However, the strength and clinical meaning of these associations vary according to breast cancer subtype, treatment regimen, sampling time point, and analytical platform. Pretreatment tissue, early on-treatment samples, and surgical residual disease address distinct baseline response-associated, pharmacodynamic, and prognostic questions and should therefore be interpreted separately. Residual disease represents a treatment-selected ecosystem rather than simply a smaller version of the untreated tumor. We integrate available evidence into a time-resolved framework linking baseline spatial architecture, treatment-related remodeling, residual disease organization, and subsequent clinical outcome. Translation into clinical practice will require standardized spatial definitions and measurements, reproducible assessment of organized immune structures, subtype- and regimen-specific validation, and demonstration of added value beyond established pathological indicators. Spatially resolved analysis may improve understanding of heterogeneous neoadjuvant responses and support more precise post-treatment risk assessment.