Liquid biopsies for the diagnosis of early-stage gastric cancer: A 5-year systematic review

Gastric cancer remains one of the leading causes of cancer-related mortality worldwide, largely due to its late-stage diagnosis. Liquid biopsy has emerged as a promising, minimally invasive method for early cancer detection, leveraging circulating biomarkers such as nucleic acids, extracellular vesicles, and tumor cells. Objective: This systematic review aimed to evaluate the emerging role of liquid biopsy as a diagnostic tool for the early detection of primary gastric cancer, focusing on the past five years of published research. Methods: Following PRISMA guidelines and based on the PICO framework, a comprehensive literature search was conducted across PubMed and Scopus databases, yielding 620 articles. After screening and eligibility assessment, 16 studies were included. Quality evaluation was performed using the QUADAS-2 tool and Analytical Validation Summaries. Results: The included studies demonstrated consistently high diagnostic performance of various liquid biopsy-derived biomarkers. Notably, circulating non-coding RNAs-particularly miRNAs, circRNAs, lncRNAs, and tsRNAs-showed high sensitivity and specificity in early-stage gastric cancer detection. DNA methylation signatures, cfDNA fragmentomics, lipidomic profiles, and folate receptor-positive CTCs, also emerged as valuable diagnostic modalities. Most studies reported area under the curve (AUC) values exceeding 0.85, with several outperforming conventional serum markers, such as CEA and CA19-9. Conclusions: Liquid biopsy holds significant promise as a non-invasive, accurate diagnostic approach for early gastric cancer. RNA-based and cfDNA-based biomarkers, in particular, exhibit strong potential for integration into routine screening protocols. Further large-scale, prospective validation studies are warranted to support clinical translation and standardization.