What is the role of genetic testing in prostate cancer?

Genetic Testing in Prostate Cancer

Genetic testing should be offered to all men with metastatic prostate cancer and those with specific personal or family history patterns, as it significantly impacts treatment decisions, screening protocols, and family risk assessment.

Who Should Undergo Genetic Testing

Strong Recommendations for Testing:

• Men with metastatic castration-resistant prostate cancer (mCRPC), regardless of family history (67% consensus) 1
• Men with prostate cancer (Gleason ≥7) and family history of HBOC-related cancers 1, 2
• Men with prostate cancer and two or more close blood relatives with cancers in the following syndromes:
  • Hereditary Breast and Ovarian Cancer (HBOC) syndrome (93% consensus) 1
  • Hereditary Prostate Cancer (HPC) syndrome (86% consensus) 1
  • Lynch Syndrome (LS) (86% consensus) 1
• Men with tumor sequencing showing mutations in cancer-risk genes (77% consensus) 1
• Men with personal/family history of three or more cancers including: breast, pancreatic, prostate (Gleason ≥7), melanoma, sarcoma, adrenocortical carcinoma, brain tumors, leukemia, diffuse gastric cancer, colon cancer, endometrial cancer, thyroid cancer, kidney cancer 1

Testing Considerations for High-Risk Populations:

• Ashkenazi Jewish men have higher carrier rates of BRCA1/2 mutations (>2%) with a 16% chance of developing prostate cancer by age 70 2
• Approximately 11.8% of men with metastatic prostate cancer have germline mutations in DNA repair genes 2
• 6% of high-risk localized prostate cancer patients have germline DNA repair mutations, compared to 2% in low/intermediate risk patients 2

Which Genes to Test

Genes with Strong Evidence for Testing:

• BRCA1/BRCA2: For suspected HBOC (97% consensus) 1, 2
  • BRCA2 has strongest association with aggressive prostate cancer (2-6 fold increased risk) 2
  • BRCA1 has less consistent association with prostate cancer risk 2
• HOXB13: For suspected hereditary prostate cancer (95% consensus) 1, 2
• DNA Mismatch Repair genes (MLH1, MSH2, MSH6, PMS2): For suspected Lynch syndrome (73% consensus) 1, 2
  • Confer 2-5 fold increased risk of prostate cancer 2

Additional Genes to Consider:

• For men with mCRPC undergoing genetic testing for treatment determination:
  • BRCA1/2 (88% consensus) 1
  • ATM (62% consensus) 1
• Other DNA repair genes with emerging evidence: CHEK2, PALB2, RAD51D, ATR, NBN 2

Impact on Prostate Cancer Screening

Screening Recommendations Based on Genetic Status:

• BRCA2 mutation carriers (80% consensus for factoring into screening discussions) 1:
  • Begin screening at age 40 or 10 years before youngest prostate cancer diagnosis in family 1, 2
  • Annual PSA screening or interval determined by baseline PSA (76% consensus) 1
• HOXB13 mutation carriers (53% consensus for factoring into screening discussions) 1:
  • Begin screening at age 40 or 10 years before youngest prostate cancer diagnosis in family (52% consensus) 1
  • Annual PSA screening or interval determined by baseline PSA (75% consensus) 1
• BRCA1 carriers: Consider prostate cancer screening beginning at age 40 2

Impact on Prostate Cancer Management

Treatment Considerations Based on Genetic Status:

• BRCA2 mutation status should be factored into:
  • Early-stage/localized prostate cancer management (64% consensus) 1
  • High-risk/advanced prostate cancer management (97% consensus) 1
  • mCRPC treatment discussions (88% consensus) 1
• BRCA1 mutation status should be factored into mCRPC treatment discussions (83% consensus) 1
• ATM mutation status should be factored into:
  • High-risk/advanced prostate cancer management (59% consensus) 1
  • mCRPC treatment discussions (56% consensus) 1
• Men with BRCA2 mutations have more aggressive disease and should not be managed with active surveillance 2

Clinical Implications and Pitfalls

Important Considerations:

• Relying solely on family history for risk assessment is insufficient, as only 45.5% of mutation carriers have mutations concordant with personal and family history 2
• Genetic testing results have implications beyond the patient, affecting family members who may benefit from cascade testing and enhanced cancer screening 3, 4
• Genetic counseling should be part of the testing process to ensure patients understand the implications of results 5, 4

Common Pitfalls to Avoid:

1. Overlooking testing in metastatic disease: All men with metastatic prostate cancer should be considered for genetic testing regardless of family history 1, 2
2. Focusing only on BRCA1/2: Multiple genes beyond BRCA1/2 are implicated in prostate cancer risk and should be included in testing panels 1, 2
3. Ignoring tumor sequencing results: Men with tumor sequencing showing mutations in cancer-risk genes should have confirmatory germline testing 1
4. Failing to adjust management based on genetic status: BRCA2 mutation carriers in particular require more aggressive management approaches 1, 2

Genetic testing in prostate cancer continues to evolve, with emerging evidence supporting its role in risk assessment, screening protocols, treatment selection, and family risk management. A multidisciplinary approach involving urologists, oncologists, genetic counselors, and primary care providers is essential for optimal implementation of genetic testing in prostate cancer care.