What genetic testing and regular bloodwork are recommended for a patient with a family history of pancreatic cancer in first-degree relatives for surveillance?

Genetic Testing and Surveillance for Patients with Family History of Pancreatic Cancer

For a patient with first-degree relatives affected by pancreatic cancer, genetic testing should include a comprehensive multigene panel covering BRCA2, BRCA1, PALB2, ATM, CDKN2A, STK11, MLH1, and MSH2, with referral to genetic counseling strongly recommended. 1

Genetic Testing Recommendations

Who Should Be Referred for Genetic Testing

Referral for genetic counseling and testing is indicated when:

• The patient has pancreatic cancer in a first-degree relative plus one additional close relative with pancreatic cancer 1
• The patient has Ashkenazi Jewish ancestry with any family history of pancreatic cancer 1
• Three or more cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer exist in the family 1
• Three or more cases of pancreatic cancer and/or melanoma occur in the family 1

Specific Genes to Test

The most comprehensive approach includes testing for:

• BRCA2 (most common cause, found in 2.8-17% of familial pancreatic cancer families and 3.7% of familial pancreatic cancer probands) 1, 2
• BRCA1 (found in 1.2% of familial pancreatic cancer probands) 2
• PALB2 (found in 0.9-3.7% of patients with familial pancreatic cancer and 0.6% of familial pancreatic cancer probands) 1, 2
• ATM (found in 2.4% of familial pancreatic cancer patients, 4.6% in families with three or more affected individuals) 1
• CDKN2A (found in 2.5% of familial pancreatic cancer probands) 2
• STK11 (Peutz-Jeghers syndrome) 1
• MLH1 and MSH2 (Lynch syndrome) 1

Important context: Multigene panel testing identifies pathogenic germline variants in approximately 16.9% of individuals with family history of pancreatic cancer, with BRCA1/2 accounting for 37% of these mutations. 3 However, approximately 80% of familial pancreatic cancer cases have no identified genetic cause, making comprehensive panel testing essential rather than single-gene testing. 4

Surveillance Bloodwork Recommendations

Routine Laboratory Surveillance

The following bloodwork should be added to regular panels:

• Fasting blood glucose and/or HbA1c should be tested routinely as part of surveillance, with 76.1% expert consensus supporting this recommendation 5
• New-onset diabetes should prompt immediate investigation regardless of the patient's age or time since last surveillance 5

Tumor Marker Testing

CA19-9 is NOT recommended for routine screening:

• CA19-9 should only be used as an additional surveillance test when worrisome features are detected on imaging, not as a primary screening tool 6, 5
• The American Gastroenterological Association explicitly does not recommend CA19-9 as a screening test for pancreatic cancer 6

Critical pitfall: Relying on CA19-9 for screening is inappropriate because it lacks sensitivity and specificity for early pancreatic cancer detection in asymptomatic individuals. 6

Imaging-Based Surveillance (If Criteria Met)

Eligibility for Formal Pancreatic Surveillance

Surveillance is recommended when the patient meets high-risk criteria (>5% lifetime risk):

• Two or more first-degree relatives with pancreatic cancer 6
• One first-degree relative plus one second-degree relative with pancreatic cancer 1
• Identified pathogenic mutation in BRCA2, ATM, PALB2 (with at least one blood relative with pancreatic cancer) 1
• CDKN2A or STK11 mutation carriers (regardless of family history) 1
• BRCA1 mutation carriers (consensus reached for surveillance, though family history criteria remain debated) 1

Surveillance Protocol

When surveillance is indicated:

• Begin at age 50-55 for familial risk without identified mutation, or age 50 (or 10 years younger than youngest affected relative) for mutation carriers 1, 6
• Use alternating MRI/MRCP and endoscopic ultrasound (EUS) at 12-month intervals 6, 5
• Continue annual surveillance when no pancreatic abnormalities are present 5
• Repeat imaging within 3-6 months if concerning abnormalities are detected 5

Critical pitfall: For CDKN2A carriers specifically, do not delay surveillance until age 50—begin at age 40 or 10 years younger than the youngest affected relative due to earlier age of onset in this syndrome. 5

Practical Implementation Algorithm

Step 1: Document Family History

• Record all first- and second-degree relatives with pancreatic cancer, including age at diagnosis 4
• Note any family history of breast, ovarian, melanoma, or colorectal cancers 1
• Document Ashkenazi Jewish ancestry if present 1

Step 2: Refer for Genetic Counseling

• Refer if patient has one first-degree relative with pancreatic cancer plus additional family history features 1, 4
• Genetic counseling should precede testing to ensure appropriate test selection and interpretation 3

Step 3: Order Comprehensive Panel Testing

• Request multigene panel including BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, MLH1, MSH2 1, 2
• Avoid single-gene testing given the genetic heterogeneity of familial pancreatic cancer 7

Step 4: Add Routine Bloodwork

• Add fasting glucose and/or HbA1c to regular surveillance panels 5
• Do NOT add CA19-9 to routine panels 6

Step 5: Determine Imaging Surveillance Eligibility

• If mutation identified or meets familial criteria, refer to high-volume center for formal pancreatic surveillance program 5
• Surveillance should occur at centers with multidisciplinary teams experienced in managing high-risk individuals 5

Step 6: Counsel on Modifiable Risk Factors

• Emphasize smoking cessation (smoking lowers age of pancreatic cancer onset by several years) 6
• Discuss weight management 4

Important caveat: The presence of family history warrants cancer surveillance strategies, not avoidance of appropriate diabetes or weight management therapies. 4 Having one first-degree relative with pancreatic cancer increases risk approximately 2.3-fold, while two affected first-degree relatives raises risk by about 6.4-fold. 4