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<p>The DESTINY-Breast06 trial demonstrated survival benefits of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low/ultralow metastatic breast cancer. However, the associated clinicopathological features, HER2 testing consistency, and utility of artificial intelligence (AI)-assisted interpretation remain unclear. We analyzed 1455 HER2-non-amplified cases and conducted a multicenter ring study across 45 laboratories, with 209 tissue sections evaluated by manual and AI-assisted scoring. Compared to HER2-ultralow cases, HER2-null tumors exhibited higher histological grade (<i>p</i> &lt; 0.001), lower estrogen receptor (ER) expression, and elevated Ki-67 (all <i>P</i> &lt; 0.05). Triple-negative breast cancer (TNBC) patients in the HER2-null subgroup were significantly younger (<i>P</i> = 0.040). Significant staining variability was observed between antibodies: the 4B5 clone was associated with more HER2 0 and 1+ scores, while MXR001 yielded higher rates of HER2-low results (<i>P</i> &lt; 0.05). Inter-laboratory concordance was moderate (68.89%), being poorest for HER2 1+ (57.58%; Kappa = 0.566). AI-assisted interpretation improved observer agreement (Kappa: 0.703 vs. 0.610 in non-amplified cases) and reduced ambiguous immunohistochemistry (IHC) 2+/0 assignments. These findings delineate distinct clinicopathological characteristics of HER2-ultralow/null tumors, highlight HER2 IHC reproducibility challenges, and validate AI as an effective tool for standardizing scoring to optimize patient selection for T-DXd therapy.</p>

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HER2-low and ultralow expression of invasive breast carcinoma: clinicopathological features and immunohistochemical consistency analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Yu-han Dong,
  • Yi-tong Xu,
  • Xi-zi Jiang,
  • Lu Xu,
  • Rui-Jiao Yu,
  • Rui Wang,
  • Qing-fu Zhang

摘要

The DESTINY-Breast06 trial demonstrated survival benefits of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low/ultralow metastatic breast cancer. However, the associated clinicopathological features, HER2 testing consistency, and utility of artificial intelligence (AI)-assisted interpretation remain unclear. We analyzed 1455 HER2-non-amplified cases and conducted a multicenter ring study across 45 laboratories, with 209 tissue sections evaluated by manual and AI-assisted scoring. Compared to HER2-ultralow cases, HER2-null tumors exhibited higher histological grade (p < 0.001), lower estrogen receptor (ER) expression, and elevated Ki-67 (all P < 0.05). Triple-negative breast cancer (TNBC) patients in the HER2-null subgroup were significantly younger (P = 0.040). Significant staining variability was observed between antibodies: the 4B5 clone was associated with more HER2 0 and 1+ scores, while MXR001 yielded higher rates of HER2-low results (P < 0.05). Inter-laboratory concordance was moderate (68.89%), being poorest for HER2 1+ (57.58%; Kappa = 0.566). AI-assisted interpretation improved observer agreement (Kappa: 0.703 vs. 0.610 in non-amplified cases) and reduced ambiguous immunohistochemistry (IHC) 2+/0 assignments. These findings delineate distinct clinicopathological characteristics of HER2-ultralow/null tumors, highlight HER2 IHC reproducibility challenges, and validate AI as an effective tool for standardizing scoring to optimize patient selection for T-DXd therapy.