大约20%的乳腺癌（BCs）过表达人类表皮生长因子受体2（HER2），这是一种具有酪氨酸激酶活性的跨膜糖蛋白，由ERBB2基因编码。在历史上，HER2过表达与疾病复发率增加和预后较差有关。然而，不同类型的抗HER2化合物和组合疗法的不断增加正在逐步改善HER2阳性乳腺癌患者的预后，因此需要专业知识来优先考虑整体生存期延长和生活质量，并且不能忽视用低耗损率获得进一步治疗的可行性。在这种情况下，替卡替尼是一种口服酪氨酸激酶抑制剂，最近在监管机构的批准下被使用，证据来自HER2CLIMB，这是一项随机对照试验，将转移性乳腺癌患者随机分配到接受替妥珠单抗和卡培他滨联合替卡替尼或安慰剂治疗。该研究的一个独特特点是将有新发或活跃脑转移的患者纳入研究，这是临床试验中传统上被排除的人群。因此，HER2CLIMB为乳腺癌和脑转移患者的整体生存期延长提供了第一个扎实的证据，满足了长期存在的医学需求，尤其是考虑到HER2阳性疾病患者中中枢神经系统转移的高发生率。本综述概述了替卡替尼治疗晚期乳腺癌的分子和临床背景。重点关注了这种治疗创新的技术之旅，从临床前数据到临床实践。版权所有©2023 Elsevier Ltd. 保留所有权利。

Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice.Copyright © 2023 Elsevier Ltd. All rights reserved.