Discordance between Immunohistochemistry and In Situ Hybridization to Detect HER2 Overexpression/Gene Amplification in Breast Cancer in the Modern Age A Single Institution Experience and Pooled Literature Review Study: Discordance between HER2 overexpression and gene amplification in breast cancer

Abstract Microabstract: Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status. We found that IHC-/ISH+ and IHC+/ISH- discordance constituted 2.7% of 1125 cases and 3.2% of those with an unequivocal HER2 IHC status, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature revealed a significantly higher IHC+/ISH- discordance than IHC-/ISH+. Background: Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12-25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status, as its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported. Methods: We determined the frequency of HER2 IHC/ISH discordance in these patients, along with a pooled literature review analysis. Results: Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC-/ISH+ and 17 IHC+/ISH-, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43468 cases with IHC and ISH performed. The IHC-/ISH+ and IHC+/ISH- discordances were seen in all antibody clones and ISH methods utilized. The IHC+/ISH- discordance was significantly higher than IHC-/ISH+ (13.8% vs. 3.0%, P