Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland - on behalf of the UK national coordinating committee for breast pathology

Sep 24, 2026

Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative, with limited data on pathologist reproducibility. Patient and methods: Sixteen expert UK pathologists scored 50 digital HER2 IHC slides; agreement used Fleiss multiple-rater kappa and Cohen’s Kappa, with re-scoring after a washout period. Results: Absolute agreement occurred in 6% (all 3+), poor agreement in 10% due to heterogeneity and cytoplasmic staining. Conclusion: HER2-low breast cancer shows lower concordance, with most cases reproducibly classified. Refining reporting criteria can improve consensus scoring and patient selection for targeted therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

HER2 classification and diagnostic need

Article Summary

Keywords and background

Patient and methods

Results

Conclusion

The Breast 70 (2023) 82–91 Contents lists available at ScienceDirect The Breast journal [homepage:](homepage: www.journals.elsevier.com/the-breast)[ www.journals.elsevier.com/the-breast](homepage: www.journals.elsevier.com/the-breast) Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland –on behalf of the UK national coordinating committee for breast pathology Mohamed Zaakouka, b, Cecily Quinn c, d, Elena Provenzanoe, f, Clinton Boyd g, Grace Callagy h, Soha Elsheikh i,j, Joe Flint k, Rebecca Millican-Slater l, Anu Gunavardhan m, Yasmeen Mirn, Purnima Makhijao, Silvana Di Palmap, Susan Pritchard q, Bruce Tanchelr, Emad Rakhas, Nehal M. Atallah s, t, Andrew H.S. Lees, Sarah Pinder u, Abeer M. Shaabana, v, * a Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK b Cancer Pathology, National Cancer Institute, Cairo University, Cairo, Egypt c Department of Histopathology, St Vincent’s University Hospital, Elm Park, Ireland d UCD School of Medicine, Dublin, Ireland e Addenbrookes Hospital and NIHR Cambridge Biomedical Research Centre, Cambridge, UK f Department of Histopathology, Addenbrookes Hospital, Cambridge, UK g Histopathology, Belfast Health and Social Care Trust, Belfast, UK h Discipline of Pathology, University of Galway, School of Medicine, Lambe Institute for Translational Research, Galway, Ireland i Department of Cellular Pathology, Royal Free Hospital, London, UK j Research Department of Pathology, University College London, Cancer Institute, London, UK k Birmingham Tissue Analytics, University of Birmingham, UK l Department of Cellular Pathology, St James’s University Hospital, Leeds, UK m Department of Histopathology, Glan Clwyd Hospital Betsi Cadwaladr University Health Board, Bodelwyddan, UK n Pathology, Liverpool University Hospitals Foundation Trust, Liverpool, UK o Pathology, Barts Health NHS Trust, London, UK p Cellular Pathology Department, Royal Surrey Hospital NHS Foundation Trust, Guildford, UK q Pathology, Wythenshawe Hospital Manchester Foundation Trust, Manchester, UKr Cellular Pathology, Heart of England NHS Foundation Trust, Birmingham, UK s Histopathology Department, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK t Department of Pathology, Faculty of Medicine, Menoufia University, Egypt u School of Cancer & Pharmaceutical Sciences, Kings College London, London, UK v Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK A R T I C L E I N F O Keywords: Breast cancer HER2-Low HER2-Ultralow Consistency Concordance Immunohistochemistry A B S T R A C T Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. Patient and methods: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen’s Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after awashout period. Results: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/ 50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Interobserver agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. * Correspo

FAQs

What does the study evaluate regarding HER2-low breast cancer?

The study evaluates how consistently expert pathologists score HER2-low status in breast carcinoma when interpreting digitally scanned HER2 IHC slides.

How were agreement measures calculated in the study?

Overall agreement was quantified using Fleiss multiple-rater kappa and Cohen’s Kappa statistics, with additional re-scoring after a washout period for low-concordance cases.

What factors contributed to low concordance in some cases?

Poor agreement was linked to heterogeneous HER2 expression, cytoplasmic staining, and low expression near the 10% cut-off value.

What is the study’s main conclusion and recommended next step?

HER2-low breast cancer has lower concordance among expert pathologists, and while most cases are reproducible, a minority remains challenging. Refining reporting criteria for consensus scoring is recommended to support targeted therapy patient selection.

Sep 24, 2026

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