Treatment with PARP inhibitors in the maintenance of ovarian cancer has been a revolution in the natural history of the disease, especially in those cases carrying BRCA mutations. Within this population, it has been described that alterations in the RING region of BRCA-1 confer resistance to PARP inhibitors by forming a hypomorphic protein that can activate RAD51. There is little data on whether different functional domains in the BRCA 1 and 2 genes can modulate the response to PARP inhibitors and there is no validation of these in real-life data.
Among the 195 collected cases of high-grade ovarian cancer, 38 patients were identified as BRCA gene mutation carriers, either germinal or somatic.
To determine the functional domain of each of the mutations, Clinvar search engine was used.
Statistical analysis was performed using nonparametric tests due to the small sample size.
27 patients were treated with iPARP maintenance and are included in the study.
The median age at diagnosis was 55 years.
33% were treated as first line maintenance, 42% after first relapse and 25% in subsequent lines. 15% received Niraparib, 78% received Olaparib and 7% received the combination of Olaparib and Bevacizumab as maintenance treatment.
Among the BRCA 1 mutation carriers (55.5% of the total), 13% had mutations in the DBD domain, 13% in BRCT and 6% in RING. The rest were located outside the functional domains of the protein.
Among patients with BRCA-2 mutation, 16% had mutations in the DBD domain and 58% in RAD51.
With a median follow-up of 23 months (range 2-79), thirty-three percent of patients have experienced disease progression after iPARP treatment. It is noteworthy that among cases carrying mutations in the RING domain, the progression-free interval with iPARP was only 2 months.
Even so, no statistically significant differences were detected between genotype and progression-free interval.
Despite the small number of cases and the paucity of progression events, no differential pattern between genotype and duration of response with iPARP treatment is apparent. In the few cases with mutations in the RING domain, the benefit with iPARP is very limited, although these data require validation in series with larger numbers of patients.