Detection of molecular signatures of homologous recombination deficiency in endometrial cancer (180)

Abstract

<b>Objectives:</b> Homologous recombination repair deficiency (HRD) is observed in endometrial cancer (EC). Tumors harboring HRD are candidates for poly-ADP-ribose polymerase inhibitor (PARP inhibitor), and several PARP inhibitor trials in EC are underway. However, the prevalence and mechanism of HRD in endometrial cancer are less characterized. <b>Methods:</b> Ninety-five patients with endometrial cancer with a median follow-up of 55 months were included in this study. The homologous repair status was determined using genomics scar scores (including loss-of-heterozygosity, large-scale transitions, number of telomeric allelic imbalances, and ploidy). In addition, microsatellite instability (MSI), tumor mutation burden (TMB), and genomic mutation landscape were obtained using a panel-based next-generation sequencing assay. <b>Results:</b> Among 95 patients, we detected 15/95 (15.8%) patients with HRD (HRD score > 0). Homologous repair pathway and DNA damage pathway alterations did not contribute to HRD. Patients with HRD were associated with increased <i>TP53</i> mutation (HRD vs HRP, 92.3% vs 15.4%, p < 0.0001) and lower TMB (HRD vs HRP; 2.8 vs 26.3, p=0.02). Although patients with HRD presented significantly higher stages (p = 0.03), only marginal p values were found related to recurrence rate (p = 0.08). Median PFS was numerically higher in HRD (20 months, 95% CI: 14.1 - 25.9) versus HRP (40 months, 95% CI: 7.1 -72.9). Additionally, the HRD score was not related to the clinical outcomes of. platinum-based chemotherapy (<i>n</i> = 45) or immunotherapy (<i>n</i> = 20) for the treatment of recurrence. <b>Conclusions:</b> A subset of endometrial tumors has genomic features suggestive of HRD and has a tendency towards a worse prognosis. However, EC patients with HRD may be more likely to benefit from therapies, such as PARP inhibitors.