• Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA. Electronic address: chen_yuan@dfci.harvard.edu.
• Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
• Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA.
• Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, USA.
• Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, USA.
• Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
• Department of Population Science, American Cancer Society, Atlanta, USA.
• Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, USA.
• Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, USA.

BACKGROUND: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors.

PATIENTS AND METHODS: We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program.

RESULTS: In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 [95% confidence interval (CI) 4.11-20.77] among those aged ≤60 years, 3.00 (95% CI 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI 1.10-1.94) among those aged >70 years (P_{heterogeneity} = 3×10^-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (P_{heterogeneity} ≤0.01).

CONCLUSIONS: Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.