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We will explore a proposed testing strategy using somatic tumor testing as an initial triage whereby those patients found with somatic testing to have HRD gene mutations are referred to genetics to determine if the mutation is germline. For now, germline and somatic tumor testing provide important and non-overlapping clinical information. The objective of this review article is to focus on the current germline and somatic contributors to ovarian cancer and the state of both germline and somatic HRD testing. In the near future, patients with germline or somatic HRD will likely be candidates for a growing list of targeted therapies in addition to poly (ADP-ribose) polymerase (PARP) inhibitors, and, as a result, establishing an infrastructure for widespread HRD testing is imperative. Furthermore, an additional 5-7% of ovarian cancer cases will have somatic HRD.
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The list of inherited mutations associated with ovarian cancer continues to grow with the literature currently suggesting that up to one in four cases will have germline mutations, the majority of which result in HRD. For now, germline and somatic tumor testing provide important and non-overlapping clinical information. HRD impairs normal DNA damage repair which results in loss or duplication of chromosomal regions, termed genomic loss of heterozygosity (LOH). However, through germline and tumor sequencing an understanding of the larger phenomenon of homologous recombination deficiency (HRD) has emerged. To understand the role of PARPis in the treatment of advanced ovarian cancerĢ.Abstract : Until recently our knowledge of a genetic contribution to ovarian cancer focused almost exclusively on mutations in the BRCA1/2 genes. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. In this session, we discuss the role of PARPis in the treatment of advanced ovarian cancer, with particular focus on the use of HRD testing to better define optimal therapy for front-line treatment of these patients.ġ. Background: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. The HRD score has come to the fore as important individualised information in patients with advanced ovarian cancer, due to its correlation with response to maintenance PARPis in the first-line therapeutic setting. Available tools have computed the following: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions to derive a summated HRD score. The presence of HRD leads to detectable signature or genomic scar which can be scored by different tools. The lack of high-fidelity HRR in these cells leads to reliance on error-prone DNA repair pathways (e.g.: non-homologous end joining), further genomic instablity and cell death. PARPis are able to induce synthetic lethality in cells with HRD by binding to and trapping PARP1 and PARP2 to single-stranded DNA breaks, which generates double-stranded breaks. HRD results in irreparable DNA damage and increased sensitivity to platinum chemotherapy, as well as increased susceptibility to poly-ADP ribose polymerase (PARP) inhibitors. High grade serous ovarian cancer is characterized by genomic instability, with ~50% of advanced tumors harboring homologous recombination repair (HRR) pathway deficiency (HRD).