Subtyping-Directed Precision Treatment Refines Traditional One-Size-Fits-All Therapy for HR+/HER2− Breast Cancer

The standard approach of using one-size-fits-all endocrine therapy for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers has faced significant challenges because of variations in treatment response among individuals. To overcome this challenge, we conducted a comprehensive study that integrated data from both "bench" (multiomics sequencing and functional drug response testing) and "bedside" (multicenter real-world and clinical trial cohorts) studies. Classification of HR+/HER2- breast cancer into four subtypes enabled effective subtyping-directed precision treatment strategies: endocrine therapy alone for the canonical luminal subtype, the addition of cyclin-dependent kinase 4/6 and poly (ADP-ribose) polymerase (PARP) inhibitors for the proliferative subtype, immunotherapy for the immunogenic subtype, and tyrosine kinase inhibitors for the receptor tyrosine kinase-driven subtype. The development of clinically applicable deep learning-based digital pathology classification demonstrated that matched treatment guided by subtyping-directed precision treatment strategies outperformed unmatched approaches in a real-world cohort and the I-SPY2 trial. Overall, this study emphasizes the superiority of subtyping-directed precision treatment strategies for HR+/HER2- breast cancer. SIGNIFICANCE: A comprehensive understanding of subtypes of HR+/HER2- breast cancer facilitates development of a multipronged precision medicine approach that can be translated from bench to bedside.