Is genetic testing for pancreatic cancer indicated in individuals and their family members?

Genetic Testing for Pancreatic Cancer and Family Members

Genetic testing should be offered to all patients diagnosed with pancreatic adenocarcinoma, regardless of family history, as well as to unaffected individuals from families with known hereditary syndromes or familial pancreatic cancer. 1

Who Should Undergo Genetic Testing

Patients with Pancreatic Cancer

• All patients diagnosed with pancreatic adenocarcinoma should undergo genetic testing, even if family history is unremarkable 1
• Testing should be performed early in the disease course due to:
  • Limited prognosis of pancreatic cancer patients
  • Potential to guide therapeutic decisions
  • Importance for family risk assessment 1
• Approximately 4-20% of pancreatic cancer patients carry pathogenic germline variants, with higher prevalence in Ashkenazi Jewish ancestry (5.5-19%) 1

Unaffected Family Members

Genetic testing should be offered to the following unaffected individuals:

• Members of families with an identified pathogenic cancer susceptibility gene variant 1
• Individuals from families meeting criteria for familial pancreatic cancer (≥2 first-degree relatives with pancreatic cancer) 1
• Individuals from families meeting criteria for hereditary syndromes linked to pancreatic cancer 1

Testing Approach

• Testing should ideally begin with an affected family member (highest likelihood of informative result) 1
• If no affected individual is available, testing may be performed in unaffected individuals, but negative results are considered clinically uninformative 1
• Use multigene panel testing that includes: BRCA1, BRCA2, PALB2, ATM, CDKN2A, TP53, STK11, MLH1, MSH2, MSH6, PMS2, and EPCAM 1
• For individuals with suspected hereditary pancreatitis, testing for PRSS1 and SPINK1 may be considered, but only with clinical evidence of pancreatitis 1

Clinical Implications of Genetic Testing Results

For Patients with Pancreatic Cancer

• Identification of germline mutations may inform treatment decisions, particularly regarding systemic therapy options 1
• BRCA1/2 and PALB2 mutations may indicate potential responsiveness to platinum-based chemotherapy or PARP inhibitors 1

For Family Members

• Finding a pathogenic variant enables targeted testing in at-risk relatives 1
• Allows for appropriate cancer risk management and surveillance 1
• Negative testing in a family with a known mutation provides reassurance 1

Pancreatic Cancer Surveillance for High-Risk Individuals

Surveillance recommendations for individuals with pathogenic variants:

• CDKN2A or STK11: Begin screening at age 40 (CDKN2A) or 30-35 (STK11), or 10 years younger than earliest pancreatic cancer diagnosis in family, whichever is earlier 1
• Other pancreatic cancer-associated genes (BRCA1/2, ATM, PALB2, Lynch syndrome genes): Consider screening only with additional family history of pancreatic cancer, beginning at age 50 or 10 years younger than earliest pancreatic cancer diagnosis in family 1
• Hereditary pancreatitis genes (PRSS1, SPINK1): Begin screening at age 40 or 20 years after onset of pancreatitis, whichever is earlier 1

Surveillance modalities:

• Contrast-enhanced MRI/MRCP and/or endoscopic ultrasound 1
• Preferably performed at high-volume centers with expertise in pancreatic cancer 1

Pitfalls and Caveats

• Approximately 80% of patients with familial pancreatic cancer have no identifiable genetic cause 1
• A negative genetic test does not eliminate the risk of pancreatic cancer in families with strong history 1
• Variants of uncertain significance should not be used for clinical decision-making 1
• Approximately half of patients with pancreatic cancer found to carry pathogenic variants have no family history of pancreatic cancer 1
• Genetic testing should be accompanied by appropriate genetic counseling to discuss implications, limitations, and psychological impact 1

In conclusion, genetic testing for pancreatic cancer has significant implications for both treatment decisions and family risk assessment. The evidence strongly supports universal testing for patients with pancreatic cancer and selective testing for unaffected family members based on family history or known genetic syndromes.