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 in Cancer: Purpose and Procedure

Primary Purpose

HRD testing is performed to predict the magnitude of benefit from PARP inhibitor therapy and platinum-based chemotherapy, primarily in high-grade serous ovarian cancer, and increasingly in breast and prostate cancers. 1, 2

The test does not simply identify biological HRD status—rather, its clinical validity is best assessed in terms of predicting PARP inhibitor benefit, which directly impacts survival outcomes. 1

Clinical Indications by Cancer Type

Ovarian Cancer (Primary Application)

• Test all patients with high-grade serous ovarian, fallopian tube, or peritoneal carcinoma to optimize PARP inhibitor use in both first-line and recurrent settings. 1
• HRD occurs in approximately 50% of high-grade serous ovarian cancers, even without BRCA1/2 mutations. 3
• Testing should be completed by the end of upfront chemotherapy to facilitate comprehensive counseling about maintenance PARP inhibitor benefit. 4

Prostate Cancer

• Test metastatic castration-resistant prostate cancer (mCRPC) patients who have progressed on abiraterone or enzalutamide for HRR gene mutations (BRCA1, BRCA2, ATM, and others). 5
• HRR gene mutations occur in 11.8% of men with metastatic prostate cancer. 6
• PARP inhibitors like olaparib are FDA-approved for BRCA1/2-mutated mCRPC after progression on androgen receptor-directed therapy. 5

Breast Cancer

• HRD testing is increasingly relevant for triple-negative and BRCA-mutated breast cancers, though the evidence base is less developed than in ovarian cancer. 1, 2

Testing Methodology

Three Main Categories of HRD Tests

1. HRR Pathway Gene Testing (BRCA and Beyond) 1

• BRCA1/2 mutation testing remains the gold standard for identifying patients most likely to benefit from PARP inhibitors. 2
• Germline BRCA mutations: detected in 12-15% (BRCA1) and 5-7% (BRCA2) of ovarian cancer cases. 1
• Somatic BRCA mutations and other HRR genes (RAD51, RAD51C, RAD51D, PALB2, ATM, CHEK2) can also cause HRD. 1

2. Genomic Scar/Instability Assays 1

• Two commercially available assays incorporating genomic instability are clinically validated: MyChoice CDx (Myriad Genetics) and similar platforms. 1, 7
• These measure patterns of somatic mutations that accumulate in HRD cancers (loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions). 1
• Genomic instability scores help identify additional patients beyond BRCA-mutated who may benefit from PARP inhibitors. 2

3. Functional Assays 1

• Provide real-time assessment of HRD status, though less commonly used in routine practice. 1
• May be needed in combination with other tests to address the dynamic nature of HRD. 1

Recommended Testing Algorithm

Step 1: Germline Testing

• Pursue genetic counseling and germline BRCA1/2 testing shortly after diagnosis for all ovarian cancer patients. 4
• This identifies hereditary cancer risk and guides family cascade testing. 6

Step 2: Somatic Tumor Testing

• Perform somatic HRD testing once adequate tumor tissue is available (formalin-fixed paraffin-embedded tissue from surgery or biopsy). 4, 3
• For patients with germline BRCA wildtype, reflex to somatic testing. 4
• Somatic testing identifies tumor-specific BRCA mutations, other HRR gene alterations, and genomic instability scores. 4

Step 3: Integration of Results

• Both germline and somatic testing offer complementary information—germline identifies hereditary risk, while somatic provides tumor-specific therapeutic guidance. 4
• If barriers exist, either strategy (germline with reflex to somatic, or somatic first) is evidence-based. 4

Clinical Utility and Limitations

What HRD Tests Can Do

• Predict magnitude of PARP inhibitor benefit in different clinical scenarios (first-line maintenance, recurrent platinum-sensitive disease). 1
• Identify patients with superior response to platinum-based chemotherapy. 1
• Guide treatment selection and scheduling decisions. 1

Critical Limitations and Pitfalls

Lack of Negative Predictive Value 1

• Current tests fail to consistently identify patients who derive NO benefit from PARP inhibitors. 1
• A negative HRD test does not exclude potential PARP inhibitor benefit in many studies. 1

Dynamic Nature of HRD 1

• HRD status can change over time through reversion mutations that restore homologous recombination proficiency. 1
• Existing tests measure historical genomic scars, not current DNA repair capacity. 1

Prostate Cancer Specificity 5

• In prostate cancer, PARP inhibitor efficacy is strongest for BRCA1/2 mutations. 5
• The PROfound trial showed minimal activity in ATM, CDK12, and other HRR mutations (Cohort B failed primary endpoint). 5
• Do not overestimate PARP inhibitor efficacy in non-BRCA HRR mutations. 5

Practical Implementation Considerations

Timing

• Complete testing before maintenance therapy decisions in ovarian cancer. 4
• Test at progression on androgen receptor-directed therapy in prostate cancer. 5
• If not performed upfront, somatic testing is valuable at recurrence. 4

Sample Requirements

• Adequate tumor tissue from surgical specimens or biopsies. 3
• Next-generation sequencing platforms typically used. 8, 3

Test Selection

• MyChoice CDx is the most widely validated commercial assay. 7, 3
• Selection should optimize turnaround time, cost, result format, and logistical burden. 4
• In-house NGS-based tests (like GIScar, GS Focus HRD) show high concordance with MyChoice CDx (kappa 0.8,90% accuracy). 8, 3

Future Directions

Better biomarkers are urgently needed to identify current homologous recombination proficiency status and provide real-time functional assessment. 1

Composite biomarkers combining platinum sensitivity, genomic scars, and functional assays may improve treatment stratification. 1

Integration with other predictive biomarkers will be necessary as PARP inhibitors evolve into combination therapies with anti-angiogenesis agents, checkpoint inhibitors, and other DNA repair inhibitors. 1