What are the recommendations for genetic testing in high-risk breast cancer patients?

Genetic Testing Recommendations for High-Risk Breast Cancer Patients

All patients with breast cancer aged ≤65 years should be offered BRCA1/2 testing, and those >65 years should be tested if they meet specific risk criteria including triple-negative breast cancer, personal/family history suggesting pathogenic variants, male sex at birth, or Ashkenazi Jewish ancestry. 1

Who Should Receive Genetic Testing

Newly Diagnosed Breast Cancer Patients

• Age ≤65 years: All patients should be offered BRCA1/2 testing 1
• Age >65 years: Testing recommended if patient:
  • Is a candidate for PARP inhibitor therapy
  • Has triple-negative breast cancer
  • Has personal/family history suggesting pathogenic variant
  • Was assigned male sex at birth
  • Has Ashkenazi Jewish ancestry or belongs to population with founder mutations 1

Patients with Recurrent or Second Primary Breast Cancer

• All patients with recurrent breast cancer (local or metastatic) who are candidates for PARP inhibitor therapy 1
• All patients with second primary cancer in contralateral or ipsilateral breast 1

Patients with Previous History of Breast Cancer (No Active Disease)

• All patients diagnosed ≤65 years 1
• Patients diagnosed >65 years if they meet specific criteria (similar to newly diagnosed patients >65) 1

Which Genes to Test

Core Testing

• BRCA1/2 testing is the minimum recommended for all eligible patients 1

Expanded Testing

• High-penetrance genes beyond BRCA1/2 (PALB2, TP53, PTEN, STK11, CDH1) should be offered to appropriate patients based on personal/family history 1
• Moderate-penetrance breast cancer genes may be offered if they will inform second primary cancer risk or family risk assessment 1
• Multi-gene panel selection should consider patient's personal and family history 1

Special Populations

Ashkenazi Jewish Ancestry

• Should be offered testing for the three BRCA founder mutations 1
• If negative and other criteria are met, consider full sequence testing 1

Early-Onset Breast Cancer

• Individuals with breast cancer aged <30 years with negative BRCA1/2 testing should consider TP53 testing, especially with family history of sarcoma, brain tumor, or adrenocortical carcinoma 1

Pre- and Post-Test Counseling

Pre-Test

• Patients should receive sufficient information for informed consent 1
• Consultation with a provider experienced in clinical cancer genetics is recommended when available 1

Post-Test

• Patients with pathogenic variants should receive individualized post-test genetic counseling 1
• Variants of uncertain significance should not alter management 1
• Patients without pathogenic variants but with significant family history may still benefit from counseling 1

Clinical Implications of Testing Results

Positive Results

• Informs medical therapy decisions, including PARP inhibitor eligibility 1
• Influences surgical decision-making 1
• Refines estimates of second primary cancer risk 1
• Guides family risk assessment 1
• May indicate need for risk-reducing surgeries (mastectomy, salpingo-oophorectomy) 1

Negative Results

• In high-risk families without identified mutations, women still have approximately four-fold increased risk of breast cancer 2
• Management should be based on personal and family history 1

Common Pitfalls and Caveats

• Variants of uncertain significance: Should not alter clinical management; patients should be followed for potential reclassification 1
• Incomplete testing: Some mutations (large rearrangements) may not be detected by primary sequencing and require supplementary testing 1
• Testing unaffected relatives: When no affected family member is available for testing, significant limitations in interpreting results should be discussed 1
• Over-reliance on negative results: A negative test does not eliminate risk in families with strong history 1, 2
• Under-testing: Failure to test beyond BRCA1/2 may miss clinically significant mutations in other high-penetrance genes 1

Genetic testing for breast cancer has evolved significantly, and current guidelines emphasize broader testing criteria to ensure that high-risk individuals are identified and appropriately managed to reduce morbidity and mortality associated with hereditary breast cancer.