越来越多的数据表明，HER2阳性（HER2+）乳腺癌（BC）亚型对靶向抗HER2治疗显示出差异性反应。本研究旨在调查这些差异以及潜在的分子机制。利用一大组乳腺癌患者（n = 7390）。评估了HER2+免疫组化（IHC）亚型，特别是HER2 IHC 3+和HER2 IHC 2+ /扩增的临床病理特征和差异基因表达（DGE），并与新辅助和辅助治疗中的病理学完全缓解（pCR）和生存相关。还调查了雌激素受体（ER）状态的作用。与HER2 IHC 3+肿瘤相比，具有IHC 2+ /扩增的BC患者显示出明显较低的pCR率（22％对57％，P <0.001），不论HER2基因拷贝数如何，生存期较短，较少被分类为HER2丰富型，并富集于曲妥珠单抗耐药和ER信号通路基因。 ER阳性显著降低了IHC 2+ /扩增而不是IHC 3+ BC患者对抗HER2治疗的反应。在HER2+ BC中，HER2蛋白的过表达是致病途径的驱动因子，也是抗HER2治疗反应的主要预测因子。 ER信号通路在具有模糊HER2表达的BC中更为主导。应考虑基于IHC亚型进行个体化抗HER2治疗。 ©2023。作者（们）。

Increasing data indicate that HER2-positive (HER2 + ) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms.A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated.Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients.In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.© 2023. The Author(s).