Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately unavoidable for all but a small minority of patients who achieve an enduring remission and possibly cure. Over the past two decades, significant advances in our understanding of the underlying molecular mechanisms of HER2-driven oncogenesis have translated into pharmaceutical advances, with the developing of increasingly sophisticated therapies directed against HER2. These include novel, more potent selective HER2 tyrosine kinase inhibitors (TKIs); new anti-HER2 antibody-drug conjugates; and dual epitope targeting antibodies, with more advanced pharmacological properties and higher affinity. With the introduction of adjuvant T-DM1 for incomplete responders to neoadjuvant therapy, fewer patients are relapsing, but for those who do relapse, disease that may be resistant to standard first- and second-line therapies requires new approaches. Furthermore, the risk of CNS relapse has not been abrogated by current (neo)adjuvant strategies; therefore, current research efforts are being directed towards this challenging site of metastatic disease. In this article, we review the currently available clinical data informing the effective management of HER2-positive breast cancer beyond standard first-line therapy with pertuzumab, trastuzumab, and taxanes, and the management of relapse in patients who have already been exposed to both these agents and T-DM1 for early breast cancer (EBC). We additionally discuss novel anti-HER2 targeted agents and combinations in clinical trials, which may be integrated into standard treatment paradigms in the future.
尽管近期取得进展，HER2阳性晚期乳腺癌（ABC）在很大程度上仍是一种无法治愈的疾病。除极少数获得持久缓解甚至可能治愈的患者外，所有患者最终都不可避免地对传统抗HER2药物产生耐药性。过去二十年间，我们对HER2驱动肿瘤发生的分子机制的理解取得重大进展，并转化为药物研发的进步，针对HER2的疗法日益精进。这些进展包括新型、更强效的选择性HER2酪氨酸激酶抑制剂（TKIs）；新型抗HER2抗体-药物偶联物；以及具有更先进药理特性和更高亲和力的双表位靶向抗体。随着T-DM1辅助治疗被引入新辅助治疗反应不佳的患者，复发患者数量有所减少，但对于确实复发的患者，其疾病可能对标准一线和二线疗法产生耐药性，需要新的治疗方法。此外，当前（新）辅助策略并未消除中枢神经系统（CNS）复发的风险；因此，目前的研究工作正针对这一具有挑战性的转移部位展开。本文综述了当前可用的临床数据，这些数据为HER2阳性乳腺癌在帕妥珠单抗、曲妥珠单抗和紫杉类药物标准一线治疗后的有效管理提供了信息，并为早期乳腺癌（EBC）中已接受过这些药物及T-DM1治疗患者的复发管理提供了指导。我们还讨论了临床试验中的新型抗HER2靶向药物及其组合，这些未来可能被纳入标准治疗模式。
肿瘤(癌症)患者之家