HER-2 low in breast cancer: A new perspective for anti-HER-2 therapy

HER-2 is a transmembrane receptor of the Epidermal Growth Factor Receptor (EGFR) subfamily that functions physiologically in normal cell proliferation and differentiation. HER-2 overexpression is found in 20–30% of breast cancer patients. Thus, HER-2 is established as a prognosis marker and therapeutic target for anti-HER-2. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) issued guidelines for HER-2 classification based on immunohistochemical (IHC) and in situ hybridization (ISH) examinations. Before ASCO/CAP issued the latest update to their guidelines, HER-2 classification was divided into HER-2 negative, equivocal, and positive. Only patients with HER-2 positive (HER-2 overexpression) received anti-HER-2 therapy. After the DESTINY-Breast04 trial demonstrated the efficacy of trastuzumab deruxtecan in breast cancer with low HER-2 levels, ASCO/CAP officially updated the guidelines by introducing a low HER-2 classification, which is HER-2 expression with an immunohistochemical (IHC) score of 1+ or 2+ without HER-2 gene amplification on in situ hybridization (ISH). Trastuzumab deruxtecan exerts a substantial cytotoxic burden on HER-2-expressing tumor cells, significantly improving progression-free survival and overall survival compared with conventional chemotherapy. Reclassification of low HER-2 tumors bridges a critical gap in breast cancer management, providing a new perspective for patients with low HER-2 expression with anti-HER-2 therapy, thus highlighting the importance of accurate identification of HER-2 for prognosis determination and therapeutic reference in breast cancer. This review highlights HER-2 classification, the importance of IHC and ISH assays for HER-2 expression, and anti-HER-2 therapy options for HER-2 positive and HER-2 low based on the latest guidelines.