Abstract
Approximately half of high-grade ovarian cancers are characterized by genetic and epigenetic alterations in genes involved in homologous recombination repair (HRR), most commonly BRCA1 and BRCA2. HRR defects (HRD) identified by tests of genomic instability confer PARP inhibitor sensitivity in ovarian cancers. Commercial tests that combine tumor BRCA testing with a genomic instability score (HRD test) are available in clinical practice. We seek to determine the performance of three different HRD tests to improve therapy management and prevention of ovarian cancer. Tumor samples from 50 patients with high-grade ovarian cancers were investigated for tumoral BRCA status, genomic instability, and BRCA1 promoter methylation for treatment purposes. Patients with ovarian cancer that tested positive for BRCA variants and/or genomic instability defect were referred to the Cancer Genetics Service for germline testing. A positive HRD status was observed in 54% of cases, and pathogenic variants in BRCA genes were identified in 41% of cases presenting genomic instability. BRCA1 methylation assay revealed promoter hypermethylation in 20% of ovarian cancers that tested positive for HRD and negative for BRCA1/2 variants. Among 26 women referred to cancer genetic counseling, 10 carried germline variants in HRR genes. HRD status determined eligibility for PARP inhibitor treatment in all but two ovarian cancers. This study outlines that determining genomic instability helps identify inherited ovarian cancers. HRD testing, crucial for making high-grade ovarian cancer treatment choices, must be linked to an established path of cancer genetic counseling and management of individuals at high cancer risk.
Prevention Relevance: Genomic instability status (HRD testing), which is essential for making therapy choices, is useful to identify inherited ovarian cancers. Identifying these families with high cancer risk is critical for implementing targeted cancer prevention strategies.
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