Taking the 'low' into consideration: Discussions on redefining HER2 status in breast cancer (Review)

Breast cancer is classified, based on human epidermal growth factor receptor 2 (HER2) status, as HER2-positive or HER2-negative, guiding eligibility for HER2-targeted therapies. A HER2-low tumor is a type of breast cancer, which is defined by immunohistochemistry scores of 1+ or 2+ with negative in situ hybridization. Technological advances in HER2 testing, along with improved diagnostic precision, have increased the recognition of the HER2-low subgroup. HER2-low tumors may represent a distinct biological and clinical entity. Molecular profiling further demonstrates the unique transcriptomic and mutational signatures of HER2-low tumors, particularly within hormone receptor-positive contexts. In addition, clinical trials such as DESTINY-Breast04, demonstrate notable efficacies for novel antibody-drug conjugates, such as trastuzumab-deruxtecan, in patients with HER2-low tumors. This challenges the conventional HER2 stratification and suggests guideline revisions in order to acknowledge the HER2-low status. The present review synthesized knowledge regarding HER2 biology, pathology and molecular features, and highlighted the clinical relevance and therapeutic implications of redefining HER2 status to include the HER2-low subgroup. Recognizing HER2-low as a discrete classification may refine patient stratification, optimize therapeutic selection and improve clinical outcomes in breast cancer management.