Clinicopathologic Features and Genomic Profile of Human Epidermal Growth Factor Receptor 2–Low and Human Epidermal Growth Factor Receptor 2–Ultralow Invasive Breast Carcinomas

Context.— Recent clinical trials have identified significant benefits of human epidermal growth factor receptor 2 (HER2)–targeting antibody conjugates in invasive breast carcinomas with HER2-low and HER2-ultralow expression, challenging the conventional binary HER2 status. Objective.— To examine the clinicopathologic features and genomic profile of HER2-low and HER2-ultralow invasive breast carcinomas. Design.— Two hundred thirteen cases were identified with HER2 immunohistochemistry (IHC) reported as 0, 1+, and 2+/in situ hybridization–negative with Oncotype DX results from 2017–2022. One hundred seventy-eight cases with hematoxylin-eosin and HER2 slides available were independently scored by 5 pathologists blinded to the reported HER2 results as HER2 0, 0-1, 1+, 2+, using light microscopy. For each HER2 IHC score, patient age, tumor characteristics, and HER2 mRNA expression scores were compared. Additionally, each hormone receptor IHC score was compared to its respective mRNA expression scores. Results.— The overall interobserver agreement of HER2 IHC scoring was substantial, with a κ value of 0.689 (0.658–0.710; P .001). There was no statistically significant difference in age and tumor characteristics by HER2 IHC scores. HER2 IHC scores were significantly associated with median HER2 mRNA expression scores (P .001). However, for all 3 biomarkers, significant overlaps in mRNA expression scores existed between the different IHC scores. Conclusions.— In our study, there were no significant differences in clinicopathologic features among HER2 IHC scores. In addition, there was considerable overlap in HER2 and hormone receptor mRNA scores across different IHC categories, limiting their utility as predictors of HER2 and hormone receptor IHC scores.