The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.

中文翻译：

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双重HER2阻断期间和之后HER2阳性乳腺癌的表型变化。

HER2阳性（HER2 +）乳腺癌中富含HER2的亚型（HER2-E）对HER2途径高度依赖。但是，约有20-60％的HER2 + / HER2-E肿瘤在抗HER2治疗后无法完全缓解。在这里，我们评估了拉美替尼和曲妥珠单抗新辅助治疗之前，期间和之后在PAMELA试验和乳腺癌细胞系的HER2 + / HER2-E肿瘤中的基因表达数据。我们的结果表明，HER2-E疾病的双重HER2阻断在患者的肿瘤和体外模型中均诱导了低增殖的Luminal A表型。与HR阴性疾病相比，这些生物学变化在激素受体阳性（HR +）疾病中更为明显。有趣的是，用抗HER2疗法增加管腔表型增加了对CDK4 / 6抑制的敏感性。最后，体外终止HER2靶向治疗或获得抗HER2治疗耐药性可恢复原始HER2-E表型。我们的发现支持维持性抗HER2治疗的使用以及CDK4 / 6抑制亚型转换的治疗性利用。