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Updated: May 29, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Interobserver consistency and diagnostic challenges in HER2-ultralow breast cancer: a multicenter study
1Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Background:
Recent advancements in novel antibody-drug conjugates (ADCs) have demonstrated efficacy in patients with human epidermal growth factor receptor 2 (HER2)-ultralow breast cancer (BC), expanding the eligibility for anti-HER2 targeted therapy to include some patients previously categorized as HER2 immunohistochemistry (IHC) 0. This expansion underscores the need for pathologists to accurately differentiate HER2-null and HER2-ultralow.
Materials And Methods:
Thirty-six pathologists from four centers nationwide conducted microscopic visual assessments on HER2 IHC slides from 50 consecutive BC surgical specimens, all previously diagnosed as HER2 IHC 0.
Results:
The interobserver consistency in differentiating HER2-null from HER2-ultralow, measured by Fleiss κ, was only 0.230-lower than the consistency for combined HER2 IHC 0 cases (Fleiss κ = 0.344) and binary classification (HER2-null versus HER2-non-null; Fleiss κ = 0.292). High agreement for HER2-null versus HER2-ultralow differentiation was achieved in only 4% of cases, while combining them into HER2 IHC 0 raised high agreement cases to 32%, higher than the 18% seen in the binary classification. Consensus among the 36 pathologists aligned with historical scores in 72% of cases; however, when subdividing HER2 IHC 0 into HER2-null and HER2-ultralow, the consistency dropped to 54%.
Conclusions:
The low consistency among pathologists in distinguishing HER2-null, -ultralow, and 1+ cases may impact patient eligibility for new ADC therapies. To address this challenge, there is a need for improved detection methods, artificial intelligence-assisted quantitative assessments, and larger clinical datasets to refine the definition of HER2-ultralow.
Insights
Pathologists struggle to differentiate HER2-null and HER2-ultralow breast cancer (BC) cases, impacting eligibility for new antibody-drug conjugate (ADC) therapies. Improved methods are needed for accurate HER2 assessment in BC.
Area of Science:
- Oncology
- Pathology
- Biomarker Discovery
Background:
- Novel antibody-drug conjugates (ADCs) show promise for HER2-ultralow breast cancer (BC).
- This expands anti-HER2 therapy eligibility to some HER2 immunohistochemistry (IHC) 0 cases.
- Accurate differentiation of HER2-null and HER2-ultralow is now critical.
Purpose of the Study:
- To assess pathologist consistency in differentiating HER2-null from HER2-ultralow breast cancer.
- To evaluate the impact of subclassifying HER2 IHC 0 on diagnostic agreement.
Main Methods:
- Thirty-six pathologists performed visual assessments on HER2 IHC slides from 50 HER2 IHC 0 BC specimens.
- Interobserver consistency was measured using Fleiss κ for different classification schemes.
Main Results:
- Low interobserver consistency was observed for HER2-null vs. HER2-ultralow differentiation (κ=0.230).
- High agreement was achieved in only 4% of cases for this distinction.
- Combining cases as HER2 IHC 0 improved agreement (κ=0.344) compared to binary HER2-null vs. HER2-non-null (κ=0.292).
Conclusions:
- Low pathologist consistency in distinguishing HER2-null, -ultralow, and 1+ cases may affect patient eligibility for ADCs.
- Improved detection methods, AI-assisted assessments, and larger datasets are needed to refine HER2-ultralow definitions.
