Original articles
Vol. 117: Issue 6 - December 2025
Standardizing the pathologic assessment of HER2-Low and HER2-Ultralow breast cancer: Insights from a national Italian project
Abstract
Objective
Novel therapies for HER2-(ultra)low breast cancer (BC) have changed the traditional binary classification of HER2 status into a multi-tiered system that captures the full spectrum of expression as determined by immunohistochemistry (IHC). Several pre-analytical and analytical variables can influence the accurate identification of HER2 expression within the lowest IHC range.
Herein, we present the findings of a national Italian project addressing the diagnostic challenges associated with HER2-(ultra)low BCs and their proper classification.
Material and Methods
A total of 121 pathologists from various regions and Institutions were recruited and asked to: i) complete an online survey addressing key pre-analytical and analytical issues affecting HER2 status reporting in BC; ii) score 8 cases of IHC HER2-low whole slide images (WSI) shared online; iii) participate in on-site meetings to discuss the results and evaluate 8 additional challenging WSIs. The assessments were subsequently compared to those of an expert panel.
Results
Several pre-analytical and analytical concerns emerged from the questionnaire, like reporting resection cold ischemia time and decalcification agent choice and the employment of proper HER2 controls. Regarding the WSIs, a substantial overall agreement (69%) with the expert panel was observed (74% in the online phase and 64% in the on-site phase), along with substantial to excellent consensus (≥ 61%) in over 60% of the samples. Most discordances emerged in the on- site cohort, which was enriched with challenging cases, particularly within the HER2 0+/ultralow spectrum, which demonstrated an overall agreement of 48%.
Conclusions
This nationwide study highlights the complexities of accurately classifying HER2-(ultra)low breast cancers, particularly within the HER2 ultralow subset. While a substantial level of agreement with expert assessments was achieved, the variability observed in more challenging cases underscore the need for standardized interpretation criteria, enhanced training, and continuous quality assurance measures.
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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright
Copyright (c) 2026 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology
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