Risk factors associated with early-onset versus later-onset pancreatic cancer: A systematic review and meta-analysis.

Abstract

e16487 Background: The incidence of early-onset pancreatic cancer (EOPC), predominantly pancreatic ductal adenocarcinoma, is increasing worldwide, yet its risk factor profile remains incompletely understood. While established pancreatic cancer risk factors are well characterized in older populations, it is unclear whether these exposures differentially characterize early-onset versus later-onset disease. We conducted a systematic review and meta-analysis to synthesize available evidence on factors associated with EOPC. Methods: We systematically searched MEDLINE, PubMed, Embase, Scopus, and Cochrane CENTRAL from inception to January 2026 for studies evaluating associations between established pancreatic cancer risk factors and EOPC. Eligible studies included adult patients with pancreatic cancer and compared early-onset disease, as defined by individual studies, with later-onset pancreatic cancer (LOPC). Random-effects meta-analyses pooled odds ratios (ORs) with 95% confidence intervals (CIs); heterogeneity was assessed using I². Results: Nineteen retrospective studies conducted between 1975 and 2022 across 11 countries were included, comprised of 1,486,388 participants. Definitions of EOPC varied across studies, with age thresholds ranging from < 40 to < 60 years, while LOPC was defined using thresholds from > 40 to > 70 years. In pooled case–case analyses comparing EOPC with LOPC, several established risk factors were associated with higher odds of early-onset disease. Alcohol exposure was associated with higher odds of EOPC (5 studies; n = 5,853; pooled OR = 1.40, 95% CI 1.08–1.81; p = 0.011; I² = 0.0%). Diabetes mellitus was similarly associated with lower odds of EOPC (5 studies; n = 4,476; pooled OR = 0.29, 95% CI 0.10–0.80; p = 0.016), with substantial heterogeneity (I² = 90.4%). Male sex was associated with higher odds of EOPC (11 studies; n = 1,461,133; pooled OR = 1.33, 95% CI 1.27–1.39; p < 0.0001; I² = 79.3%), with no evidence of small-study effects (Egger’s test p = 0.065). Smoking was associated with higher odds of EOPC (8 studies; n = 7,932; pooled OR = 1.79, 95% CI 1.32–2.42; p = 0.0209; I² = 57.6%). No statistically significant differences in age at diagnosis were observed for family history of pancreatic cancer, obesity, or pancreatitis. Genetic risk factors were not pooled due to insufficient data. Conclusions: Alcohol use, male sex, and smoking were associated with higher odds of EOPC, while diabetes mellitus was inversely associated with EOPC. These findings suggest that EOPC may represent a distinct etiologic subtype characterized by earlier exposure to certain lifestyle-related risk factors, alongside reduced contribution from cumulative metabolic comorbidity.