Development, validation, and evaluation of a risk assessment tool for personalized screening of gastric cancer in Chinese populations

Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the fourth leading cause of cancer death worldwide [1]. Nearly three-quarters of all new cases and deaths from GC occur in Asian countries, including China, Japan, and Korea [2]. However, among these three countries, the incidence rates of GC are higher in Japan and Korea, whereas the mortality rate is higher in China [2]. This disparity is mainly due to the differences in the early detection of GC, leading to high 5-year survival rates in Japan (60.3%) and Korea (68.9%) but a much lower rate in China (35.9%) [3]. Therefore, screening is critical to improve early detection and treatment and to ultimately reduce GC mortality in China.

Endoscopic screening has been shown to reduce GC mortality by 40% in Asian countries [4]. In Japan, a national GC screening was implemented in 1983, and endoscopic screening was recommended for individuals aged 50 years and older [5]. In Korea, a nationwide screening program was launched in 1999 to screen individuals aged 40 years and older for GC by either upper endoscopy or upper gastrointestinal series examinations [6]. However, in China, there is still no national screening policy or program, because screening in a huge population is cost-prohibitive and requires the capabilities of local doctors and access to available technology. Recently, an endoscopic screening program showed significant reductions in both incidence and mortality of upper gastrointestinal cancer among local permanent residents aged between 40 and 69 years from six high-risk areas of China [7]. Thus, tailored endoscopic screening in high-risk populations represents a more feasible and cost-effective approach in China.

Currently, the consensus on the GC screening in China is to target the subpopulation aged 40 years or older [8]. However, more than 300 million people in China meet the criteria of the consensus, making it impracticable at present [9]. Several prescreening tools prior to a gastroscopy have been developed for GC, which usually combine Helicobacter pylori (H. pylori) serology tests, serum pepsinogen (PG) I and PG II, and gastrin-17 (G-17) levels [9‐11]. Although these tools are effective in identifying high-risk individuals for GC, these serum biomarkers need to be measured in hospitals or other professional institutions and have inconsistent performance in different populations, leading to additional costs and increased difficulty in screening settings.

A number of risk prediction models based on traditional risk factors have been developed for breast cancer [12], colorectal cancer [13], and lung cancer [14]. However, to date, very few risk prediction models have been developed for GC [9, 11, 15, 16], and none has been used for organized screening programs largely due to the lack of external validations required before translation into practice. Herein, leveraging a nationwide prospective cohort, the China Kadoorie Biobank (CKB), we developed a GC risk score (GCRS) based on examination-free variables from questionnaires. We further validated its effectiveness and usefulness in an independent prospective cohort and a real-world cross-sectional endoscopy screening program, respectively. Finally, based on the GCRS, we developed an online tool, named Risk Evaluation for Stomach Cancer by Yourself (RESCUE) [17], to be utilized by the public for GC risk assessment.

In the present study, by using the largest nationwide prospective cohort in China, we developed a GC risk assessment tool of GCRS based on eleven variables that could be easily determined without any physical examinations. We validated the GCRS with good calibration and discrimination in the independent Changzhou cohort, demonstrating the great potential of GCRS for GC risk prediction and stratification. When applying the GCRS to a real-world endoscopy screening program, we detected approximately 80% of all the identified GC cases in about one-quarter of individuals with high GCRS. To the best of our knowledge, the present study is the first to provide a questionnaire-based GC risk assessment tool based on a large-scale cohort study that can be used for risk stratification in an endoscopic screening setting of the Chinese population.

To date, several risk-prediction models have been developed for GC, but few are translated into practice. For example, the Japan Public Health Center-based Prospective Study (JPHC Study) developed a prediction model including age, sex, smoking status, consumption of high-salt food, family history of gastric cancer, H. pylori antibody, and serum pepsinogen, which resulted in a C-statistic of 0.768 for discrimination [15]. In China, there are two risk prediction models for GC, predominantly based on serum PG I, PG II, gastrin-17 (G-17), and anti-H. pylori antibody, which were developed in a population-based follow-up study [11] and a hospital-based cross-sectional study [9], respectively. These two models also showed good discrimination (C-statistic of 0.803 and area under the curve of 0.76, respectively). However, these risk prediction models, mainly based on one study population, have a potential risk of over-fitting and should be subjected to rigorous external validations in the future. Of note, these abovementioned models based on serology tests not only add additional costs but also increase the degree of screening complexity, which may decrease the overall participation and efficiency. In the present study, we developed the questionnaire-based GCRS by using the largest Chinese cohort and independently validated the tool in an external cohort with good discrimination (Harrell’s C-index: 0.736). The large sample size and rigorous design ensured the quality and applicability of our GC risk assessment tool, which may be useful for tailored screening practices in the general population.

