What is the purpose and procedure of the Homologous Recombination Deficiency (HRD) test in patients with suspected or confirmed ovarian, breast, or prostate cancer?

HRD Testing: Purpose and Procedure

Primary Purpose

HRD testing identifies patients with high-grade serous ovarian, fallopian tube, and peritoneal carcinomas who will derive the greatest magnitude of benefit from PARP inhibitor therapy, with BRCA mutation testing combined with genomic instability assays serving as the current standard approach. 1, 2

The test does not simply determine biological HRD status—it predicts the degree of PARP inhibitor benefit and guides treatment selection and scheduling decisions. 1

Clinical Indications by Cancer Type

Ovarian Cancer (Primary Application)

• All patients with newly diagnosed high-grade serous ovarian carcinoma (HGSOC) should undergo HRD testing to optimize PARP inhibitor use in both first-line maintenance and platinum-sensitive relapsed settings. 2
• Testing is particularly critical for patients with personal or family history of breast or ovarian cancer. 2
• The test determines whether patients receive maintenance olaparib, especially when combined with bevacizumab in GIS-positive/BRCA wildtype patients. 2

Breast and Prostate Cancer (Emerging Applications)

• In metastatic castration-resistant prostate cancer (mCRPC), HRR gene mutation testing (including BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) guides PARP inhibitor use after progression on abiraterone or enzalutamide. 3
• BRCA1/2 mutations in prostate cancer represent Category 1 indications for olaparib or rucaparib. 3
• HRD testing has significant implications for breast and pancreatic cancers, though ovarian cancer has the most robust clinical validation. 1

Testing Methodology: Three-Tiered Approach

Tier 1: BRCA Mutation Testing (Gold Standard)

• BRCA1/2 germline and somatic mutation testing remains the most validated predictor of PARP inhibitor benefit with Level I evidence for clinical validity and utility. 2
• Germline BRCA mutations occur in 12-15% (BRCA1) and 5-7% (BRCA2) of HGSOC cases. 1
• All patients should undergo genetic counseling and germline testing shortly after diagnosis. 4

Tier 2: Genomic Instability Assays

• Two commercially available assays incorporating genomic instability scores (GIS) or loss of heterozygosity (LOH) have Level I evidence for identifying additional HRD-positive patients beyond BRCA mutations. 2
• MyChoice CDx (Myriad Genetics) is the FDA-referenced standard assay used in clinical practice. 5, 6
• These tests measure "genomic scars"—patterns of somatic mutations resulting from historical HRD. 7
• Somatic tumor testing should be sent once an adequate tumor sample is available. 4

Tier 3: Functional Assays (Investigational)

• Functional assays provide real-time assessment of current HRD status but require prospective validation before clinical implementation. 2
• These assays address the dynamic nature of HRD, which can change due to reversion mutations restoring homologous recombination proficiency. 1

Practical Testing Algorithm

Step 1: Initial Testing Strategy

• Pursue both germline and somatic testing for all HGSOC patients, as they provide complementary information. 4
• If barriers exist, either strategy is evidence-based: germline testing with reflex to somatic for BRCA wildtype patients, or somatic testing first. 4

Step 2: Timing Considerations

• Complete HRD testing before finishing upfront chemotherapy to facilitate comprehensive counseling about anticipated maintenance PARP inhibitor benefit. 4
• For patients not tested upfront, somatic testing is valuable at recurrence. 4

Step 3: Result Interpretation

• HRD-positive status (BRCA mutation OR positive genomic instability score) predicts superior PARP inhibitor benefit. 1, 2
• Platinum sensitivity itself serves as a powerful biomarker of HRD and contributes to benefit even in HRD-negative populations. 2

Critical Limitations and Pitfalls

Lack of Negative Predictive Value

• Current HRD tests fail to consistently identify patients who derive no benefit from PARP inhibitors—this is their most significant limitation. 1, 2
• All platinum-sensitive relapsed HGSOC patients benefit from PARP inhibitor maintenance regardless of BRCA or HRD status; testing only determines magnitude of benefit. 2

Dynamic Nature of HRD

• HRD status can change over time through reversion mutations in BRCA genes that restore homologous recombination proficiency. 1
• Existing tests measure historical genomic scars, not current real-time HRR capacity. 1

Gene-Specific Efficacy Differences

• Do not overestimate PARP inhibitor efficacy in non-BRCA HRR mutations—the PROfound trial showed minimal activity in ATM, CDK12, and other HRR gene mutations. 3
• BRCA1/2 mutations demonstrate the strongest predictive value. 3

Specimen Requirements

• Testing requires adequate tumor tissue samples, preferably from contemporaneous biopsies to account for tumor evolution. 1
• Both formalin-fixed paraffin-embedded (FFPE) tissue and circulating tumor DNA (ctDNA) can be used for somatic testing. 3

Future Directions

• Composite biomarkers combining platinum sensitivity, genomic scar testing, and functional assays are urgently needed to provide both historical evidence of HRD and real-time HRR capacity. 1, 2
• Comprehensive genomic assays based on whole genome sequencing could simultaneously provide HRR gene mutations, mutational signatures, and reversion mutations. 1