Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature

Melissa K Frey, Bhavana Pothuri, Melissa K Frey, Bhavana Pothuri

Abstract

Until recently our knowledge of a genetic contribution to ovarian cancer focused almost exclusively on mutations in the BRCA1/2 genes. However, through germline and tumor sequencing an understanding of the larger phenomenon of homologous recombination deficiency (HRD) has emerged. HRD impairs normal DNA damage repair which results in loss or duplication of chromosomal regions, termed genomic loss of heterozygosity (LOH). 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. Furthermore, an additional 5-7% of ovarian cancer cases will have somatic HRD. 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. 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. For now, germline and somatic tumor testing provide important and non-overlapping clinical information. 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. This strategy allows for rapid access to genomic information that can guide targeted treatment decisions and reduce the burden on genetic counselors, an often limited resource, who will only see patients with a positive somatic triage test.

Keywords: Genetics; Ovarian cancer; Tumor testing.

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