Diagnostic Value of Serum HE4, TFF3, and CA72-4 for Gastric Cancer Stratified by Helicobacter pylori Infection Status

Aims/Background: Gastric cancer remains a leading cause of cancer-related mortality worldwide. Helicobacter pylori (Hp) infection is a major risk factor, but the diagnostic performance of serum biomarkers may vary according to Hp infection status. This study aimed to evaluate the diagnostic value of serum human epididymis protein 4 (HE4), trefoil factor 3 (TFF3), and carbohydrate antigen 72-4 (CA72-4), individually and in combination, for gastric cancer stratified by Hp infection status using a propensity score-matched retrospective case-control design. Methods: This retrospective study was conducted at Jinshazhou Hospital of Guangzhou University of Chinese Medicine, from January 2022 to December 2025. Propensity score matching (1:1 nearest neighbor matching, caliper 0.1) was performed to balance age, sex, body mass index (BMI), smoking history, alcohol consumption history, chronic kidney disease, chronic liver disease, and Hp infection status between groups. After matching, 268 gastric cancer patients and 268 healthy controls were included. Serum levels of HE4, TFF3, and CA72-4 were measured. Between-group comparisons of each marker, stratified by Hp status, were performed. Logistic regression was used to construct combined diagnostic models, and receiver operating characteristic (ROC) curve analysis was performed to evaluate the area under the curve (AUC). Results: After matching, all covariates achieved good balance with standardized mean differences <0.1. In the total population, serum levels of HE4, TFF3, and CA72-4 were significantly higher in the gastric cancer group than in the control group (all p < 0.001). Multivariate logistic regression identified all three markers as independent risk factors for gastric cancer (HE4: odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.03–1.06; TFF3: OR = 1.19, 95% CI: 1.13–1.26; CA72-4: OR = 1.46, 95% CI: 1.34–1.62; all p < 0.001). The combined model yielded an AUC of 0.899 (0.872–0.925) in the total population, significantly superior to any single marker (all p < 0.001). After stratification by Hp status, the AUC of TFF3 was significantly higher in Hp-positive individuals than in Hp-negative individuals (p < 0.001); no significant differences were observed for HE4 or CA72-4 between the two strata (p > 0.05). Conclusion: The diagnostic value of serum HE4, TFF3, and CA72-4 for gastric cancer varies according to Hp infection status. In Hp-positive patients, TFF3 demonstrates significantly higher diagnostic performance compared with Hp-negative individuals. HE4 and CA72-4 demonstrate stable performance across Hp strata, with no statistically significant differences observed. The combined detection of these biomarkers demonstrates favorable diagnostic performance regardless of Hp status. These findings suggest that Hp status-stratified testing provides an auxiliary strategy for optimizing differential diagnosis of gastric cancer.