Human Epidermal Growth Factor Receptor 2 (HER2)-Ultralow Breast Cancer: Incidence, Clinicopathologic Features, and Need for Refined Scoring System.

Patients with metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC), defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization negative, have demonstrated clinical benefit from antibody-drug conjugates, such as trastuzumab deruxtecan. The DESTINY-Breast06 trial further demonstrated that patients with hormone receptor-positive, HER2-ultralow (UL) metastatic BC also benefit from HER2-targeted therapies. This study aimed to evaluate the incidence, staining characteristics, and clinicopathologic features of HER2-UL BC. We retrospectively analyzed scanned HER2 IHC slides (PATHWAY anti-HER2/neu 4B5) from 400 primary BC cases diagnosed between January and March 2024. Two breast pathologists reevaluated and recategorized HER2 IHC results into HER2-positive, HER2-low, HER2-UL, and HER2-null (N). HER2-UL was defined as incomplete or weak membranous staining in ≤10% of tumor cells, whereas HER2-N showed complete absence of membranous staining. Staining was analyzed by distribution, location, and quality. Clinicopathologic comparisons were performed across HER2-negative groups. Original HER2 classification based on the 2023 American Society of Clinical Oncology and College of American Pathologists guidelines included HER2 IHC 0 (146, 37%), HER2 IHC 1+ (188, 47%), HER2 IHC 2+/fluorescence in situ hybridization negative (33, 8%), and HER2-positive (HER2 IHC 2+/fluorescence in situ hybridization positive or 3+) (33, 8%). Upon rereview, with HER2-low, HER2-UL, and HER2-N incorporated into the classification framework, 63 cases (16%) were HER2-N, 118 (29%) HER2-UL, 186 (47%) HER2-low, and 33 (8%) HER2-positive. In HER2-UL cases, median membranous staining was 3% (range, 1%-9%). Nonspecific staining patterns, such as granular cytoplasmic staining, cytoplasmic blush, edge staining, and dot-like peritumoral staining, were frequently observed in recategorized cases. No significant clinicopathologic differences were found among HER2-N, HER2-UL, and HER2-low groups, except for higher invasive lobular carcinoma frequency in HER2-N (P = .034) and older age in HER2-UL patients. Notably, 55% (80/146) of initial HER2 IHC 0 cases were categorized as HER2-UL. As HER2-targeted therapies expand to HER2-UL tumors, accurate classification is critical. Implementation of a refined scoring system could improve diagnostic accuracy and therapeutic targeting.