No abstract

The classification of Human Epidermal Growth Factor Receptor 2 (HER2) expression is optimized to detect HER2-amplified breast cancer (BC). However, novel HER2-targeting agents are also effective for BCs with low levels of HER2. This raises the question whether the current guidelines for HER2-testing are sufficiently reproducible to identify HER2 low BC. The aim of this multicenter international study was to assess the interobserver agreement of HER2 low scoring according to the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Furthermore, we evaluated whether the agreement improved by redefining immunohistochemistry (IHC) scoring criteria, or by adding fluorescent in situ hybridization (FISH). We performed a two-round study of 105 non-amplified BCs. During the first assessment, sixteen pathologists used the latest version of the ASCO/CAP guidelines. After a consensus meeting, the same pathologists scored the same digital slides using modified IHC scoring criteria based on the 2007 ASCO/CAP guideline, and an extra ‘ultralow’ category was added. Overall, the interobserver agreement was limited (4.7% of cases with 100% agreement) in the first round, but this improved by clustering IHC categories. In the second round, the highest reproducibility was seen when comparing IHC 0 versus the grouped cluster of ultralow/1+/2+ (74.3% of cases with 100% agreement). FISH results were not statistically different between HER2 0 and HER2 low cases, regardless of the IHC criteria used. In conclusion, our study suggests that the modified 2007 ASCO/CAP criteria were more reproducible to distinguish HER2 0 from HER2 low cases as compared to the 2018 ASCO/CAP criteria. However, the reproducibility was still moderate, which was not improved by adding FISH. This could lead to suboptimal selection of patients eligible for novel HER2-targeting agents. There is a need for clearer, more reproducible IHC definitions, training and/or development of more accurate methods to detect HER2 low BC.