What is the recommended treatment approach for a female patient with a personal or family history of breast or ovarian cancer, considering HRD (Homologous Recombination Deficiency) testing and potential treatment with PARP (Poly (ADP-ribose) polymerase) inhibitors, such as olaparib (azd2281), in addition to standard chemotherapy?

HRD Testing in Ovarian Cancer: Clinical Approach

For female patients with personal or family history of breast or ovarian cancer, particularly those with high-grade serous ovarian carcinoma (HGSOC), HRD testing should be performed using BRCA mutation testing combined with commercially available genomic instability assays to predict magnitude of PARP inhibitor benefit and guide treatment selection. 1

Testing Strategy Algorithm

Initial Testing Approach

• Perform both germline and somatic BRCA testing for all patients with HGSOC, regardless of age or family history 2, 3
• If barriers exist to simultaneous testing, pursue germline testing first with reflex to somatic testing for BRCA wildtype patients 3
• Add genomic instability score (GIS) or loss of heterozygosity (LOH) testing using commercially available assays (myChoice CDx or FoundationOne CDx) to identify HRD beyond BRCA mutations 1

What HRD Testing Actually Measures

HRD testing encompasses three categories of assays 1:

• HRR pathway gene mutations (BRCA1, BRCA2, RAD51C, RAD51D, PALB2) that identify specific causes of HRD 1
• Genomic "scars" (GIS and LOH scores) that measure patterns of somatic mutations accumulating in HRD cancers 1
• Functional assays (RAD51 foci formation) that provide real-time readout of HRD status, though not yet clinically validated 1

Clinical Utility by Treatment Setting

First-Line Maintenance Therapy

• BRCA mutation status (germline or somatic) consistently identifies patients deriving greatest benefit from PARP inhibitors in platinum-sensitive disease 1
• The hazard ratio for PARPi benefit in BRCA-mutated patients is remarkably consistent across trials, demonstrating robustness as a positive predictive biomarker 1
• GIS-positive/BRCA wildtype patients also benefit from PARPi, particularly when combined with bevacizumab (olaparib FDA approval based on PAOLA-1 trial) 1
• Niraparib received FDA approval for "all comers" based on PRIMA trial, though magnitude of benefit varies by HRD status 1

Platinum-Sensitive Relapsed Disease

• All patients with platinum-sensitive relapsed HGSOC benefit from PARPi maintenance, regardless of BRCA or HRD status (FDA/EMA approved for "all comers") 1
• HRD testing determines magnitude of benefit: BRCA-mutated > HRD-positive > HRD-negative populations 1
• Clinical utility lies in counseling patients about anticipated benefit and deciding between chemotherapy plus bevacizumab versus chemotherapy alone with subsequent PARPi maintenance 1

Beyond Second-Line Therapy

• BRCA mutation testing is required for olaparib/rucaparib monotherapy approval in this setting 1
• Niraparib approval extends to HRD-positive patients using FDA-approved companion diagnostics 1

Critical Limitations and Pitfalls

Negative Predictive Value Problem

• Existing HRD tests lack negative predictive value and fail to consistently identify patients deriving no benefit from PARPis 1
• BRCA wildtype patients still derive significant (though numerically smaller) benefit from PARPi therapy 1
• Platinum sensitivity itself is a powerful biomarker of HRD, contributing to benefit in HRD-negative populations 1

Dynamic Nature of HRD

• HRD status is not static: reversion mutations in BRCA genes can restore homologous recombination proficiency (HRP) and cause resistance 1, 4
• Genomic scar assays measure historical HRD but do not capture real-time HRR capacity or resistance mechanisms 1, 4
• Testing at initial diagnosis may not reflect HRD status at recurrence after platinum exposure 4

Test Selection Considerations

• Both germline and somatic testing offer complementary information and should ideally be performed 3
• Germline testing identifies hereditary cancer risk requiring cascade family testing 2, 3
• Somatic testing captures tumor-specific BRCA mutations (5-7% of HGSOC) and broader genomic instability 1
• Timing matters: ensure HRD status is known at completion of upfront chemotherapy to facilitate maintenance therapy decisions 3

Evidence Quality Assessment

The ESMO 2020 guidelines provide Level I evidence for 1:

• Germline BRCA mutations: Good clinical validity and utility
• Tumor BRCA mutations: Good clinical validity and utility
• GIS assays: Good clinical validity and utility
• LOH assays: Good clinical validity, good utility in relapsed setting

Level II evidence exists for 1:

• Somatic BRCA mutations alone: Good/fair clinical validity
• Non-BRCA HRR gene mutations: Marginal clinical utility (limited data)

Future Directions

Composite biomarkers combining platinum sensitivity, genomic scar testing, and functional assays are needed to provide both historical evidence of HRD and real-time HRR capacity 1

Functional assays (RAD51 foci) show promise for real-time HRD assessment but require prospective validation in larger clinical cohorts before clinical implementation 1

The field urgently needs better biomarkers to identify current homologous recombination proficiency status and address the dynamic nature of HRD phenotype 1