Fong Caroline, Chau Ian
Gastrointestinal/Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
Cancers (Basel). 2022 Aug 6;14(15):3824. doi: 10.3390/cancers14153824.
Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. Although limited progress was made in the decade following ToGA, there is now an abundance of novel therapeutic approaches undergoing investigation in parallel. Additionally, new data from randomised trials have indicated efficacy of the antibody-drug conjugate trastuzumab deruxtecan in chemorefractory patients and increased responses with the addition of first-line immune checkpoint blockade to trastuzumab and chemotherapy. This review will outline the data supporting HER2 targeting in gastric cancers, discuss mechanisms of response and resistance to HER2-directed therapies and summarise the emerging therapies under clinical evaluation that may evolve the way we manage this subset of gastric cancers in the future.
胃癌是全球癌症相关死亡的主要原因。20%的胃癌存在人表皮生长因子受体2（HER2）基因扩增导致的过表达，这定义了一个适合HER2靶向治疗的亚组。具有开创性的ToGA研究使得单克隆抗体曲妥珠单抗联合铂类-氟嘧啶一线化疗用于HER2阳性胃癌的治疗成为标准治疗方案。尽管在ToGA研究后的十年里进展有限，但现在有大量新的治疗方法正在同时进行研究。此外，随机试验的新数据表明，抗体药物偶联物曲妥珠单抗德卢替康对化疗难治性患者有效，并且在曲妥珠单抗和化疗基础上加用一线免疫检查点阻断剂可增加反应。本综述将概述支持胃癌HER2靶向治疗的数据，并讨论对HER2靶向治疗的反应和耐药机制，总结正在进行临床评估的新兴疗法，这些疗法可能会改变我们未来治疗这一亚组胃癌的方式。
