Performance and clinical utility of homologous recombination deficiency (HRD) determined by genome-wide loss of heterozygosity (LOH).

Abstract

e15025 Background: Homologous recombination deficiency (HRD) status plays an important role in identifying patients with ovarian cancer likely to benefit from Poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum-based chemotherapies. Methods: ACTHRD is an NGS-based assay was designed to determine the homologous recombination deficiency (HRD) status based on the extent of genome-wide loss of heterozygosity (gLOH) and the detection of BRCA1/2 genes alteration. More than that, ACTHRD also assesses the mutational status of 22 homologous recombination repair (HRR) genes. We evaluated the performance and clinical utility of the ACTHRD and compared it with the FDA-approved companion test myChoice CDx. Results: Of the 36 specimens assayed, 24 were determined to be HRD, and 10 were determined to be homologous recombination repair proficient (HRP). The results showed high concordance with myChoice CDx with 100% positive percent agreement (PPA) and 90.91% negative percent agreement (NPA) in the HRD status estimation. Except one case showed HRD in the ACTHRD but showed homologous recombination proficiency (HRP) in the comparator panel. This patient responded to platinum-based chemotherapy and remained disease-free for up to 56 months. One BRCA1/2 wild-type patient was identified as HRD by myChoice CDx but not eligible for ACTHRD test due to low tumor cellularity experienced refractory 13 months after the initiation of the treatment. We further found that ovarian cancer patients identified as HRD by ACTHRD had significantly prolonged progression-free survival (PFS) after being treated with platinum-containing chemotherapies, regardless of BRCA1/2 mutational status. Conclusions: The ACTHRD assay provides high accuracy for identifying deleterious BRCA1/2 alterations and determining the HRD status of ovarian cancers. The analytical robustness of the test has been validated and indicates its suitability for clinical use. Notably, the prognosis data demonstrates that ACTHRD can predict eligible patients for platinum-based chemotherapy and may also be sensitive to PARPi treatment.