HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.
HER2阳性乳腺癌约占所有乳腺癌病例的15-20%。该亚型具有侵袭性强、预后差的特点。抗HER2疗法显著改善了疾病的自然病程。尽管如此，约20%的患者仍因原发性或获得性治疗耐药而复发，且转移性病灶目前仍无法治愈。本文综述了抗HER2治疗耐药的主要机制，重点关注新型HER2靶向疗法。抗HER2药物的进展包括开发新型抗体偶联药物，其在偶联工艺、新型连接子及有效载荷方面均有改进。此外，德曲妥珠单抗增强了恩美曲妥珠单抗的疗效，新型药物曲妥珠单抗-duocarmazine目前正在进行临床试验以评估其疗效。抗HER2药物与其他药物的联合应用也在评估中。免疫检查点抑制剂的加入对部分患者显示出一定获益，这表明需要有效的生物标志物对患者进行精准分层。此外，CDK4/6抑制剂和酪氨酸激酶抑制剂也被纳入新治疗策略的设计中。拉帕替尼、奈拉替尼和图卡替尼已获批用于HER2阳性转移患者，但目前仍需通过临床试验优化联合策略、降低毒性并明确最佳适用场景。临床研究应与新生物标志物的发现验证、耐药机制的深入理解及药物作用机制的进一步探索同步加强。
肿瘤(癌症)患者之家