Although screening by endoscopy could reduce the mortality of GC [4, 7], the availability of endoscopic instruments and expertise for mass screening remains questionable and impractical. Even though some countries, such as Japan and Korea, have implemented a national GC screening program [5, 6], most have adopted screening approaches for high-risk populations. The initial prescreening tools, generally based on risk prediction models, provide a tailored screening for the general population. In the present study, we evaluated the initial GCRS in the Yangzhou screening program and found that 81.6% of the identified GC cases were correctly allocated to undergo endoscopy in the at-high-risk individuals who accounted for only about one-quarter of all screenings; moreover, none of the GC cases was detected in participants at low risk, suggesting that the low-risk populations could also be identified reliably. Thus, the developed GCRS may be employed to a tailored endoscopy screening, which could substantially decrease endoscopy workload and cost, compared with endoscopy for all. However, the incidence rate of GC changed remarkably in different areas across China [39], while the developed GCRS may represent the average level of the Chinese populations. Therefore, further external validation with re-calibrated estimates based on local incidence would be necessary for clinical use [40], especially for setting actionable cut points in different areas of China.

Nevertheless, additional studies are warranted to address several concerns regarding the applicability of the GCRS. First, although the GCRS was developed, replicated, and evaluated in twelve geographic areas of China, the tool needs to be evaluated or optimized in other areas or populations. For example, efforts are required to evaluate the generalizability of the GCRS to hospital-based screening. Second, the GCRS may help inform decision-making for GC screening, but several questions remain to be addressed, including optimal cutoff points of risk stratification, starting and stopping ages, and intensity of screening. Third, the prevalence rate of GC in the CKB was lower than expected, which was probably due to volunteer bias that individuals with GC were not inclined to attend the survey in the CKB at baseline. Nevertheless, the prevalent GC cases might be undetected through questionnaires, which could also contribute to the low prevalence rate and lead to inaccurate estimates of predictors. Fourth, although previous cancer diagnosis was used in this study as a predictor for GC, which was in line with that in lung cancer [41], additional studies are warranted to explore the potential benefit of endoscopic screening in prevalent cancer patients. Fifth, concern still exists regarding whether or how much the GCRS-directed screening can improve the cost-effectiveness of endoscopic screening, compared with the current “one-size-fits-all” approach, which needs to be further assessed in future studies. At last, H. pylori infection is the most important risk factor of GC, and we have also reported that a polygenic risk score with 112 genetic variants is effective for risk stratification of GC [23]. However, the information was not available in the discovery and validation cohorts in this study. Therefore, additional studies are needed to develop a comprehensive score with the GCRS, H. pylori infection status, polygenic risk score, and other serum biomarkers (e.g., PG I, PG II, and gastrin-17) to further optimize the risk prediction of GC. Moreover, the utility of these scores needs to be evaluated in endoscopy screening practices.

Several limitations of the present study should be noted. First, the lifestyle and personal history information was self-reported at baseline, which may cause some misclassifications and have biased the risk estimates of variables included in the GCRS. Second, we only evaluated the overall GC risk, but the risk estimate might differ depending on tumor location, stage, and subtype that were not obtained with details in the follow-up of cohorts. Third, H. pylori infection, the most important risk factor of gastric cancer [42], and family history of upper gastrointestinal cancers [43] were unavailable in the development and validation cohorts and thus not included in the GCRS.

Based on a three-stage design, we reported a high-performance GC risk assessment tool GCRS that can be easily accessible to the general population. This may be useful for participants to be aware of their GC risk and thus to adopt healthy lifestyles to reduce GC risk. Importantly, this tool can be integrated into health management or physical examination systems and be used to direct individuals to a tailored endoscopy screening by risk stratification. The web-based GCRS, i.e., RESCUE, is now available with risk prediction and recommendations for lifestyle changes and a tailored endoscopy screening. These efforts are likely to facilitate personalized GC prevention and lead to reductions in GC incidence and mortality in China.