Comprehensive evaluation of genomic and functional assays for homologous recombination deficiency with high-grade epithelial ovarian cancer: Platinum sensitivity and prognosis.

Abstract

Objective: Homologous recombination deficiency assays, guiding treatment of poly (adenosine diphosphate ribose) polymerase inhibitors, are increasingly applied in clinics. This study aimed to evaluate the predictive performance of homologous recombination deficiency status at genomic and functional perspective on the efficacy of platinum-based chemotherapy in ovarian cancer.

Methods: Between 2016 and 2019, 134 patients with high-grade ovarian cancer were retrospectively analyzed. Formalin-fixed paraffin-embedded tissues were subjected to DNA sequencing using the AmoyDx HRD Complete Panel. The genomic scar score and the genomic instability score were calculated based on copy number variation events. Furthermore, the RAD51 and SLFN11 protein levels in tumors were assessed by immunohistochemistry.

Results: Of all patients, 106 of 134 (79.1%) were homologous recombination deficiency (genomic scar score)-positive, with a higher platinum sensitivity rate than those who were homologous recombination deficiency (genomic scar score)-negative (78.3% vs 57.1%, p = .023). Similarly, 104 of 134 (77.6%) were homologous recombination deficiency (genomic instability score)-positive, with increased platinum sensitivity compared with homologous recombination deficiency (genomic instability score)-negative (77.9% vs 60.0%, p = .049). The overall concordance rate of homologous recombination deficiency status defined by the 2 scores was 98.5%. Genomic scar score and genomic instability score determined homologous recombination deficiency-positive statuses correlated with better progression-free survival (p = .0019, p = .0041) and overall survival (p = .018, p = .031). Patients with nuclear RAD51-loss or SLFN11-positive expression were likely to be homologous recombination deficiency-positive by genomic scar score/genomic instability score (94.1% and 97.6%; 94.1% and 95.2%, respectively). Patients with nuclear RAD51-loss and SLFN11-positive expression had better overall survival than those with RAD51-positive and SLFN11-negative expression. Among homologous recombination deficiency statuses, RAD51 and SLFN11 expressions, homologous recombination deficiency (genomic scar score)-positive was most associated with progression-free survival and platinum sensitivity. Multivariate regression analysis showed that homologous recombination deficiency (genomic scar score)-positive status was a good prognostic factor, implying a higher possibility of platinum sensitivity.

Conclusion: Genomic scar score, given by AmoyDx HRD Complete Panel, was most associated with the efficacy of platinum treatment in patients with high-grade ovarian cancer. Validation is warranted via prospective studies.