Wanderley, C. W. S.; Michaud, D. E.; Shimada, K.; Nelson, A.; Fu, J.; Schnitt, S. J.; Tolaney, S. M.; Mittendorf, E. A.; Barroso-Sousa, R.; Waks, A.; Tarantino, P.; Guerriero, J. L.

Novel anti-HER2 antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have shown efficacy in tumors with varying HER2 expression, including HER2-low and even tumors with minimal HER2 presence. This has sparked interest in the biology underlying the HER2 expression spectrum. Using molecular and multiplexed imaging, we revealed distinct immune and stromal features in treatment-naive, hormone receptor (HR)-positive HER2-low versus HER2-0 tumors. HER2-0 tumors exhibit inflammatory and tissue remodeling gene signatures, with enrichment of APOE tumor-associated macrophages (TAMs) and DOCK4 CD4 T cells. In contrast, HER2-low tumors are more immunosuppressed, with elevated cell cycle, metabolic, and estrogen signaling pathways, suggesting increased proliferative activity. These findings underscore key biological differences between HR-positive HER2-low and HER2-0 breast cancers, and may inform more tailored therapeutic strategies.