Concordance for Low HER2 Protein Expression in Breast Cancer Tissue Using Standard Immunohistochemistry Assays

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In a study reported in JAMA Oncology, Fernandez et al found that scoring accuracy for low HER2 protein expression (0 or 1+) in breast cancer tissue on standard immunohistochemistry (IHC) assays was poor. As observed by the investigators, the findings pose issues for investigation of fam-trastuzumab deruxtecan-nxki, which has been found to be effective in breast cancer with IHC scores of 1+ or 2+ but not 0, as read in central pathology laboratories.

Study Details

The study included an evaluation of data from College of American Pathologists (CAP) proficiency surveys for HER2 expression in breast cancer from 2019 and 2020. Participating laboratories (n = 1,391–1,452) received two tissue microarrays of 10 HER2 cores, each twice per year. HER2 assays were performed using standard methods of the laboratories. The tissue microarrays were scored and returned to CAP as part of its quality assessment program. The total survey data set in the current analysis covers the scores over 2 years from the laboratories of 40 HER2 cores from each laboratory (20 cores twice per year, for a total of 80).

An independent analytic data set consisted of a Yale University–based study of concordance among 18 pathologists reading digitally scanned images of 170 breast cancer biopsies performed in 2018, with samples enriched for HER2 2+ and 3+ cases.

Key Findings

Among 80 cores evaluated in the CAP survey, 52 (65%) had a concordance rate of ≥ 90%. High concordance was limited to scores of 0 and 3+. Lowest agreement was found between HER2 = 0 vs HER2 = 1+. Of the 80 cores, 56 were considered negative (HER2 score of 0 or 1); in 25% of these cores, there was ≤ 70% agreement. Overall, 19% of cases read by the laboratories had results with ≤ 70% concordance for HER2 scores of 0 vs 1+.

Of 170 biopsies read by 18 pathologists in the Yale University set, 92 were read as 0 by at least 1 pathologist; using a ≥ 90% cutpoint for agreement, at least 17 of 18 pathologists agreed on 0 vs 1+ for 24 (26% concordance) of the 92 cases. A total of 45 biopsies were read as 3+ by at least 1 pathologist; using the ≥ 90% cutpoint, at least 17 of 18 raters agreed on 2+ vs 3+ for 26 (58% concordance) of the 45 cases. A significant difference was observed for 0/1+ concordant cases vs 2+/3+ concordant cases (χ2 = 12.07, P < .001).

The investigators concluded, “In this study using a current standard ERBB2 [HER2] IHC assay, the scoring accuracy for ERBB2 [HER2] IHC in the low range (0 and 1+) was poor. This inaccuracy in the real world could lead to misassignment of many patients for treatment with trastuzumab deruxtecan.”  

David L. Rimm, MD, PhD, of the Department of Pathology, Yale School of Medicine, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by the Breast Cancer Research Foundation, National Cancer Institute, and others. For full disclosures of the study authors, visit

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