What factors increase the risk of pancreatic cancer?

Risk Factors for Pancreatic Cancer

Cigarette smoking is the single most important modifiable risk factor for pancreatic cancer, accounting for 25-30% of cases, and should be the primary target for risk reduction counseling. 1

Genetic and Familial Risk Factors

Family history represents one of the strongest risk factors for pancreatic cancer and warrants systematic assessment in all patients:

• Having one first-degree relative with pancreatic cancer increases risk 4.6-fold, while two affected first-degree relatives increase risk 6.4-fold 1
• Early-onset pancreatic cancer in the family (diagnosed before age 50) confers even higher risk, with a standardized incidence ratio of 9.31 1
• Approximately 10% of pancreatic cancers have a familial component, though 80% of these families have no identifiable genetic mutation 1

Specific genetic syndromes with elevated pancreatic cancer risk include:

• Peutz-Jeghers syndrome (STK11 mutation): 132-fold increased risk 1
• Hereditary pancreatitis (PRSS1/SPINK1 mutations): 26-87-fold increased risk, with 40% cumulative lifetime risk by age 75 1
• BRCA2 mutations: Most common inherited disorder in familial pancreatic cancer, with prevalence of 2-6% in moderate-to-high-risk families 1
• Other pathogenic germline alterations: BRCA1, ATM, PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53 1

Clinical action required: All patients with pancreatic cancer should undergo germline genetic testing regardless of family history, as typical clinical features poorly predict mutation carriers 1. Take a thorough family history specifically documenting pancreatitis, melanoma, and cancers of the pancreas, colorectum, breast, and ovaries in first- and second-degree relatives 1.

Chronic Pancreatitis and Diabetes

Chronic pancreatitis increases pancreatic cancer risk 5-15-fold, with hereditary pancreatitis conferring the highest risk (50-70-fold) 1, 2:

• Alcohol-induced chronic pancreatitis accounts for 60-70% of chronic pancreatitis cases in Western countries 2
• The mechanism involves chronic inflammation leading to progressive pancreatic tissue destruction 2

Diabetes mellitus demonstrates a complex bidirectional relationship with pancreatic cancer:

• Diabetes increases pancreatic cancer risk (HR 1.4-2.2) 1
• New-onset diabetes in patients over age 50 may be an early manifestation of pancreatic cancer and warrants investigation 3
• Patients with pancreatic cancer and diabetes have significantly higher mortality (HR 1.52) compared to those without diabetes 1

Dietary and Lifestyle Factors

Modifiable dietary risk factors include:

• High intake of red meat, processed foods, saturated fat, and butter independently increase risk 1
• Heavy alcohol consumption (beyond its role in causing chronic pancreatitis) increases risk by approximately 9% 1
• Protective factors: High fruit and folate intake may reduce risk 1

Obesity increases pancreatic cancer risk 1.2-1.5-fold 1, making weight loss a reasonable risk-reduction strategy for high-risk individuals 1.

Other Risk Factors

Additional factors with established associations:

• Non-O blood group: 1.4-fold increased risk, accounting for 13-19% attributable fraction 1
• Helicobacter pylori infection: 1.5-fold increased risk 1
• Ashkenazi Jewish ancestry: Higher likelihood of BRCA1/2 mutations (5.5-19% prevalence) 1
• Age: Majority of cases diagnosed above age 65, with mean age at onset of 71 years for men and 75 years for women 1, 3

Risk Reduction Strategies

For all patients, especially those with familial risk:

• Smoking cessation is mandatory 1, 2
• Weight loss for overweight/obese individuals 1
• Avoidance of heavy alcohol consumption 1
• Dietary modification: reduce red meat and processed foods, increase fruit and vegetable intake 1

For high-risk individuals with genetic predisposition:

• Referral for genetic counseling and testing 1
• Consider pancreatic cancer screening beginning at age 50, or 10 years younger than earliest family diagnosis, whichever is earlier 1
• For CDKN2A carriers: screening may begin at age 40 1
• For STK11 carriers: screening may begin at age 30-35 1

Common pitfall: Do not dismiss family history concerns in patients without identified genetic mutations, as 80% of familial pancreatic cancer cases have no known genetic cause but still carry significantly elevated risk 1.