Introduction/Background The efficacy of the Myriad myChoice® Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors has been demonstrated in several phase III trials. However, its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test.
Methodology As part of the ENGOT HRD European Initiative, a subset of the PAOLA-1/ENGOT-ov25 phase 3 trial was analyzed in the Geneva University Hospitals with the OncoScan™ CNV Assay and an in-house algorithm developed using TCGA data. Results were compared to Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the Olaparib+Bev and placebo+Bev arms.
Results The analysis of the TCGA cohort revealed that a normalization of the number of LST (large-scale state transitions) by the number of whole-genome doubling events allows a better separation and classification of HRD samples than the Myriad GIS. On the 469 PAOLA-1 samples, the Geneva test yielded a lower failure rate than Myriad (10/469 vs 59/469 inconclusive results) and positive and negative agreement values of 96% (204/213) and, respectively, 81% (159/197). In Geneva HRD-positive samples, the hazard ratio (HR) was 0.40 (95% CI: 0.28–0.57; figure 1). For Myriad, the HR was 0.35. In BRCA wild-type and Geneva HRD-positive samples, the HR was 0.53 (Myriad: 0.41). Of note, in this subpopulation the Geneva test and the Myriad test yielded a similar 1-year PFS (87% and 88%) but a different 2-year PFS (52% vs 60%).
Conclusion The proposed test is a viable alternative to the Myriad myChoice HRD test and can easily be implemented in a clinical laboratory for routine practice. The performance of the tests is similar in terms of hazard ratio but the lower failure rate of the Geneva HRD test allows a 10% increase in the number of patients receiving a conclusive laboratory result.
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