Eiger Daniel, Agostinetto Elisa, Saúde-Conde Rita, de Azambuja Evandro
Academic Promoting Team, Institut Jules Bordet, L'Universite Libre de Bruxelles (U.L.B.), 1000 Brussels, Belgium.
Medical Oncology and Haematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy.
Cancers (Basel). 2021 Mar 1;13(5):1015. doi: 10.3390/cancers13051015.
Since human epidermal growth factor receptor-2 (HER2) characterization, going through clinical research and regulatory approval of HER2-targeted therapies, much has elapsed and is still unfolding. Hitherto, only breast cancer (BC) patients with HER2 immunohistochemistry 3+ or with HER2 gene fluorescence in-situ hybridization (FISH) amplification (a.k.a., HER2-positive BC) have benefited from anti-HER2 agents. In recent years, however, much of the research effort has been expanded, with positive outcomes being reached for formerly known HER2-negative BC that yet express HER2 to some degree (HER2 immunohistochemistry 1+ or 2+, but FISH negative) and are currently being classified as HER2-low BC for the purpose of trial enrollment. In this sense, our aim is to review the body of evidence of HER2-low BC that led to the study of first-generation anti-HER2 agents, like trastuzumab, and how they have failed to achieve any clinical applicability in this setting. In addition, we review new data that is leading to the growing success of the new generation of drugs, especially the promising HER2-directed antibody-drug conjugates. A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.
自人类表皮生长因子受体2（HER2）被鉴定以来，历经HER2靶向治疗的临床研究和监管审批，许多时间已经过去，且相关进展仍在不断展开。迄今为止，只有HER2免疫组化3+或HER2基因荧光原位杂交（FISH）扩增的乳腺癌（BC）患者（即HER2阳性BC）从抗HER2药物中获益。然而，近年来，研究工作大量扩展，对于一些以前已知的HER2阴性BC患者取得了积极成果，这些患者仍在一定程度上表达HER2（HER2免疫组化1+或2+，但FISH阴性），目前为了试验入组被归类为HER2低表达BC。从这个意义上说，我们的目的是回顾导致第一代抗HER2药物（如曲妥珠单抗）研究的HER2低表达BC的证据体系，以及它们在这种情况下如何未能实现任何临床应用。此外，我们回顾了导致新一代药物越来越成功的新数据，尤其是有前景的HER2导向抗体药物偶联物。我们还对正在进行的联合抗HER2药物与免疫疗法、内分泌疗法和CDK4/6抑制剂等不相关药物的巩固性临床试验背后的原理进行了叙述性综述。希望所有这些正在进行的研究工作至少能在一定程度上，将抗HER2药物在HER2阳性疾病中所见的生存获益扩展到更大比例的HER2低表达BC患者。
