Dynamic HER2 reassessment and precision sequencing after trastuzumab in HER2-positive advanced gastric cancer

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has transformed the treatment of HER2-positive advanced gastric cancer. Trastuzumab-based chemotherapy has been established as the first effective biomarker-defined approach for this disease; however, the frequent loss of HER2 expression after treatment has limited the benefits of continued HER2 targeting beyond progression. This biological instability may explain why earlier attempts to extend HER2-targeted therapy after trastuzumab did not consistently produce clinical benefits. In the phase III DESTINY-Gastric04 trial, trastuzumab deruxtecan emerged as the preferred second-line treatment for patients with persistent HER2-positive disease on repeat biopsy, highlighting the importance of contemporaneous tumor biology over archival HER2 status. Key challenges remain, particularly in decision making when repeat biopsy is not feasible and when managing tumors that convert to nonactionable HER2 states after trastuzumab treatment. In this review, we examine the biological and clinical implications of dynamic HER2 reassessment and outline a practical framework for treatment sequencing in advanced gastric cancer.