目前，约80％的乳腺癌（BCs）被分类为人类表皮生长因子受体2（HER2）阴性[免疫组织化学（IHC）0、1+或2+/原位杂交（ISH）阴性]；传统上被归类为HER2阴性的BCs中有约60％表达了低水平的HER2。 HER2-低（IHC 1+或IHC 2+/ISH-）状态通过批准使用trastuzumab deruxtecan用于治疗不可切除/转移性HER2-低 BC而成为具有临床行动力的。 迫切需要更深入了解HER2-低疾病的患者。 本全球、多中心、回顾性研究（NCT04807595）纳入了2014年至2017年被确诊为HER2阴性不可切除/转移性BC（任何激素受体（HR）状态）的患者的组织样本。病理学家在本地实验室接受Ventana 4B5和其他检测方法对低表达程度进行评分培训后，盲目地重新评分HER2 IHC染色的幻灯片作为HER2-低（IHC 1+或IHC 2+/ISH-）或HER2 IHC 0。评估了HER2-低的患病率和历史评分与重新评分之间的一致性。检查了人口统计学、临床病理学特征、治疗方法和结果。 在789名HER2阴性不可切除/转移性BC患者的重新评分样本中，整体HER2-低患病率为67.2％（HR阳性71.1％，HR阴性52.8％）。历史评分和重新评分的HER2状态之间的一致性中等（81.3％；κ=0.583）；HER2-低的阳性一致性（87.5％）高于HER2 IHC 0（69.9％）。超过30％的历史IHC 0病例在整体上（所有检测方法）和使用Ventana 4B5进行重新评分后，被重新评分为HER2-低。 HER2-低和HER2 IHC 0在患者特征、接受的治疗或临床结果方面没有显著差异。 约三分之二的历史HER2阴性不可切除/转移性BC患者可能从HER2-低定向治疗中受益。我们的数据表明，可以考虑在具有历史IHC 0评分的患者中进行HER2重新评估，以优化选择接受治疗的患者。此外，通过标准化病理学家培训可以实现对HER2-低 BC患者的准确识别。 版权所有© 2023 作者。由Elsevier Ltd.出版。保留所有权利。

Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed.This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined.In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes.Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.