Accuracy of human epidermal growth factor receptor 2 (HER2) immunohistochemistry scoring by pathologists in breast cancer, including the HER2-low cutoff : HER2 IHC scoring concordance in breast cancer.
| Title: | Accuracy of human epidermal growth factor receptor 2 (HER2) immunohistochemistry scoring by pathologists in breast cancer, including the HER2-low cutoff : HER2 IHC scoring concordance in breast cancer. |
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| Authors: | Wróbel A; Oncology R&D, AstraZeneca, Postępu 14, Warsaw, 02-676, Poland. agata.wrobel@astrazeneca.com.; Vandenberghe M; R&D, AstraZeneca, Cambridge, UK.; Scott M; R&D, AstraZeneca, Cambridge, UK.; Jones F; R&D, AstraZeneca, Cambridge, UK.; Matsuo T; R&D, AstraZeneca, Cambridge, UK.; Boothman AM; R&D, AstraZeneca, Cambridge, UK.; Whiteley J; R&D, AstraZeneca, Cambridge, UK.; Barker C; R&D, AstraZeneca, Cambridge, UK. |
| Source: | Diagnostic pathology [Diagn Pathol] 2025 Apr 04; Vol. 20 (1), pp. 35. Date of Electronic Publication: 2025 Apr 04. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101251558 Publication Model: Electronic Cited Medium: Internet ISSN: 1746-1596 (Electronic) Linking ISSN: 17461596 NLM ISO Abbreviation: Diagn Pathol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central, 2006- |
| MeSH Terms: | Erb-b2 Receptor Tyrosine Kinases*/analysis ; Erb-b2 Receptor Tyrosine Kinases*/metabolism ; Breast Neoplasms*/pathology ; Breast Neoplasms*/diagnosis ; Immunohistochemistry*/methods ; Biomarkers, Tumor*/analysis; Humans ; Female ; Pathologists ; Reproducibility of Results ; Observer Variation |
| Abstract: | Background: Breast cancer was previously categorized as human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+, IHC 2+ / in situ hybridization [ISH]-positive) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Recent studies of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, have explored the spectrum of HER2 expression in tumors categorized as HER2-negative, including HER2-low (IHC 1+, IHC 2+/ISH-) and HER2-ultralow (IHC 0 with membrane staining). Clinical relevance of HER2-low and HER2-ultralow is reinforced by encouraging efficacy findings in these populations.; Objective: To assess HER2-low and HER2-ultralow scoring performance by pathologists, and compare real-world HER2-low scoring with centralized scoring by trained pathologists.; Methods: Formalin-fixed, paraffin-embedded breast cancer samples stained by the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche) assay were selected to ensure adequate representation across all HER2 IHC scores (N = 500). Samples were rescored in a central laboratory by three pathologists trained in HER2-low scoring, and a majority consensus generated. Agreement between consensus and historical real-world HER2 scores was assessed by Fleiss' kappa across HER2 scores (IHC 0, 1+, 2+, 3+).; Results: Substantial agreement was observed among central pathologists across HER2 scores (κ = 0.69), for the HER2-low cutoff (IHC 0 vs. IHC 1+, 2+, 3+; κ = 0.79), and the HER2-ultralow cutoff (IHC 0 absent membrane staining vs. IHC 0 with membrane staining, 1+, 2+, 3+; κ = 0.68). Substantial agreement was observed between real-world pathologists and central consensus for the HER2-low cutoff (κ = 0.72).; Conclusions: Pathologists can reproducibly score HER2-low and HER2-ultralow when supported by training. Findings may aid decision-making for patients with breast cancer who are potentially eligible for HER2-directed therapy.; (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: AstraZeneca has a governance framework and processes to ensure that commercial sources have appropriate patient consent and ethical approval in place for collection of samples for research purposes, including use by for-profit companies. The AstraZeneca Biobank in the UK is licensed by the Human Tissue Authority (Licence No. 12109) and has National Research Ethics Service Committee (NREC) approval as a Research Tissue Bank (RTB) (REC No 22/NW/0102), which covers the use of the samples for this project. Consent for publication: Not applicable. Competing interests: All authors are employees of AstraZeneca. MV, MS, FJ, TM, A-MB, JW, and CB hold shares in AstraZeneca. |
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| Contributed Indexing: | Keywords: Breast cancer; HER2-low; HER2-ultralow; Immunohistochemistry; Scoring |
| Substance Nomenclature: | EC 2.7.10.1 (Erb-b2 Receptor Tyrosine Kinases); 0 (Biomarkers, Tumor); EC 2.7.10.1 (ERBB2 protein, human) |
| Entry Date(s): | Date Created: 20250404 Date Completed: 20250515 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11969812 |
| DOI: | 10.1186/s13000-025-01624-3 |
| PMID: | 40186179 |
| Database: | MEDLINE |
Journal Article