Tumor ecology and the paradox of clean margins in multicentric breast cancer: an exploratory organoid-based functional study

The gene-centric view of cancer has provided important mechanistic insights, but does not fully account for the clinical heterogeneity observed in complex cases. An eco-evolutionary framework instead conceptualizes tumors as dynamic systems shaped by interactions among malignant clones, stromal components, immune populations and the surrounding microenvironment. Multicentric/multifocal breast cancer (MMBC) provides a relevant context in which to explore this biological complexity. Using patient-derived organoids, we observed that organoids derived from histologically tumor-free margins can display stem-like and basal-like features under defined culture conditions, whereas those from primary tumor regions may exhibit more differentiated phenotypes. These observations suggest that histological margin status alone may not fully capture the functional heterogeneity of peritumoral tissue. Our findings support the hypothesis that biological influences within the margin region may contribute to shaping cellular phenotypes beyond the presence of overt malignant cells. Overall, this study highlights the potential value of integrating organoid-based functional approaches with eco-evolutionary concepts to further investigate the biological landscape of the peritumoral field in MMBC.