Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo; Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo.
ESMO Open. 2024 Sep;9(9):103679. doi: 10.1016/j.esmoop.2024.103679. Epub 2024 Aug 22.
Therapeutic developments in the targeting of human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer have followed the dramatic success of HER2-expressing breast cancer treatment, which has facilitated the expansion of indications for anti-HER2 agents to include not only conventional HER2-positive breast cancer, but also HER2-low and HER2-ultralow subgroups. The targetability of HER2-low gastric cancer, however, has yet to be established. Hence, further studies are needed to comprehensively understand the clinicopathological features, specific gene alterations, and distinct tumor immune microenvironment of HER2-low gastric cancer and compare them with those for HER2-positive or -negative gastric cancer. Antibody-drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable. In this context, a deeper understanding of the novel anti-HER2 agents, including antibody-drug conjugates, bispecific T-cell engager antibodies, and a combination of these agents, as well as new forms of immunomodulatory agents are also required. Redefining and re-categorizing HER2 status through not only immunohistochemistry/fluorescence in situ hybridization but also evaluating ERRB2 copy number gain or protein overexpression levels measured using DNA or RNA sequencing might be helpful for identifying populations with HER2-expressing tumors who would ideally benefit from anti-HER2 treatment. The current paper reviewed recent clinical trials, focusing particularly on HER2-low gastric cancer together with basic/translational findings, and discuss perspectives on further therapeutic development in the treatment of this distinct subgroup.
在针对人表皮生长因子受体 2（HER2）表达的胃癌的治疗方法取得显著进展之后，HER2 表达型乳腺癌的治疗也取得了巨大成功，这使得抗 HER2 药物的适应证不仅扩大到了常规的 HER2 阳性乳腺癌，还扩大到了 HER2 低表达和 HER2 超低表达亚组。然而，HER2 低表达胃癌的靶向性尚未得到证实。因此，需要进一步研究以全面了解 HER2 低表达胃癌的临床病理特征、特定基因改变和独特的肿瘤免疫微环境，并将其与 HER2 阳性或阴性胃癌进行比较。针对 HER2 的抗体药物偶联物在使 HER2 低表达胃癌具有靶向性方面发挥着重要作用。在这种情况下，还需要更深入地了解新型抗 HER2 药物，包括抗体药物偶联物、双特异性 T 细胞衔接抗体以及这些药物的联合应用，以及新型免疫调节药物。通过免疫组织化学/荧光原位杂交不仅评估 ERRB2 拷贝数增加或使用 DNA 或 RNA 测序测量的蛋白过表达水平，重新定义和重新分类 HER2 状态，可能有助于识别具有 HER2 表达肿瘤的人群，这些人群最适合接受抗 HER2 治疗。本文综述了最近的临床试验，特别是针对 HER2 低表达胃癌的临床试验，同时结合基础/转化研究结果，讨论了进一步治疗这一独特亚组的治疗方法的发展前景。
