Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, AP-HP, Paris Descartes University, 20 rue Leblanc, 75015, Paris, France.
Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, 75006, Paris, France.
Drugs. 2020 Mar;80(4):401-415. doi: 10.1007/s40265-020-01272-5.
The discovery of human epidermal growth factor receptor 2 (HER2) overexpression in 15-20% of gastric adenocarcinomas has been a key advance in the global care of this disease. Validated by the ToGA trial in the first-line setting of advanced HER2-positive (+) gastric cancer (GC), trastuzumab, an anti-HER2 monoclonal antibody (mAb), was the first therapeutic agent to significantly improve the prognosis of these patients. Since these results, many attempts have been made to improve the clinical outcomes of patients with HER2+ GC. However, all the other HER2-targeting molecules have failed to show a survival benefit in large phase III studies. The value of continuing trastuzumab after disease progression has been suggested by several retrospective studies. However, recent results of a randomized phase II trial showed no benefit from this strategy. On the other hand, novel therapeutic methods, such as immunotherapy, are emerging as new tools in the strategy of care of advanced GC, even if their benefit in the specific HER2+ population remains undetermined. Furthermore, substantial progress has been made in the understanding of the mechanisms leading to resistance to anti-HER2 therapies, and in the screening methods to detect them, thus opening new perspectives. The aim of this review was firstly to summarize the existing data on the specific strategy of care of HER2+ advanced GC, and secondly, to describe current knowledge regarding the potential mechanisms of resistance to HER2-targeting therapies. Lastly, we report the prospects for overcoming these potential obstacles, from future therapeutic strategies to new detection methods.
人类表皮生长因子受体 2（HER2）在 15-20%的胃腺癌中的过表达的发现，是该疾病全球治疗的重要进展。在曲妥珠单抗治疗 HER2 阳性（+）晚期胃癌（GC）的一线治疗中，ToGA 试验验证了曲妥珠单抗，一种抗 HER2 单克隆抗体（mAb），是第一种显著改善这些患者预后的治疗药物。自这些结果公布以来，人们已经尝试了许多方法来改善 HER2+GC 患者的临床结局。然而，所有其他针对 HER2 的分子都未能在大型 III 期研究中显示出生存获益。几项回顾性研究表明，在疾病进展后继续使用曲妥珠单抗可能具有价值。然而，最近一项随机 II 期试验的结果显示，这种策略没有获益。另一方面，免疫疗法等新型治疗方法正在作为晚期 GC 治疗策略的新工具出现，尽管它们在特定的 HER2+人群中的获益仍不确定。此外，人们对导致抗 HER2 治疗耐药的机制以及检测这些耐药机制的方法有了更深入的了解，从而开辟了新的前景。本文综述的目的首先是总结目前关于 HER2+晚期 GC 特定治疗策略的现有数据，其次是描述目前关于针对 HER2 靶向治疗耐药的潜在机制的知识。最后，我们报告了克服这些潜在障碍的前景，包括未来的治疗策略和新的检测方法。
