What is the preferred testing approach, germline testing or somatic testing, for a patient with a suspected BRCA (Breast Cancer Gene) mutation and no personal history of breast or ovarian cancer?

Germline Testing vs Somatic Testing of BRCA

For patients with suspected BRCA mutations and no personal history of breast or ovarian cancer, germline testing is the only appropriate approach—somatic testing requires tumor tissue and is therefore not applicable in cancer-free individuals. 1, 2

Testing Strategy for Individuals Without Cancer

When Germline Testing is Indicated

Individuals with a first-degree relative (such as a mother) with ovarian, fallopian tube, or primary peritoneal cancer should be referred for genetic counseling and offered germline BRCA1/2 testing, regardless of their own age or cancer history. 1 This represents one of the strongest family history criteria and requires no additional affected relatives or age restrictions. 1

Additional family history criteria warranting germline testing include: 2

• Three or more breast and/or ovarian cancers on the same side of the family, with at least one diagnosed before age 50
• Two breast cancers in close relatives diagnosed before age 40
• Any first- or second-degree blood relative meeting personal history criteria for testing

Optimal Testing Approach

Testing should ideally begin with the affected family member (the person with cancer) who has the highest likelihood of carrying a mutation. 1, 2 If the affected relative tests positive for a specific mutation, the unaffected individual can then undergo targeted testing for that familial mutation, which is faster and less expensive. 1

If no living affected family member is available for testing, testing unaffected relatives is reasonable with appropriate counseling about the limitations of this approach. 2

Testing Strategy for Individuals With Cancer

Sequential Testing Approach is Critical

For patients diagnosed with epithelial ovarian cancer, germline testing must be performed first, and if negative, somatic tumor testing should follow—never the reverse sequence. 3 This hierarchical approach is essential because:

• Germline DNA sequencing is the most sensitive approach and should be done at the time of initial diagnosis. 3
• If germline testing is negative for BRCA mutations, then tumor tissue DNA should be sequenced, as an additional 5-7% of women will have somatic mutations. 3
• Critically, up to 5% of germline mutations will be missed if relying on tumor somatic mutation results to determine whether to perform germline testing. 3

Why Sequence Matters for Mortality and Quality of Life

Missing a germline mutation has grave implications for family members who may be falsely reassured that they are not at risk. 3 The consequences include:

• Family members lose the opportunity for life-saving risk-reducing salpingo-oophorectomy, which dramatically reduces ovarian cancer mortality when performed between ages 35-40 for BRCA1 carriers and 40-45 for BRCA2 carriers. 1
• Enhanced breast cancer surveillance with MRI and mammography starting at age 25-30 improves early detection and survival but cannot be implemented if the germline mutation is missed. 1
• Cascade testing of at-risk family members becomes impossible. 1

Current Guidelines for Cancer Patients

BRCA mutation testing (germline and/or somatic) is recommended at diagnosis for all patients with high-grade non-mucinous tubo-ovarian carcinoma regardless of stage. 3 The 2024 ESGO-ESMO-ESP consensus achieved 98% agreement on this recommendation. 3

For ovarian cancer specifically: 3

• Germline BRCA1/2 mutations are present in 13-15% of women with epithelial ovarian cancer
• Somatic mutations are found in an additional 5-7%
• Testing should include a multigene panel with at minimum: BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PMS2, and PALB2

Pre-Testing Requirements

Genetic counseling must be provided before testing to discuss benefits, risks, and limitations. 2 The European Society for Medical Oncology emphasizes that informed consent and genetic counseling must be completed before any BRCA testing. 3, 1

Counseling should address: 1, 2

• The probability of finding a mutation
• Implications for the patient and family members
• Meaning of possible results including variants of uncertain significance
• How results will influence medical management, including enhanced surveillance and risk-reducing surgeries

Critical Pitfall to Avoid

Never perform somatic testing first or use somatic testing results to decide whether germline testing is needed—this approach will miss germline mutations in up to 5% of cases. 3 When somatic BRCA1/2 mutations are identified on tumor sequencing, germline testing must be recommended, as 55.7% of these patients will have pathogenic germline BRCA1/2 mutations. 4

Ovarian cancer screening (CA-125, transvaginal ultrasound) should not be offered even to high-risk individuals, as it does not reduce mortality and causes significant harm through false-positive results leading to unnecessary surgeries. 1 Risk-reducing surgery, not screening, is the evidence-based approach for BRCA mutation carriers. 1