Zardavas Dimitrios, Cameron David, Krop Ian, Piccart Martine
From the Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, United Kingdom; and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Am Soc Clin Oncol Educ Book. 2013. doi: 10.1200/EdBook_AM.2013.33.e2.
HER2-positive breast cancer (BC) constitutes a molecular subtype of the disease with an aggressive biologic behavior. Trastuzumab revolutionized the treatment of this disease, changing its natural history. Lapatinib is active in the metastatic setting, approved for patients who were pretreated with trastuzumab. However, resistance to anti-HER2 agents is a major clinical issue, occurring in both early-stage and advanced disease, and new treatment options are clearly needed. An abundance of HER2-targeted agents are being clinically developed: monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates (ADC). Combining HER2-targeted agents in regimens of dual HER2 blockade has already reached clinical practice in the metastatic setting, confirming the preclinical efficacy of enhanced HER2 inhibition. Promising results have been generated in the neoadjuvant setting, and large randomized trials are seeking evidence for dual HER2 blockade in the adjuvant setting. ADC represent another hope for improved treatment outcomes of HER2-positive BC, as exemplified by the positive results of clinical trials employing trastuzumab-DM1 (trastuzumab emtansine, T-DM1). Moreover, an understanding of the molecular mechanisms mediating resistance to HER2 blockade has opened new therapeutic avenues, with several targeted agents entering clinical trials. This paper presents the clinical data of the HER2-targeted agents under development, as well as an overview of the biologic rationale for the development of agents aimed at circumventing anti-HER2 resistance.
人表皮生长因子受体2（HER2）阳性乳腺癌（BC）是该疾病的一种分子亚型，具有侵袭性生物学行为。曲妥珠单抗彻底改变了这种疾病的治疗方式，改变了其自然病程。拉帕替尼在转移性乳腺癌治疗中有效，被批准用于接受过曲妥珠单抗预处理的患者。然而，对抗HER2药物的耐药性是一个主要的临床问题，在早期和晚期疾病中均会出现，显然需要新的治疗选择。大量针对HER2的药物正在进行临床开发：单克隆抗体、小分子抑制剂和抗体药物偶联物（ADC）。在转移性乳腺癌治疗中，将针对HER2的药物联合用于双重HER2阻断方案已应用于临床实践，证实了增强HER2抑制的临床前疗效。在新辅助治疗中已取得了有前景的结果，大型随机试验正在寻找辅助治疗中双重HER2阻断的证据。ADC为改善HER2阳性乳腺癌的治疗结果带来了新希望，以使用曲妥珠单抗-美坦新（ado曲妥珠单抗，T-DM1）的临床试验阳性结果为例。此外，对介导HER2阻断耐药性的分子机制的了解开辟了新的治疗途径，几种靶向药物已进入临床试验。本文介绍了正在开发的针对HER2的药物的临床数据，以及旨在规避抗HER2耐药性的药物开发的生物学原理概述。
