What are the guidelines for BRCA1/2 (Breast Cancer Gene 1 and 2) germline testing in patients with a personal or family history of breast cancer?

BRCA1/2 Germline Testing for Breast Cancer

All patients newly diagnosed with breast cancer who are 65 years or younger should be offered BRCA1/2 testing, regardless of family history or tumor characteristics. 1

Age-Based Testing Criteria

Patients ≤65 Years at Diagnosis

• Offer BRCA1/2 testing to all patients with stage I-III or de novo stage IV/metastatic breast cancer, without requiring any additional risk factors or family history 1
• This universal approach for younger patients reflects the therapeutic implications of PARP inhibitor eligibility, surgical decision-making for contralateral risk reduction, and family cascade testing benefits 2

Patients >65 Years at Diagnosis

Offer BRCA1/2 testing if ANY of the following criteria are met: 1

• Candidates for PARP inhibitor therapy (early-stage or metastatic disease)
• Triple-negative breast cancer subtype
• Personal or family history suggesting hereditary predisposition
• Male sex assigned at birth
• Ashkenazi Jewish ancestry or populations with founder mutations

The rationale for age-stratified criteria recognizes that women over 65 meeting NCCN criteria have a 9.0% likelihood of carrying pathogenic variants compared to 3.5% in those not meeting criteria 2

Recurrent or Second Primary Breast Cancer

Recurrent Disease (Local or Metastatic)

• Offer BRCA1/2 testing to all patients with recurrent breast cancer who are candidates for PARP inhibitor therapy, regardless of family history 1
• This recommendation achieved 97.50% expert consensus, reflecting the direct therapeutic impact of olaparib, which improved 3-year invasive disease-free survival to 85.9% versus 77.1% with placebo in BRCA1/2 carriers with high-risk, HER2-negative early-stage breast cancer 2

Second Primary Breast Cancer

• Offer BRCA1/2 testing to all patients with contralateral or ipsilateral second primary breast cancer 1
• Women with second breast primaries have significantly higher rates of BRCA1/2 pathogenic variants compared to those with only primary breast cancer, particularly robust in Caucasian and African American populations 1

Patients with Prior Breast Cancer (No Active Disease)

Diagnosed ≤65 Years

• Offer BRCA1/2 testing if results will inform personal risk management or family risk assessment 1
• Testing in this population guides risk-reducing strategies for second primary malignancies and enables cascade testing for family members 1

Diagnosed >65 Years

Offer testing if results will inform risk management AND patient meets ANY of: 1

• Personal or family history suggesting pathogenic variant
• Male sex assigned at birth
• Triple-negative breast cancer
• Ashkenazi Jewish ancestry or founder mutation populations

Multi-Gene Panel Testing Beyond BRCA1/2

High-Penetrance Genes

Offer testing for PALB2, TP53, PTEN, STK11, and CDH1 as these genes: 1, 2

• Inform medical therapy decisions (PALB2 shows high response rates to PARP inhibitors in metastatic disease) 1
• Influence surgical decision-making (bilateral mastectomy versus breast-conserving surgery)
• Refine second primary cancer risk estimates
• Enable family risk assessment

Studies demonstrate that 15.1% of BRCA1/2-negative patients with strong personal/family history harbor pathogenic variants in other cancer predisposition genes 3

Moderate-Penetrance Genes

• May be offered to patients undergoing BRCA1/2 testing, though these currently provide no treatment benefits for the index breast cancer 1
• Value lies in informing second primary cancer risks and family assessment 1

Panel Selection Strategy

• Tailor multi-gene panels to personal and family history 1
• Consultation with clinical cancer genetics specialists is recommended when selecting panels or interpreting complex results 1, 2

Critical Implementation Points

Genetic Counseling Access

• Patients undergoing testing should have access to providers experienced in clinical cancer genetics to guide decision-making 1
• Patients with pathogenic variants require individualized post-test genetic counseling 1
• Even patients without pathogenic variants may benefit from counseling if significant family history exists 1

Variants of Uncertain Significance (VUS)

• Do not alter management based on VUS 1
• Patients must understand VUS may be reclassified as pathogenic, requiring periodic follow-up 1

Family Cascade Testing

• Identifying pathogenic variants enables cascade testing for at-risk relatives, allowing family members to pursue surveillance and risk-reduction strategies before cancer develops 2, 4

Common Pitfalls to Avoid

• Do not restrict testing based solely on family history in patients ≤65 years—the universal testing approach captures BRCA carriers who lack obvious family history 1
• Do not delay testing in patients who may be PARP inhibitor candidates, as this directly impacts treatment options with proven mortality benefit 2
• Do not overlook male breast cancer patients, who warrant testing regardless of age given high pathogenic variant rates 1
• Do not assume negative BRCA1/2 testing excludes hereditary risk in patients with strong family history—consider expanded panel testing 1, 3