175 Cost-efficient analysis of BRCAness status in high-grade serous ovarian carcinomas

Introduction/Background* Paclitaxel/carboplatin (TCbP) is a standard therapy for high-grade serous ovarian cancer (HGSOC), however many patients do not benefit from this combination. Methodology Genetic profiling was performed for 71 HGSOC consecutive patients, who received neoadjuvant chemotherapy (NACT). Result(s)* BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 vs. 3.8 months; P = 0.007). 51 HGSOCs with sufficient quality of tumor DNA were examined by the SeqCap EZ CNV/LOH Backbone Design NGS panel, which systematically spans the entire genome at 50 kb intervals. All 13 tumors obtained from BRCA1/2 germline mutation carriers and 12 sporadic HGSOCs had high number of evenly spread chromosomal breaks, that was defined as a BRCAness phenotype; median TFI for this combined group approached 9.5 months. The remaining 26 HGSOCs had similarly high global LOH score (above 20%); however, in contrast to BRCAness tumors, LOH involved large chromosomal segments; these patients had significantly lower TFI (3.7 months; P = 0.006). Comparison between this newly developed BRCAness test, which discriminated tumors simply by the number of affected genomic segments, and the commonly accepted HRD scoring system, revealed high concordance of the results and at least non-inferior clinical performance of our assay. Virtually all tumors with BRCAness (23/25 [92%]) demonstrated gain at MYC locus, while this event was less common in non-BRCAness HGSOCs (12/26 [46%]; P = 0.0006). All patients with CCNE1 amplification (n = 7), TP53 R175H substitution (n = 6), and RB1 mutation (n = 4) had poor response to TCbP. Conclusion* BRCA1/2 germ-line testing has superior performance in identifying responders to TCbP. Simple and rapid PCR-based tests for MYC and CCNE1 amplification allow to classify patients for potential responders and non-responders with a reasonable level of accuracy. BRCAness phenotype can be reliably detected by a laboratory-scale NGS assay, which evaluates the total number of chromosomal breaks. It is of concern that TCbP is being routinely administered both to potential responders and to potential non-responders to this scheme. Novel treatment options for the latter category of HGSOC patients need to be searched within preclinical and clinical studies.