From Therapy to Cancer Prevention Using HRD Testing on Patients with High-grade Ovarian Cancer.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Approximately 50% of high-grade ovarian cancers harbor genetic/epigenetic alterations in homologous recombination repair (HRR) genes, primarily BRCA1/2.
• Defects in HRR, detected via genomic instability, sensitize ovarian cancers to PARP inhibitors.
• Commercial homologous DNA repair deficiency (HRD) tests combining tumor BRCA testing and genomic instability scores are clinically available.

Purpose of the Study:

• To evaluate the performance of three distinct HRD tests.
• To improve ovarian cancer therapy management and prevention strategies.
• To correlate HRD status with treatment eligibility and inherited cancer risk.

Main Methods:

• Tumor samples from 50 high-grade ovarian cancer patients were analyzed for BRCA status, genomic instability, and BRCA1 promoter methylation.
• Patients testing positive for BRCA variants or genomic instability underwent germline testing.
• HRD status was assessed using three different commercial assays.

Main Results:

• A positive HRD status was observed in 54% of cases.
• Pathogenic BRCA variants were found in 41% of patients with genomic instability.
• BRCA1 promoter hypermethylation was detected in 20% of HRD-positive, BRCA1/2-variant-negative cancers.
• Ten out of 26 referred women carried germline HRR variants.
• HRD status determined PARP inhibitor eligibility in most cases.

Conclusions:

• HRD testing is crucial for guiding PARP inhibitor treatment in ovarian cancer.
• Genomic instability assessment aids in identifying potentially inherited ovarian cancers.
• Integrating HRD testing with genetic counseling pathways is essential for managing high-risk individuals and optimizing ovarian cancer care.