Abstract:

Gastric cancer is a prevalent malignant neoplasm globally, characterized by insidious onset, lack of specific clinical manifestations, and a tendency for patients to present at advanced stages with poor prognosis. Therefore, the quest for highly specific and sensitive biomarkers to assist in diagnosis, guide treatment, and predict prognosis holds paramount significance. Circulating tumor DNA (ctDNA), consisting of cell-free DNA fragments released by tumor cells into the plasma, carries tumor-specific genetic features and epigenetic alterations. In comparison to conventional tissue biopsies, ctDNA offers numerous advantages. It enables the capture of tumor genomic profiles from minimally invasive blood samples, overcomes tumor heterogeneity, and allows for dynamic monitoring of treatment response and prediction of recurrence risk. In the realm of early diagnosis, researchers have developed a detection method called CancerSEEK by combining peripheral blood ctDNA mutations with protein markers, achieving a sensitivity of over 69% in the early detection of gastric, esophageal and pancreatic cancers. Another study utilized a combined detection of 153 methylated DNA sites to diagnose stage Ⅰ, Ⅱ, and Ⅲ gastric cancer with sensitivities of 44%, 59% and 78%, respectively, and a specificity of 92%. Regarding treatment guidance, ctDNA testing facilitates the selection of gastric cancer patients who may benefit from targeted therapies against human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 2 (FGFR 2) and epidermal growth factor receptor (EGFR). Furthermore, immunotherapy in combination with chemotherapy has become the standard treatment regimen for advanced gastric cancer. Evaluating microsatellite status, tumor mutation burden and EB virus-associated gastric cancer through ctDNA analysis can predict the efficacy of immunotherapy. However, specific gene mutations such as TGFBR2, RHOA and PREX2 indicate a poor response to immunotherapy. For gastric cancer patients undergoing neoadjuvant or palliative chemotherapy, the dynamic changes in ctDNA copy number instability, copy number variation and mutation allele frequency load during chemotherapy significantly correlate with treatment efficacy. Dynamic monitoring through ctDNA analysis is beneficial for timely adjustment of treatment strategies before imaging changes occur. In the realm of predicting recurrence and prognosis, research has shown that minimal residual disease (MRD) may be the primary cause of post-treatment relapse in patients with locally advanced cancer, which has been confirmed through follow-up studies in breast, lung and colorectal cancers. The utilization of ctDNA testing to detect postoperative MRD in gastric cancer has revealed that ctDNA positivity at any time point during follow-up is associated with an increased risk of recurrence. Furthermore, patients with ctDNA-positive results experience shorter disease-free survival and overall survival, with a median lead time of 4.5 to 6.0 months compared to radiographic recurrence. Additionally, ctDNA analysis has shown correlations between TP53 mutations, MET amplification, THBS1 and TIMP-3 methylation, and tumor progression or peritoneal metastasis, indicating similarly poor prognosis. Despite the tremendous potential of ctDNA as a minimally invasive biomarker for tumor screening and monitoring, its application in gastric cancer still faces certain limitations and challenges. This article provided a comprehensive review of the current status and prospects of ctDNA in the field of gastric cancer..

Key words: Gastric cancer, Circulating tumor DNA, Liquid biopsy, Biomarker