The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Abstract

The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.

Keywords: biomarkers; homologous recombination deficiency; ovarian cancer; poly(ADP-ribose) polymerase inhibitors.

Figure 1

Timeline of US Food and Drug Administration (US FDA) PARPi approvals. PARPi approvals by the US FDA (described in blue boxes) and European Medicines Agency (EMA) (described in green boxes) between 2014 and 2020. AdvOC, advanced ovarian cancer; CR, complete response; gBRCA-mut, germline BRCA1/2 mutation; HRD, homologous recombination deficiency; PR, partial response; rOC, recurrent ovarian cancer.

Figure 2

Current clinical-grade genomic scar assays to determine HRD positivity. Left panel: myChoice CDx (Myriad Genetics) uses a proprietary formula to calculate a genomic instability score (GIS) based on three genomic elements: LOH, TAI, and LST. GIS ≥42 and/or BRCA1/2 mutation status would be denoted as homologous recombination deficiency (HRD) positivity. On the PRIMA trial (NCT02655016), investigating frontline maintenance niraparib in patients with advanced ovarian cancer who have complete or partial response to frontline chemotherapy, the proportion of enrolled patients who were denoted HRD positive, negative, and indeterminate/unknown is presented. Right panel: FoundationOne CDx (Foundation Medicine) includes the %LOH score measuring the percentage of genomic LOH as a marker of HRD positivity, %LOH ≥16 is denoted as %LOH-high. On the ARIEL3 trial (NCT01968213), investigating switch maintenance rucaparib in patients with platinum-sensitive relapsed ovarian cancer who have complete or partial response to the most recent line of platinum-based chemotherapy, the proportion of enrolled patients who were denoted BRCA1/2 mutant, %LOH-high, -low, and -indeterminate are presented. LOH, loss of heterozygosity; LST, large-scale transition; mut, mutant; TAI, telomeric allelic imbalance; wt, wild type.