BACKGROUND There has been substantial interest in HER2 intratumoral heterogeneity as an explanation for the development of resistance to anti-HER2 therapies in breast cancer, particularly to trastuzumab emtansine (T-DM1). METHODS Through a literature-based approach, we discuss mechanisms of resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer. RESULTS We describe results from clinical studies reporting the effect of anti-HER2 strategies particularly ADCs and their mechanistic effect. We review biological findings underlying HER2 heterogeneity and its implication in the development of novel anti-HER2 drugs including new ADCs in clinical development like trastuzumab deruxtecan (DS-8201). CONCLUSIONS We suggest potential mechanisms to optimize these compounds and their future clinical implementation.

中文翻译：

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HER2异质性和对抗HER2抗体-药物偶联物的抗性。

背景技术HER2肿瘤内异质性引起了人们极大的兴趣，作为对乳腺癌，特别是曲妥珠单抗坦坦（T-DM1）的抗HER2治疗产生耐药性的解释。方法通过基于文献的方法，我们讨论了乳腺癌中对靶向HER2的抗体-药物偶联物（ADC）的抗性机制。结果我们描述了临床研究的结果，这些结果报告了抗HER2策略（特别是ADC）的作用及其机理作用。我们回顾了HER2异质性的潜在生物学发现及其在新型抗HER2药物（包括曲妥珠单抗deruxtecan（DS-8201））临床开发中的新型ADC的开发中的意义。结论我们建议优化这些化合物及其未来临床应用的潜在机制。