Schlam Ilana, Tarantino Paolo, Tolaney Sara M
Department of Hematology and Oncology, Tufts Medical Center, Boston, MA 02111, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancers (Basel). 2022 Aug 18;14(16):3996. doi: 10.3390/cancers14163996.
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.
人表皮生长因子受体2（HER2）阳性乳腺癌约占所有乳腺癌的15%，与其他乳腺癌亚型相比，在历史上其预后较差。随着HER2靶向治疗的发展，HER2阳性疾病患者的预后有了显著改善；然而，许多患者出现对这些治疗的原发性或获得性耐药，这导致晚期疾病的早期复发或进展。在这篇叙述性综述中，我们讨论了对不同HER2靶向治疗的耐药机制，包括单克隆抗体、小分子酪氨酸激酶抑制剂和抗体药物偶联物。我们回顾了诸如与HER2结合受损、受体抑制不完全、其他受体信号增加、与雌激素受体相互作用以及PIK3CA通路激活等机制。我们还讨论了肿瘤免疫微环境和HER2异质性的作用，以及对新型抗体药物偶联物的独特耐药机制。更好地理解这些机制以及克服它们的潜在策略将使我们能够继续改善乳腺癌患者的预后。
