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Background <p>Human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates (ADCs) have expanded the clinical relevance of HER2 expression beyond the traditional HER2-positive versus HER2-negative framework. HER2-low breast cancer, commonly defined as immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH), is now treatment-relevant in selected advanced-disease settings. HER2-ultralow disease, characterized as IHC 0 with membrane staining below the IHC 1 + threshold, further challenges routine pathological interpretation.</p> Main body <p>This pathology-centered review summarizes the evolution of HER2 classification from binary status to a clinically relevant expression continuum and clarifies the definitions of true HER2-zero, HER2-ultralow, HER2-low, and HER2-positive disease. Particular emphasis is placed on the zero/ultralow/1 + boundaries, reflex ISH or fluorescence in situ hybridization (FISH) testing for IHC 2 + cases, assay and fixation variables, nonspecific staining, intratumoral heterogeneity, specimen discordance, and interobserver variability. DESTINY-Breast06 and subsequent regional approvals have made HER2-ultralow actionable in defined hormone receptor-positive advanced-disease settings. A practical workflow is proposed for assessment, quality control, consensus review, and reporting.</p> Conclusions <p>HER2-low and HER2-ultralow should be interpreted as clinically relevant extensions of established HER2 testing rather than as simple new labels. Responsible implementation requires standardized IHC scoring, careful morphological correlation, validated assays, transparent reporting language, and multidisciplinary communication. A reproducible pathology-centered workflow is essential for translating ADC-era advances into precise and equitable breast cancer care.</p>

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HER2-low and HER2-ultralow breast cancer in the antibody-drug conjugate era: diagnostic challenges and reporting workflow

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Kuan Liang,
  • Ziang Jia,
  • Haiwen Lu,
  • Ziling Yan,
  • Haihui Huang,
  • Xia Liu

摘要

Background

Human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates (ADCs) have expanded the clinical relevance of HER2 expression beyond the traditional HER2-positive versus HER2-negative framework. HER2-low breast cancer, commonly defined as immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH), is now treatment-relevant in selected advanced-disease settings. HER2-ultralow disease, characterized as IHC 0 with membrane staining below the IHC 1 + threshold, further challenges routine pathological interpretation.

Main body

This pathology-centered review summarizes the evolution of HER2 classification from binary status to a clinically relevant expression continuum and clarifies the definitions of true HER2-zero, HER2-ultralow, HER2-low, and HER2-positive disease. Particular emphasis is placed on the zero/ultralow/1 + boundaries, reflex ISH or fluorescence in situ hybridization (FISH) testing for IHC 2 + cases, assay and fixation variables, nonspecific staining, intratumoral heterogeneity, specimen discordance, and interobserver variability. DESTINY-Breast06 and subsequent regional approvals have made HER2-ultralow actionable in defined hormone receptor-positive advanced-disease settings. A practical workflow is proposed for assessment, quality control, consensus review, and reporting.

Conclusions

HER2-low and HER2-ultralow should be interpreted as clinically relevant extensions of established HER2 testing rather than as simple new labels. Responsible implementation requires standardized IHC scoring, careful morphological correlation, validated assays, transparent reporting language, and multidisciplinary communication. A reproducible pathology-centered workflow is essential for translating ADC-era advances into precise and equitable breast cancer care.