Clinicopathologic Features and Digital Imaging Analysis of HER2 Protein in Breast Carcinomas With Different HER2 Fluorescence in Situ Hybridization Patterns

Background: HER2-targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer (BC), which represents 15% to 20% of all BC cases. HER2 status is assessed via immunohistochemistry (IHC) and/or in situ hybridization (ISH), dividing BCs into five groups (G1-G5). Patients and methods: In a study of 2,702 primary BC cases, comprising 12.7% G1, 0.2% G2, 2.8% G3, 8.5% G4, and 75.9% G5, we analyzed clinicopathologic features and HER2 protein expression digitally for each ISH group. Results: Notably, G5 cases had a higher proportion of lobular carcinoma (13.9%) compared to other groups. G3 cases showed the highest percentage of grade 3 tumors (56.9%), while G5 cases had the lowest (21.4%). Additionally, G5 cases had the highest rate of estrogen receptor (ER) positivity (84.6%), while G1-HC (high copy number) cases had the lowest (70.4%). Most G1-HC cases were HER2 IHC 3+ (76.1%), while most G5 cases were IHC 0/1+ (75.7%). IHC 2+ was most common in G1-LC (low copy number) and G3 cases (83.8% and 90.7%, respectively), with G4 cases predominantly IHC 2+ (56.3%) and IHC 1+ (30.1%). Discordant HER2 IHC and ISH results were observed in 12 cases (0.4%), including 7 G1-HC (2.3%), 4 G1-LC (10.8%), and 1 G5 case (0.1%). Digital quantification of HER2 IHC levels in all groups except G5 revealed that G1-HC tumors had the highest HER2 protein expression, followed by G3, with G4 showing the lowest. Conclusion: These findings offer valuable insights into the clinicopathologic characteristics and future management for different HER2 ISH groups.