Multimodal assessment of exceptional responders refines subtyping-directed precision treatment in HR+/HER2– breast cancer

BACKGROUND We previously defined 4 hormone receptor + /human epidermal growth factor receptor 2 – (HR + /HER2 – ) subtypes: SNF1 canonical luminal, SNF2 immunogenic, SNF3 proliferative, and SNF4 RTK driven. The FASCINATE-N proof-of-concept trial demonstrated that subtyping-directed precision treatment improves pathologic complete response in locally advanced HR + /HER2 – breast cancer, yet efficacy remains suboptimal. METHODS We integrated transcriptomic, genomic, digital pathology, and clinical data from this trial ( n = 230) and focused on exceptional responders to explore opportunities for refining treatment strategies. RESULTS In SNF1, we uncovered that perineural invasion diminished endocrine therapy efficacy, suggesting the potential benefit of incorporating perineural blockade. Digital pathology and spatial transcriptomics identified that the spatial architecture of the tumor-stromal-immune interface influenced apatinib efficacy in SNF4, highlighting the importance of interfering with the tumor microenvironment. In the SNF3 group, exceptionally well responders exhibited multiple mutations in DNA repair genes and cell cycle activation, correlating with the efficacy of poly (ADP-ribose) polymerase and CDK4/6 inhibitors. Additionally, we illustrated that lymphatic vessel infiltration was linked to improved immunotherapy outcomes in HR + /HER2 – SNF2 tumors. CONCLUSION Overall, our study emphasizes the importance of multimodal assessments in optimizing precision treatments for HR + /HER2 – breast cancer. FUNDING National Natural Science Foundation of China, grant numbers U25C2032, 82441028, and 82573645; The Shanghai Key Laboratory of Breast Cancer, grant number 12DZ2260100; The Human Phenome Data Center of Fudan University. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT05582499.