The age-dependent association of risk factors with pancreatic cancer

Abstract

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.

Keywords: age; lifestyle modification; pancreatic cancer; polygenic risk score; risk factor.

Figure 1.. Age-specific association of pancreatic cancer risk with combinatory risk factors among participants from two prospective cohorts.

Five established risk factors for pancreatic cancer were considered: ever-smoking, obesity, >2-year diabetes, tall height, and non-O blood group. Participants with missing information on more than one of the factors were excluded. (A) Age-stratified hazard ratios by number of risk factors from Cox proportional hazards regression conditioned on age (in months) and calendar year of the survey cycle and sex/cohort and adjusted for race/ethnicity (white, black, other, or unknown). Only lower limits of 95% CIs are shown. Heterogeneity between the age groups of ≤60 years and >70 years was tested by using the random-effects meta-regression method, comparing participants with 3–5 risk factors to those with no risk factors. (B) Age-varying hazard ratios per additional risk factor from Cox B-spline piecewise regression with age as the time scale and conditioned on sex/cohort and calendar year of the survey cycle and adjusted for race/ethnicity (white, black, other, or unknown). Solid curve represents point estimates and dashed curves represent 95% CIs. CI, confidence interval.

Figure 2.. Age-specific proportion of incident pancreatic cancers attributable to established risk factors among participants from two prospective cohorts.

Population attributable fraction estimates the proportion of incident pancreatic cancers in the study population that theoretically would not have occurred if the risk factor had been absent and demographic factors (age, sex, and race/ethnicity) remained unchanged.