Human Epidermal Growth Factor Receptor 2 (HER2) in Advanced Gastric Cancer: Current Knowledge and Future Perspectives

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.