What testing is recommended for a patient with a family history of pancreatic cancer in a first-degree relative and a maternal relative?

Genetic Testing and Surveillance for Family History of Pancreatic Cancer

This patient requires genetic counseling and comprehensive multigene panel testing, followed by consideration for pancreatic surveillance if specific criteria are met. 1, 2

Step 1: Refer for Genetic Counseling and Testing

Genetic counseling with comprehensive multigene panel testing is indicated because this patient has a first-degree relative with pancreatic cancer. 3, 2 The American College of Medical Genetics specifically recommends referral for any individual with a first-degree relative with pancreatic cancer plus one additional close relative with pancreatic cancer. 3

Genes to Test

The comprehensive panel should include: 3, 1, 2

• BRCA2 (most common cause of familial pancreatic cancer, found in 2.8-17% of familial cases) 3, 1
• BRCA1 (modest increased risk) 3, 1
• PALB2 (found in 0.9-3.7% of familial pancreatic cancer patients) 3, 1
• ATM (found in 2.4% of familial pancreatic cancer patients, 4.6% in families with three or more affected) 3, 2
• CDKN2A/p16 (associated with 13-22-fold increased risk) 3, 1
• STK11 (Peutz-Jeghers syndrome, 132-fold increased risk) 3, 1
• Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2 - 8.6-fold increased risk) 3, 1, 2

Special Consideration for Ashkenazi Jewish Ancestry

If the patient has Ashkenazi Jewish ancestry, genetic testing is particularly important regardless of the number of affected relatives, as there is a 5.5-31% chance of carrying one of the three founder BRCA mutations. 3 The American College of Medical Genetics specifically recommends referral for "Ashkenazi Jewish ancestry and pancreatic cancer at any age" in the family. 3

Step 2: Determine Surveillance Eligibility

Surveillance eligibility depends on whether a pathogenic mutation is identified and the specific family history pattern. 1, 2

If Pathogenic Mutation is Found:

• STK11 carriers: Surveillance regardless of family history (99% consensus, Grade 1 evidence) 1
• CDKN2A/p16 carriers: Surveillance regardless of family history (77% consensus), though stronger recommendation with at least one affected first-degree relative (99% consensus) 1, 4
• BRCA2 carriers: Surveillance with at least one affected first-degree relative OR two affected relatives of any degree (93% consensus) 3, 1
• PALB2 carriers: Surveillance with at least one affected first-degree relative (83% consensus) 3, 1
• ATM carriers: Surveillance with at least one affected first-degree relative (88% consensus) 1
• Lynch syndrome carriers: Surveillance with at least one affected first-degree relative (84% consensus) 3, 1
• BRCA1 carriers: Surveillance with at least one affected first-degree relative (69.6% consensus, Grade 3 evidence) 1

If No Mutation Found (Familial Risk):

Surveillance is indicated if the patient meets one of these criteria: 1

• At least 3 affected blood relatives with pancreatic cancer, with at least one being a first-degree relative (97% consensus, Grade 2 evidence) 1
• At least 2 affected first-degree relatives who are first-degree relatives to each other (93% consensus, Grade 2 evidence) 1
• At least 2 affected blood relatives on the same side of the family, with at least one being a first-degree relative (88% consensus, Grade 2 evidence) 1

Based on the information provided (one first-degree relative and one maternal relative), this patient would NOT automatically qualify for surveillance unless a high-risk mutation is identified. 1

Step 3: Surveillance Protocol (If Eligible)

When to Begin:

• STK11 carriers: Age 30-35 years, or 10 years younger than earliest family diagnosis, whichever is earlier 1, 4
• CDKN2A/p16 carriers: Age 40 years, or 10 years younger than earliest family diagnosis, whichever is earlier 1, 4
• Other mutation carriers: 5 years earlier than familial pancreatic cancer criteria 1
• Familial risk without mutation: Age 50 years, or 10 years younger than youngest affected relative, whichever is earlier 1

Surveillance Modalities:

Annual surveillance should include: 1, 2

• Endoscopic ultrasound (EUS) (92.1% consensus for baseline, 89.5% for follow-up) 1
• MRI/MRCP (89.5% consensus, Grade 2 evidence) 1
• Consider adding: Fasting glucose/HbA1c (76.1% consensus) and CA19-9 (76.5% consensus), though the American Gastroenterological Association explicitly does not recommend CA19-9 as a screening test due to lack of sensitivity and specificity 1, 2

Surveillance interval should be annual (12 months) when no abnormalities are detected. 1

Critical Pitfalls to Avoid

• Do not offer surveillance without first performing genetic testing, as mutation status determines appropriate surveillance criteria and timing 1
• Do not offer surveillance to individuals who are not surgical candidates, as screening should only be performed in those who could tolerate pancreatic resection 1
• Do not delay surveillance in CDKN2A carriers until age 50—they require earlier screening starting at age 40 due to significantly elevated risk (20.7% cumulative incidence by age 70, with 52-80-fold relative risk) 1, 4
• Do not perform surveillance at low-volume centers—all screening should occur at high-volume specialty centers with multidisciplinary expertise 1
• Do not ignore new-onset diabetes in high-risk individuals, as this should prompt immediate investigation regardless of age or surveillance schedule (82.4% consensus) 1, 2

Expected Yield

Research demonstrates that approximately 12-17% of patients with a family history of pancreatic cancer will have a pathogenic germline variant identified through comprehensive panel testing. 5, 6 Among those with a first-degree relative affected, 12.5% had pathogenic variants and 18.8% had variants of uncertain significance. 5 BRCA2 mutations are most common (37% of identified pathogenic variants), followed by ATM and other homologous recombination genes. 5, 6