What are the recommendations for individuals with a germline mutation associated with an increased risk of early onset high-grade prostate malignancy?

Germline Mutations Associated with High-Grade Prostate Cancer: Screening and Management Recommendations

Men with germline mutations in BRCA1/2, ATM, CHEK2, PALB2, and MMR genes should begin prostate cancer screening at age 40, with particular emphasis on BRCA2 carriers who have a 2-6 fold increased risk of aggressive prostate cancer with reduced survival. 1

Key Germline Mutations Associated with Prostate Cancer Risk

• BRCA2 mutations are most strongly associated with a 2-6 fold increase in prostate cancer risk and significantly more aggressive disease phenotype with reduced survival compared to non-carriers 1
• BRCA1 mutations show a less consistent but still important association with prostate cancer risk 1
• Other significant germline mutations associated with increased prostate cancer risk include ATM, CHEK2, PALB2, and mismatch repair genes (MLH1, MSH2, MSH6, PMS2) 1
• Intraductal histology is particularly common in germline BRCA2 mutation carriers with prostate cancer 1

Screening Recommendations

• Begin prostate cancer screening at age 40 for men with BRCA2 mutations 1
• Consider beginning screening at age 40 for men with BRCA1 mutations 1
• Include family history of BRCA1/2 mutations in baseline evaluation prior to discussions about prostate cancer screening 1
• Refer individuals with known or suspected cancer susceptibility genes to a cancer genetics professional 1
• Use information about BRCA1/2 gene status as part of the discussion about prostate cancer screening, as patients may not be aware of their increased risk 1

Genetic Testing Recommendations

The NCCN guidelines recommend germline genetic testing for:

• Patients with a positive family history of cancer (especially breast, ovarian, pancreatic, or prostate cancer) 1
• Patients with high-risk, very-high-risk, regional, or metastatic prostate cancer, regardless of family history 1
• Patients with Ashkenazi Jewish ancestry 1
• Patients with intraductal histology on biopsy 1

Specific Genes to Test

When performing germline testing, include:

• Mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 (for Lynch syndrome) 1
• Homologous recombination genes: BRCA2, BRCA1, ATM, PALB2, and CHEK2 1
• Consider a cancer predisposition next-generation sequencing panel that includes at minimum: BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2 1
• Additional genes may be appropriate depending on clinical context (e.g., HOXB13) 1

Clinical Implications of Positive Germline Testing

• Patients with germline mutations, particularly in BRCA2, ATM, and CHEK2, have a higher likelihood of developing aggressive prostate cancer 1, 2
• The positive predictive value of biopsy for detecting intermediate/high-grade cancer is significantly higher in BRCA2 carriers with PSA levels >3.0 ng/mL (2.4% vs 0.7%; P=.04) 1
• Men with germline BRCA2 mutations should be encouraged to undergo PSA testing 1
• If mutations in BRCA2, BRCA1, ATM, CHEK2, or PALB2 are found, refer the patient for genetic counseling to assess for hereditary breast and ovarian cancer syndrome 1
• If MSI-H or dMMR is found, refer the patient for genetic counseling to assess for Lynch syndrome 1

Treatment Considerations

• Patients with germline DNA repair gene mutations may have therapeutic implications for advanced disease, including potential sensitivity to PARP inhibitors 1, 3, 4
• Patients with increased tumor mutational burden, such as in Lynch syndrome, may be particularly sensitive to immune checkpoint inhibitors 4
• Consider more aggressive treatment approaches rather than active surveillance for localized prostate cancer in patients with germline mutations, particularly BRCA2 3, 2

Important Caveats

• Baseline PSA value is a stronger predictive factor than a positive family history or race 1
• The optimal early detection paradigm for men with pathogenic germline mutations is still being defined 4
• Patients should be informed that somatic tumor sequencing has the potential to uncover germline findings, but most NGS tests are not designed or validated for germline assessment 1
• If a germline mutation is suspected from tumor testing, refer the patient for genetic counseling and dedicated germline testing 1