Interobserver variability in her2 immunohistochemistry analysis and its clinical implications with the advent of the HER2-low category
Abstract Background HER2 protein expression levels are determined by immunohistochemistry (IHQ) and has been classified as positive (3 + or 2+/ in situ hybridization positive) or negative (0, 1 + or 2+/ in situ hybridization negative) because only positive cases had the possibility of targeted thera...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
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| Series: | Surgical and Experimental Pathology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s42047-025-00199-z |
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| Summary: | Abstract Background HER2 protein expression levels are determined by immunohistochemistry (IHQ) and has been classified as positive (3 + or 2+/ in situ hybridization positive) or negative (0, 1 + or 2+/ in situ hybridization negative) because only positive cases had the possibility of targeted therapy. However, the DESTINY-Breast04 study demonstrated the activity of the drug trastuzumab-deruxtecan (T-DXd) in patients with metastatic invasive breast carcinoma with HER2 status by IHQ 1 + and IHQ 2 + with negative in situ hybridization (ISH); these patients were defined as HER2-low. The HER2-low definition is based on the inclusion criteria of clinical trials and predominantly depends on the testing protocols and IHQ classification systems proposed by the ASCO/CAP guidelines. Several studies have raised concerns regarding the adequacy of current immunohistochemical (IHC) analysis in accurately distinguishing between different HER2 status categories. Significant interobserver variability has been reported, particularly in differentiating between IHC 0 and IHC 1+, which has led to questions about the reliability and reproducibility of this method for HER2. In this context, we sought to evaluate the interobserver variation in HER2 status analysis after the advent of the HER2-low category and whether diagnostic variations would influence clinical decisions for patients if they had metastatic breast cancer. Methods 209 slides were retrieved from the archives of the Pathology Service at Hospital de Clínicas in Curitiba, Paraná, Brazil, and were reviewed by 2 pathologists. The reviewer 1 was a breast pathologist and the reviewer 2 was a surgical pathologist. The HER2 status results were recorded and compared with the original diagnosis and were subjected to statistical concordance calculations. Results Reviewer 1 and reviewer 2 agreed with the original diagnosis by 62.5% (moderate concordance kappa) and 75.8% (good concordance kappa), respectively. The agreement was 73.8% (moderate concordance kappa). The diagnoses of the 3 observers were concordant for only 42 patients (20.3%). We found that 14 slides originally diagnosed with a score of 0 were reclassified as 1 + by both reviewers. Conclusions There was interobserver variation in HER2 IHQ analysis, with the kappa index ranging from moderate to good, with the variation observed mainly in the low expression spectrum. After review, patients in the HER2-low category were detected, making these patients eligible for specific treatment in cases of recurrence or distant metastasis. |
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| ISSN: | 2520-8454 |