Evidence map›Paper›PMID 42664757›Full record

ArticleBreast (Edinburgh, Scotland)2026

Revisiting HER2-negative breast cancer in the era of HER2-low and HER2-ultralow expression: Assessment of interobserver variability.

Xiao Huang, Sarah Anderson, Valeria Dal Zotto, Shuko Harada, Andrea G Kahn, Meiling Zhou, Kui Zhang, Kanako Okamoto, Shi Wei

Abstract read
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In one paragraph

Article in Breast (Edinburgh, Scotland), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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4 · The record

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5 · Who and what money

Authors and funding

9 authors.

Xiao HuangDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Sarah AndersonDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Valeria Dal ZottoDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Shuko HaradaDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Andrea G KahnDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Meiling ZhouDepartment of Statistics, Grand Valley State University, Allendale, MI, USA.
Kui ZhangDepartment of Mathematical Sciences, Michigan Technological University, Houghton, MI, USA.
Kanako OkamotoDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Shi WeiDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: swei@uabmc.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundHER2-low and HER2-ultralow expressions have recently emerged as actionable targets in breast cancer (BC). However, data remain limited regarding the consistency of immunohistochemistry (IHC) scoring when both categories are considered. This study aimed to evaluate interobserver variability in assessing HER2-negative BC, with particular focus on the reproducibility of HER2-low and -ultralow classifications.

methodsA total of 389 consecutive HER2-negative BC cases were re-evaluated by six pathologists with varying experience (1-20 years). The panel included dedicated breast pathologists, general pathologists routinely covering breast services, and a surgical pathology fellow in training. HER2 expression was categorized as HER2-null (no staining), -ultralow, 1+, or 2+. Interobserver agreement was analyzed using Fleiss' kappa statistics and intraclass correlation coefficients (ICCs).

resultsThree scoring schemes were compared: a 4-tier scheme (null, ultralow, 1+, 2+), a 3-tier scheme (combining 1+ and 2+), and a 2-tier scheme (combining ultralow and low). The overall Fleiss' kappa values were 0.67, 0.68, and 0.77 for the 4-, 3-, and 2-tier schemes, respectively, indicating substantial agreement. Ten rater pairs demonstrated substantial agreement (0.61-0.80), and five showed moderate agreement (0.41-0.60), all involving one rater who consistently assigned lower scores. ICCs ranged from 0.75 to 0.90, reflecting good reliability. Unanimous agreement among all raters was achieved in 53.0%, 61.2%, and 85.7% of cases with the 3 tier schemes, respectively.

conclusionDespite the nuanced distinction between HER2-low and HER2-ultralow categories, IHC remains a reliable and reproducible method for evaluating HER2 expression in BC, even in the era of expanded HER2-targeted therapies, although reproducibility is lower for borderline HER2-ultralow cases.

Indexed as

Breast NeoplasmsErb-b2 Receptor Tyrosine KinasesBiomarkers, TumorFemaleHumansImmunohistochemistryObserver VariationReproducibility of ResultsBiomarkers, TumorERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesBreast cancerHER2HER2-lowHER2-ultralowInterobserver variability

Identifiers

PMID42664757
PMCPMC13640464

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