Document Type
Article
Publication Date
10-2026
Department
Department of Mathematical Sciences
Abstract
BACKGROUND: HER2-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. METHODS: A 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). RESULTS: Three 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. CONCLUSION: Despite 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.
Publication Title
Breast (Edinburgh, Scotland)
Recommended Citation
Huang, X.,
Anderson, S.,
Dal Zotto, V.,
Harada, S.,
Kahn, A. G.,
Zhou, M.,
Zhang, K.,
Okamoto, K.,
&
Wei, S.
(2026).
Revisiting HER2-negative breast cancer in the era of HER2-low and HER2-ultralow expression: Assessment of interobserver variability.
Breast (Edinburgh, Scotland),
89, 104896.
http://doi.org/10.1016/j.breast.2026.104896
Retrieved from: https://digitalcommons.mtu.edu/michigantech-p2/2943
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Version
Publisher's PDF
Publisher's Statement
© 2026 The Authors. Published by Elsevier Ltd. Publisher’s version of record: 10.1016/j.breast.2026.104896