Allen, Deborah Emma

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

5020 Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP inhibitor to the efficacy observed for the combination, we conducted a randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer. Methods: Pts were ≥ 18 yrs, KPS ≥ 70%, had adequate organ function, prior therapy with PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone or V+C. At disease progression, pts on C alone were allowed to cross over to the combination. Radiologic imaging was performed at baseline and q 3 cycles for assessment of response. Dose reduction of V was allowed to 40 mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study design had an 88% power to detect the difference between a 15% RR for C alone versus 35% for V+C, early closure if fewer responses were observed on the combination arm in the first 65 pts enrolled (half of the total projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts V+C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 pts had prior PARP therapy. Treatment was well tolerated, Gr ≥ 2 toxicities per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis (1); V+C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 36 pts on V+C and 5 PRs of 38 pts on C alone arm; thus accrual was stopped. PAR levels assessed by validated ELISA were inhibited (>80%) in PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. Exomic sequencing, gene expression studies, and Fanconi Anemia triple stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation using archival tissue are ongoing.