Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Automated summary

HER2-low and ultra-low breast cancer are new subcategories of HER2 BC, and the review outlines the criteria for distinguishing them. Clinical trials have shown the benefits of HER2-directed antibody-drug conjugates (ADCs) in treating these tumors, including trastuzumab-deruxtecan, which has been approved as the first targeted therapy for HER2-low BC. Ongoing trials, such as the DESTINY-Breast06 trial, are evaluating ADCs for HER2-ultra low BC. New guidelines are hoped to improve our understanding of tumor biology and provide new therapeutic options.