Breast Cancers With Discordant Human Epidermal Growth Factor Receptor 2 Fluorescence In Situ Hybridization-Positive (Group 1) and Immunohistochemistry-Negative (0/1+) Results Following American Society of Clinical Oncology/College of American Pathologists Guideline.

Abstract

Context.—: Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been widely used for human epidermal growth factor receptor 2 (HER2) status determination in breast cancers for about 25 years. Most laboratories use IHC as the first line of testing in both primary and metastatic breast cancers. Implementation of and updates to the ASCO/CAP guidelines have improved the reported discrepancy between IHC and FISH results.

Objective.—: To investigate the incidence of discordance between IHC and FISH after the most recent guideline update and to determine possible underlying causes.

Design.—: Breast cancer cases simultaneously tested for HER2 by IHC and FISH from January 2023 through July 2024 were identified. Information on clinicopathologic features and follow-up on cases with discordant results were obtained from electronic records.

Results.—: IHC-negative/FISH-positive discordance was identified in 10 of 956 cases (1.1%). Discordance was significantly more commonly seen in tissues from metastatic sites where ischemic and fixation times were not documented owing to unknown primary site at the time of biopsy. IHC-negative/FISH-positive cases had significantly lower HER2 copy number per cell in discordant cases.

Conclusions.—: Dual IHC and FISH testing, especially from metastatic sites, may need to be considered to ensure all patients eligible for targeted therapies are identified. Significant differences in HER2 copy numbers between discordant and concordant cases raise the possibility of underlying biologic differences and require further investigation.