Characterization of BRCA Deficiency in Ovarian Cancer.

BRCA testing is recommended in all Ovarian Cancer (OC) patients, but the optimal approach is debated. The landscape of alterations was explored in 30 consecutive OC patients: 6 (20.0%) carried germline pathogenic variants, 1 (3.3%) a somatic mutation of , 2 (6.7%) unclassified germline variants in , and 5 (16.7%) hypermethylation of the promoter. Overall, 12 patients (40.0%) showed BRCA deficit (BD), due to inactivation of both alleles of either or , while 18 (60.0%) had undetected/unclear BRCA deficit (BU). Regarding sequence changes, analysis performed on Formalin-Fixed-Paraffin-Embedded tissue through a validated diagnostic protocol showed 100% accuracy, compared with 96.3% for Snap-Frozen tissue and 77.8% for the pre-diagnostic Formalin-Fixed-Paraffin-Embedded protocol. BD tumors, compared to BU, showed a significantly higher rate of small genomic rearrangements. After a median follow-up of 60.3 months, the mean PFS was 54.9 ± 27.2 months in BD patients and 34.6 ± 26.7 months in BU patients ( = 0.055). The analysis of other cancer genes in BU patients identified a carrier of a pathogenic germline variant in . Thus, BRCA sequencing alone may miss tumors potentially responsive to specific treatments (due to promoter methylation or mutations in other genes) while unvalidated FFPE approaches may yield false-positive results.