Abstract A019: Analytical validation of homologous recombination deficiency (HRD) status in patients with ovarian cancer using the OmniSeq® INSIGHT (OSI) test

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Abstract Background: The introduction of poly (ADP-ribose) polymerase (PARP) inhibitors has transformed the therapeutic landscape for patients with epithelial ovarian, fallopian tube, and primary peritoneal cancers (EOC), particularly those harboring BRCA1/2 mutations or tumors characterized by homologous recombination deficiency (HRD). Identifying HRD status is critical to inform the selection of maintenance therapy in patients with advanced EOC because it is associated with improved clinical outcomes. Here, we present the analytical performance of Labcorp’s expanded OmniSeq® INSIGHT (OSI+HRD) test to determine HRD and inform treatment decisions. Methods: The OSI+HRD test utilizes the Illumina TSO500 High-Throughput (HT) and HRD assays, NovaSeq 6000 sequencers, and DRAGEN TSO500 HRD pipeline. The HRD component includes ∼25K genome-wide probes to assess genomic scars, including loss of heterozygosity (LOH), telomeric-allelic imbalance (TAI), and large-scale state transitions (LST). To determine HRD status, a proprietary pipeline generates a genomic instability score (GIS) score, which is used with BRCA1/2 mutational status to determine HRD status. The validation study consisted of accuracy, precision, limit of detection (LOD), limit of blank (LOB), and sample input experiments, utilizing 169 patient samples across 13 different tumor types. Results: The analytical accuracy of OSI+HRD assay to determine GIS and HRD status was evaluated by using 66 ovarian cancer specimens, orthogonally tested using a validated HRD assay. The HRD GIS values were highly concordant between the two tests (Pearson’s correlation R=0.97). For 53 samples with a definitive HRD status determined by both assays, the observed PPA and NPA were 89.47% and 97.06%, respectively. The majority of the discordant cases were either near the GIS cutoff of 42, or due to different BRCA1/2 variant classification. Three commercial HRD contrived control samples with verified HRD status were also assessed, yielding a PPA and NPA of 100%. Assay precision was assessed using 8 HRD-positive samples and 2 HRD-negative samples, to assess variability within runs, between runs and across operators, days, instruments, reagent lots, and DNA input amounts. The pooled standard deviation of GIS values for these studies for HRD-positive samples was 2.51. For HRD-negative samples, the mean absolute deviation was 1.13. The Limit of Detection (LOD) was determined using the minimum percentage of tumor nuclei needed to successfully call HRD positivity and was established to be 30%. Conclusions: This study supports the clinical validity of this HRD assay as a reliable tool for identifying patients with EOC who may benefit from PARP inhibitors. The assay successfully detected HRD status, including BRCA1/2 mutations and GIS score. This assay demonstrated 94.34% (50/53) concordance with orthogonal validated assays and high reproducibility, supporting it as a sensitive, specific and robust diagnostic option for patients with advanced EOC. Citation Format: Jie An, Hardik I. Parikh, Michael J. Collins, Erin A. DeBlasi, Erik Van Roey, Yamuna Pulivendula, Angela Stout, Hanchun T. DeFedericis, Stacey Gabrielli, Natalie Church, Nicholas Perez, Heather Boyanich, Daniel Metzger, Collin Parrow, Yvette Rodriguez, Julianna Du Hart, Jennifer Meyn, David Starks, Rachel J. Elsey, Tobias Meissner, Stephanie B. Hastings, Kyle C. Strickland, Michelle Green, Eric A. Severson, Pratheesh Sathyan, Shakti Ramkissoon, Rebecca A. Previs, Sarabjot Pabla, Taylor J. Jensen. Analytical validation of homologous recombination deficiency (HRD) status in patients with ovarian cancer using the OmniSeq® INSIGHT (OSI) test [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A019.

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