The human epidermal growth factor receptor 2 (HER2) is a well-known negative prognostic factor in breast cancer and a target of the monoclonal antibody trastuzumab as well as of other anti-HER2 compounds. Pioneering works on HER2-positive breast cancer in the 90s’ launched a new era in clinical research and oncology practice that has reshaped the natural history of this disease. In diagnostic pathology the HER2 status is routinely assessed by using a combination of immunohistochemistry (IHC, to evaluate HER2 protein expression levels) and in situ hybridization (ISH, to assess HER2 gene status). For this purpose, international recommendations have been developed by a consensus of experts in the field, which have changed over the years according to new experimental and clinical data. In this review article we will document the changes that have contributed to a better evaluation of the HER2 status in clinical practice, furthermore we will discuss HER2 heterogeneity defined by IHC and ISH as well as by transcriptomic analysis and we will critically describe the complexity of HER2 equivocal results. Finally, we will introduce the clinical impact of HER2 mutations and we will define the upcoming category of HER2-low breast cancer with respect to emerging clinical data on the efficacy of specific anti-HER2 agents in subgroups of breast carcinomas lacking the classical oncogene addition dictated by HER2 amplification.

人表皮生长因子受体 2 (HER2) 是众所周知的乳腺癌阴性预后因子，也是单克隆抗体曲妥珠单抗以及其他抗 HER2 化合物的靶标。90 年代 HER2 阳性乳腺癌的开创性工作开启了临床研究和肿瘤学实践的新纪元，重塑了该疾病的自然史。在诊断病理学中，HER2 状态通常通过结合使用免疫组织化学（IHC，以评估 HER2 蛋白表达水平）和原位杂交（ISH，以评估HER2基因状态）。为此，该领域专家的共识制定了国际建议，多年来根据新的实验和临床数据发生了变化。在这篇综述文章中，我们将记录有助于在临床实践中更好地评估 HER2 状态的变化，此外，我们将讨论由 IHC 和 ISH 以及转录组分析定义的 HER2 异质性，我们将批判性地描述 HER2 的复杂性模棱两可的结果。最后，我们将介绍HER2的临床影响突变，我们将根据新出现的关于特定抗 HER2 药物在缺乏由HER2扩增所决定的经典癌基因添加的乳腺癌亚组中的疗效的新临床数据来定义即将到来的 HER2 低乳腺癌类别。