Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer

Background The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, a decentralized HRD test based on low coverage shallow Whole Genome Sequencing (sWGS). Methods The study comprised 368 patients from the PAOLA-1 trial. The sWGS test was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). Results We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI) 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 90%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). Only 1% (95% CI; 0-3%) of its results were inconclusive. In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with sWGS and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.98 (95% CI; 0.68-1.41) and 1.05 (95% CI; 0.70-1.57) with sWGS and Myriad tests. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with sWGS and Myriad test. Conclusion The SeqOne sWGS assay offers a clinically validated approach to detect HRD.