Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15–20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.

ERBB2（编码 HER2 的基因）的扩增和/或过度表达存在于 15-20% 的浸润性乳腺癌中，并且与侵袭性表型和不良临床结果相关。分子生物学和药物开发方面的不懈研究努力导致了多种 HER2 靶向疗法的实施，包括单克隆抗体、酪氨酸激酶抑制剂和抗体药物偶联物，构成了肿瘤学从实验室到临床转化的最佳范例之一。每种药物类别都改善了患者的治疗效果，重要的是，不同 HER2 靶向疗法的组合和序贯使用提高了早期疾病的治愈率，并大大延长了晚期疾病患者的生存期。在这篇综述中，我们描述了 HER2 阳性晚期乳腺癌治疗现代范例发展的关键步骤，包括选择和测序新一代 HER2 靶向疗法，并总结了关键研究的疗效和安全性结果。然后，我们概述了目前已知与 HER2 靶向治疗耐药相关的因素，例如 HER2 瘤内异质性、替代信号通路的激活和免疫逃逸机制，以及未来可能用于克服的潜在策略这种抵抗力并进一步改善患者的治疗效果。