| Summary: | PARP inhibitors yield interesting outcomes for patients with ovarian tumors harboring <i>BRCA1</i> or <i>BRCA2</i> mutation, but also with other tumors with homologous repair (HR) deficiency. About 40% of variants are variants of unknown significance (VUS), blocking the use of PARP inhibitors. In this study, we analyzed NGS data from 78 metastatic patients treated with PARP inhibitors. We tested NGS data and in silico predictions to classify VUS as potentially benign or deleterious. Among 41 patients treated with olaparib, three had tumors harboring benign and 26 pathogenic variants, while 12 had VUS. Progression-Free Survival (PFS) analysis showed that benign variants did not respond to olaparib whereas pathogenic variants were associated with a median PFS of 190 days. Surprisingly, median PFS of patients with VUS-carrying tumors suggested that some of them may be sensitive to PARP inhibitors. By testing different in silico predictions and variant allelic frequency, we obtained an algorithm predicting VUS sensitivity to PARP inhibitors for patients with a Performance Status below 3. Our work suggests that VUS in HR genes could be predicted as benign or deleterious, which may increase the number of patients eligible for PARP inhibitor treatment. Further studies in a larger sample are warranted to validate our prediction algorithm.
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