Proteogenomic Characterization Reveals Subtype‐Specific Therapeutic Potential for HER2‐Low Breast Cancer

The molecular heterogeneity and distinct features of HER2-low breast cancer are poorly understood, limiting their precise management. To address this issue, longitudinal multiomic profiling of HER2-low breast cancer is performed, including genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics, using 250 well-characterized samples, and identified three proteomic subtypes: PS1 (estrogen response signaling enriched), PS2 (angiogenesis enriched), and PS3 (proliferation enriched and HER2-high like). These three proteomic subtypes have distinct features and potential therapeutic strategies, namely, endocrine therapy, antiangiogenic therapy, and anti-HER2 therapy, and are validated in external datasets and PDO models. In addition, a detailed description of the genomic characteristics and a map of the lactate modification landscape of HER2-low breast cancer are provided. This research provides complementary information, reveals the molecular characteristics of HER2-low breast cancer, and suggests potential precise therapeutic strategies for patients with this type of cancer.