Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.
人表皮生长因子受体2（HER2）酪氨酸激酶在20%的乳腺癌中过度表达，与HER2阴性乳腺癌相比预后较差。传统治疗方案通常采用化疗联合HER2靶向单克隆抗体，如曲妥珠单抗和帕妥珠单抗。以曲妥珠单抗-美坦新偶联物（T-DM1）和曲妥珠单抗-德鲁替康（T-DXd）为代表的HER2靶向抗体偶联药物（ADCs）已成为乳腺癌治疗的新型药物类别。这类药物通过连接子将细胞毒性载荷与单克隆抗体结合，构成ADC的基本结构。为克服对T-DM1和T-DXd的耐药性，新型联合疗法及序贯治疗方案正在积极探索中。随着能更精准攻击癌细胞且毒性更低的ADC药物不断涌现，HER2靶向治疗领域正快速发展。本文综述了HER2靶向ADC的研究现状，并对处于研发阶段的候选药物进行详细评述。临床试验对于确定最佳给药方案、阐明耐药机制、筛选最适获益人群具有关键作用。这些新型ADC药物引领着靶向癌症治疗的新时代，有望改善HER2阳性及HER2低表达乳腺癌患者的临床结局。
Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer
肿瘤(癌症)患者之家