2022-RA-913-ESGO Clinical performance evaluation of a novel deep learning solution for homologous recombination deficiency detection

Abstract

<h3>Introduction/Background</h3> Comprehensive identification of ovarian cancer (OvCa) patients that can benefit from poly (ADP-ribose) polymerase inhibitors (PARPi) treatment is currently based on genome-wide enumeration of known Homologous Recombination Deficiency (HRD) biomarkers and requires deep sequence profiles (&gt;30x). The cost and challenges of implementing available solutions currently hinders clinical adoption of HRD testing. We present the interim results for the ongoing multicenter evaluation study of SOPHiA DDM Dx HRD (SOPHiA GENETICS, SA), a novel deep learning-based solution that leverages the impact of HRD on the coverage profiles from low-pass whole-genome sequencing (lpWGS, 1x) data. <h3>Methodology</h3> In this multicenter study, we processed and analyzed according to manufacturer’s instructions, DNA from 319 formalin-fixed paraffin-embedded (FFPE) OvCa samples. We assessed the concordance between SOPHiA DDM Dx HRD solution and Myriad myChoice® CDx results. For the subset of our cohort (206 samples) included in the PAOLA-1 clinical trial, we carried out survival analysis to investigate differences in progression-free survival (PFS) in the olaparib and placebo arms of the study between patients, with HRD positive or non-positive tumors. <h3>Results</h3> We found a high overall percentage agreement, 90.48% (95% confidence interval [CI], 86.58–93.33), between SOPHiA DDM Dx HRD and Myriad myChoice® CDx status. The median PFS time for patients with HRD positive tumors was 20.8 months higher in the olaparib arm (hazard ratio [HR], 0.44; 95% CI, 0.26–0.76, P=0.003). No significant difference in PFS was observed between treatment arm in patients without HRD positive tumors (HR, 0.92; 95% CI, 0.59–1.43; P=0.69). The effect of the interaction between olaparib and HRD status on PFS, in the interim study, was similar for the two stratification methods (P=0.20). <h3>Conclusion</h3> The interim results of SOPHiA DDM Dx HRD Solution evaluation study support the value of lpWGS data for patient stratification, making it suitable for HRD testing in the clinical setting.