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Evolving Landscape of HER2-Targeted Therapies for Gastric Cancer Patients

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Opinion Statement

Gastric cancer (GC) is a deadly disease worldwide, and trastuzumab in combination with chemotherapy has been the standard first-line treatment for HER2-positive GC following the TOGA trial. Besides adjuvant therapy, HER2-directed therapy is widely used as neoadjuvant or translational therapy, and survival benefit even surgical opportunities is seen in these patients. However, resistance is not rare in recent years, and the second-line treatment for trastuzumab beyond progression has received widespread attention in GC. Moreover, current evidence cannot recommend trastuzumab for patients with IHC1+ HER2 low expression GC yet. Researchers are currently investigating whether GC patients with low HER2 expression could also benefit from HER2-directed therapies. In addition to using HER2 as a target for targeted therapy, HER2-mediated targeted delivery of cytotoxic drugs and targeted immunity have made important contributions to overcoming trastuzumab resistance in recent trials. HER2/neu-derived peptide epitopes vaccination and HER2-specific chimeric antigen receptor (CAR) therapy focus on reestablishing anti-tumor immunity in different ways and show significant anti-tumor activity. Other antibodies that target different regions of the HER2 receptor or block key downstream pathways such as AKT or PI3K also offer potential anti-tumor activity against HER2. HER2 use in GC will not be hampered by resistance or low expression and will play a bigger role. We review the current efforts to enable GC patients with trastuzumab-resistant and HER2 low-expressing accessible to HER2 targeted therapy and present our consideration for future HER2 in GC.

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Data Availability

All data supporting this study have been presented in the full text. Other relevant materials can be obtained on reasonable request to the corresponding author.

Figures and tables used in this article are original and have not been published previously.

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Funding

This research was supported by National Natural Science Foundation of China (82473266, 82160129), Key Project of Science and Technology in Gansu province (22ZD6FA054), Major scientific research project for scientific and technological innovation in the health industry of Gansu Province (GSWSZD-2024-17), General Project of Gansu Province Joint Research Fund (24JRRA929), Key Talents Project of Gansu Province (2019RCXM020), Science and Technology Project of Chengguan District of Lanzhou City (2020SHFZ0039, 2020JSCX0073), Medical Research Innovation Ability Improvement Project of Lanzhou University (lzuyxcx-2022-160), Excellent Textbook Cultivation Project of Lanzhou University (lzuyxcx-2022-45).

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  1. Lanzhou University Second Hospital, Lanzhou, 730030, China

    Lijuan He, Ben Liu, Zhuanfang Wang, Qinying Han & Hao Chen

  2. Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China

    Lijuan He, Ben Liu, Zhuanfang Wang, Qinying Han & Hao Chen

  3. Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, 730030, China

    Hao Chen

  4. Humanized animal model laboratory, Lanzhou University Second Hospital, Lanzhou, 730030, China

    Hao Chen

  5. Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

    Hao Chen

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He, L., Liu, B., Wang, Z. et al. Evolving Landscape of HER2-Targeted Therapies for Gastric Cancer Patients. Curr. Treat. Options in Oncol. 26, 260–277 (2025). https://doi.org/10.1007/s11864-025-01300-0

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