Breastfeeding Shapes a Unique Tumor-Immune Landscape in Pregnancy-Associated Breast Cancer from GEICAM-EMBARCAM study

Background Pregnancy-associated breast cancer (PABC) is an aggressive malignancy affecting young women during gestation, lactation, or the post-weaning period. Despite its clinical significance and poor prognosis, how these physiological stages shape tumor biology remains poorly understood. Here, we integrate reproductive context with molecular and immune profiling to define shared and stage-specific features of PABC and uncover potential therapeutic vulnerabilities. Methods We conducted BC360 NanoString gene expression analysis and CIBERSORTx immune deconvolution in 106 breast cancer cases, including 57 PABC patients stratified by diagnosis stage (gestation, breastfeeding, or post-weaning) and 49 non-PABC controls. Results Our study identified a shared aggressive signature across all PABC cases, marked by increased proliferation and impaired DNA repair. Notably, breastfeeding patients (PABC-BF) emerged as a distinct subset, displaying an immune-inflamed tumor profile characterized by elevated chemokines, enriched CD8⁺ and regulatory T-cell infiltration, and prominent TIGIT inhibitory checkpoint upregulation. Conclusions These findings reveal lactation as a physiological framework that shapes tumor immunity, defining a distinct tumor-immune landscape which warrants further investigation for potential therapeutic approaches.