HER2-low gastric cancer: is the subgroup targetable?

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 ERR82 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.