Current Biological, Pathological and Clinical Landscape of HER2-Low Breast Cancer

SIMPLE SUMMARY: The breakthrough in developing novel HER2-targeting antibody drug conjugates and identifying their clinical benefits in HER2-low breast cancer will dramatically revolutionize the clinical treatment landscape of HER2 negative breast cancers, as well as the pathologic evaluation of HER2 status in breast cancers. This review updates the current biological, pathological and clinical landscape of HER2-low breast cancer and proposes the future directions on clinical management, pathology practice, and translational research in this subset of breast cancer. ABSTRACT: HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC that has HER2 immunohistochemical (IHC) score of 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating this group of tumors. Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC was recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. However, HER2-low BC is still not well characterized clinically and pathologically. This review aims to update the current biological, pathological and clinical landscape of HER2-low BC based on the English literature published in the past two years and to propose the future directions on clinical management, pathology practice, and translational research in this subset of BC. We hope it would help better understand the tumor biology of HER2-low BC and the current efforts for identifying and treating this newly recognized targetable group of BC.