Serum Pepsinogen as a Biomarker for Gastric Cancer in the United States: A Nested Case–Control Study Using the PLCO Cancer Screening Trial Data

Background: Gastric cancer lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, a gastric cancer precursor, and may be useful to detect persons at increased risk of gastric cancer. Methods: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States between 1993 and 2001. ELISA-based pepsinogen tests were conducted on prediagnostic serum samples of 105 PLCO participants who developed gastric cancer and 209 age, sex, and race-matched controls. Pepsinogen positive (PGþ) was defined as pepsinogen I ≤ 70 mg/L and pepsinogen I/II ratio ≤3.0. Results of conditional logistic regression models, and sensitivity and specificity, of PGþ for gastric cancer are reported. Results: Gastric cancer cases were more likely to be PGþ (31.4% vs. 5.5%, P < 0.001) at baseline than controls. Compared to PG-, PGþ was associated with an 8.5-fold increased risk for gastric cancer [95% confidence interval (CI) ¼ 3.8–19.4]. This risk remained significant after adjusting for Helicobacter pylori, family history of gastric cancer, education, smoking, and BMI (aOR, 10.6; 95% CI, 4.3–26.2). In subgroup analysis, PGþ individuals were 11-fold more like to develop non-cardia gastric cancer (OR, 11.1; 95% CI, 4.3–28.8); conversely, they were not significantly more likely to develop cardia gastric cancer (OR, 2.0; 95% CI ¼ 0.3–14.2). PGþ status yielded low sensitivity but high specificity for both noncardia (44.3%; 93.6%) and cardia gastric cancer (5.7%; 97.2%). Conclusions: Prediagnostic serum pepsinogen levels from a large, prospective cohort study were associated with risk of gastric cancer, particularly noncardia gastric cancer. Impact: PG status may identify individuals at higher risk of noncardia gastric cancer for targeted screening or interventions.