Improvement of early gastric cancer detection via a serum-based sequential screening strategy (4S): a prospective large-scale nationwide study in China

Background: Gastric cancer (GC) is one of the most important cancers that warrant screening. A sequential strategy incorporating risk stratification may identify the minority for further endoscopic examination, and biomarkers of gastric atrophy could serve as effective prescreening tools at a low cost. However, its feasibility and acceptability has yet to be fully validated in real-world settings, and in which scenarios a higher early cancer detection rate can be achieved remains unclear. Methods: This multicenter population-based prospective study was conducted in 266 participating institutions throughout China, spanning sites of communities, hospital (outpatient clinics), and physical exam centers, from 2022 to 2024. Adults aged 40–80 years, with or without mild symptoms, meeting the criteria for being at risk of GC, were invited for serological risk evaluation by pepsinogen and gastrin-17 risk panel. Those identified as intermediate or high risk were subsequently recommended for gastroscopy, establishing the serum-based sequential screening strategy (4S) group. Meanwhile, consecutive endoscopic diagnoses were collected in a real-world clinical setting, set as the control group. The rate of gross screening positivity, endoscopic positivity, early cancer detection, and endoscopic compliance, were compared between the two groups, and among the three screening sites within the ‘4S’ group. Findings: In the ‘4S' group, 106,088 participants underwent serological risk assessments and 33.0% (34,979/106,068) fell into the medium to high-risk cohort, of which 33.3% (11,660/34,979) invitees underwent gastroscopy as recommended. Meanwhile, 27,764 subjects were included in the control group. The gross screening positive rate in the ‘4S’ group achieved 3.0‰, and gastroscopy uptake increase with risk prescreening scores (OR = 3.96, P < 0.001). When compared to the control group, the implementation of '4S' screening significantly increased the endoscopic positivity rate (2.2% vs. 0.8%, P < 0.001), and doubled the rate of early cancer detection (62.3% vs. 26.9%, P < 0.001). Compared with screening in hospital setting, community-based screening and physical examinations demonstrated superior capacity to detect tumors at an early stage (77.8% and 77.1% vs. 55.0%, P = 0.008 and 0.002), even though more cases of GC were found in the hospital setting (2.6% vs. 0.9% in community and 1.6% in physical exam). Also, the physical exam showed a poor adherence to gastroscopy (20.5% vs. 41.0% in hospital and 32.2% in community). Community or hospital-based screening showed acceptable cost-effective results by health economic analysis. Interpretation: ‘4S’ strategy stands out as a practical and economical option in China, as well as in countries encountering similar high-risk GC population. Community screening is highly recommended to improve early GC detection. More healthcare education should be introduced to enhance compliance to gastroscopy.