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Targeted therapy for gastric cancer: Current status and future directions (Review)
Dan-Dan Yuan1, Zhong-Xiu Zhu2, Xia Zhang1
1Department of Internal Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China.
Abstract:
According to the 2012 statistics of the International Agency for Research on Cancer (IARC), gastric cancer is the fifth most common malignancy, and the third leading cause of cancer-related deaths worldwide. Conventional chemotherapy and radiation have shown limited efficacy for advanced gastric cancer, showing an overall survival (OS) rate of ~10 months. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is the first approved molecularly targeted agent for HER2-overexpressing gastric cancer, which was found to prolong the OS and the progression-free survival (PFS) of patients. However, HER2 overexpression is present only in a minority of patients with gastric cancer. Hence, other targeted agents are urgently needed. Ramucirumab, a novel human IgG1 monoclonal antibody that selectively targets the extracellular domain of VEGF receptor 2 (VEGFR2), is regarded as a new standard second-line treatment for patients with advanced gastric cancer. The combination of two or more targeted agents directed against two different molecular targets may improve the survival of patients with advanced gastric cancer. Although great efforts have been made, the effect of targeted therapy for gastric cancer is limited. One key reason is that participants in clinical trials for new targeted agents were not selected by detection of the targeted molecule. Here, we review clinical trials related to molecular targets such as anti-epidermal growth factor receptor signaling including anti-HER2 and anti-EGFR1, anti-VEGF signaling, anti-mammalian target of rapamycin (mTOR), tyrosine kinase inhibitors (TKIs) and anti-MET.
Insights
Gastric cancer is a leading cause of death. Targeted therapies show promise but patient selection based on molecular targets is crucial for improving survival in advanced gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gastric cancer is a significant global health issue, ranking as the fifth most common malignancy and third leading cause of cancer-related deaths.
- Conventional treatments like chemotherapy and radiation offer limited efficacy for advanced gastric cancer, with a median overall survival of approximately 10 months.
- While targeted therapies like Trastuzumab (anti-HER2) have shown benefit, their application is limited to a subset of patients with HER2-overexpressing tumors.
Purpose of the Study:
- To review clinical trials of targeted agents for advanced gastric cancer.
- To highlight the need for improved patient selection strategies in targeted therapy trials.
- To discuss various molecular targets and their therapeutic potential in gastric cancer.
Main Methods:
- Review of clinical trials focusing on molecularly targeted agents for gastric cancer.
- Analysis of targeted therapies including those against epidermal growth factor receptor (EGFR) signaling (HER2, EGFR1), vascular endothelial growth factor (VEGF) signaling, mammalian target of rapamycin (mTOR), and MET.
- Examination of tyrosine kinase inhibitors (TKIs) as a class of targeted agents.
Main Results:
- Trastuzumab demonstrated improved survival in HER2-overexpressing gastric cancer.
- Ramucirumab has emerged as a standard second-line treatment for advanced gastric cancer.
- The efficacy of targeted therapies is often limited by the lack of molecular target detection in patient selection for clinical trials.
Conclusions:
- Targeted therapy holds significant potential for advanced gastric cancer, but current approaches are limited.
- Combining targeted agents against different molecular pathways may enhance patient survival.
- Implementing molecular target detection for patient selection in clinical trials is critical for advancing gastric cancer treatment.
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