Spatial and genomic profiling of residual breast cancer after neoadjuvant chemotherapy unveils divergent fates for each breast cancer subtype

Residual cancer burden (RCB) is a strong prognostic marker after neoadjuvant chemotherapy (NAC) in breast cancer (BC), yet some BCs defy their predicted outcomes. Using single-cell spatial transcriptomics and genomic profiling, we investigated mechanisms underlying divergent fates of BCs with high RCB across subtypes. In triple negative BC (TNBC), CXCL9+ macrophage-CD8+ T cell interactions via chemokines and interferon-gamma signaling promoted favorable outcomes, while SPP1+ macrophage-cancer cell interactions driven by hypoxia signaling correlated with poor prognosis. In non-TNBC, the extent of basal-like cancer cells and their proximity to scarce immune cells were linked to prognosis. Additionally, tumor-intrinsic subtype in hormone receptor-positive cancers and structural variations like extrachromosomal ERBB2 DNA in HER2-positive cancers predicted worse outcomes. This study highlights distinct genomic and microenvironmental strategies governing BC subtype-specific fates after NAC.