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. 2025 Apr 4;20(1):35.
doi: 10.1186/s13000-025-01624-3.

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

Agata Wróbel  1 , Michel Vandenberghe  2 , Marietta Scott  2 , Frances Jones  2 , Tsuyoshi Matsuo  2 , Anne-Marie Boothman  2 , Jessica Whiteley  2 , Craig Barker  2
Affiliations

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

Agata Wróbel et al. Diagn Pathol. .

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.

Keywords: Breast cancer; HER2-low; HER2-ultralow; Immunohistochemistry; Scoring.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Agreement between historical real-world HER2 scoring and central consensus score. a NPA and PPA were defined using central consensus score as the reference score. CI: confidence interval; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry; NPA: negative percent agreement; OPA: overall percent agreement; PPA: positive percent agreement
Fig. 2
Fig. 2
Agreement between local and consensus HER2 scores. Scores are broken down by test laboratory, surgery type, and tumor type for all evaluable samples. CNB: core-needle biopsy; HER2: human epidermal growth factor receptor 2
See this image and copyright information in PMC

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