Rationale for the Use of Homologous Recombination Proficient Molecular Profile as a Biomarker for Therapeutic Targeting in Ovarian Cancer.

Abstract

Therapeutic options for advanced-stage ovarian cancer patients are limited in those subjects with homologous recombination proficient molecular profiles. A recent review of the existing literature demonstrates evidence of enhanced relapse-free survival and overall survival associated with treatment with Vigil in the Phase 2b trial in the HRP population. Homologous recombination (HR) is a genetic rearrangement in which molecular information is exchanged between two similar molecules of double-stranded or single-stranded nucleic acids [1]. The purpose of HR is to maintain genome stability by performing high-fidelity repair of complex DNA damage such as DNA doublestrand breaks and interstrand crosslinks [2–4]. Homologous recombination is responsible for double-stranded DNA breaks and interstrand crosslink damage repair through the use of sister chromatids as a repair template. BRCA1/2 are critically important proteins in this pathway. HR deficiency (D) is the result of germline or somatic genetic alterations in HR genes (i.e., BRCA 1 or 2) [5]. Dysfunctional HR genes cause genome-wide errors and can lead to tumorigenesis [6, 7]. Tumors that are not HRD are considered HR proficient (P) and contain no functional genetic alterations in HR pathway genes, like BRCA1/2, resulting in faithful DNA repair, thereby reducing the mutation burden. While the HR pathway is responsible for repairing double-stranded breaks, the base excision repair pathway repairs single-stranded DNA breaks. Poly (ADP-ribose) polymerase proteins (PARPs) are essential proteins in this pathway. When PARPs are inhibited, single-stranded breaks are converted to double-stranded breaks during DNA replication. Synthetic lethality occurs in cells treated with a PARP inhibitor that have a BRCAmutation or are HRD. Alterations in HR pathway genes, especially mutations in BRCA1/2, can be germline and confer familial risk for breast, ovarian, prostate, and pancreatic cancer [8] or somatic. For patients who demonstrate negative germline testing, somatic HR molecular status is assessed by NGS and is most commonly evaluated by Myriad’s MyChoice CDx-testing. This involves the analysis of BRCA 1 and 2 gene mutation status, loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and largescale state transition score (LST) to determine a genomic instability score (GIS) [9]. Each is weighted and scored using a proprietary algorithm to determine the level of genomic instability. A GIS ≥42 in BRCA 1 or 2 negative patients defines HRD status. A GIS score <42 defines HRP status [10]. BRCA 1 or 2 mutations or HRDmolecular profile tumors are a sensitive ovarian cancer population to PARP inhibitor therapy [10–14] and are associated with a better prognosis in patients receiving platinumbased chemotherapy and/or bevacizumab [15]. However, ovarian cancer patients with HRP molecular status have a worse prognosis with standard-of-care therapy involving PARPIs, Edited by: Angela Cappello, University of Rome Tor Vergata, Italy