Abstract 760P
Background
Patients with advanced high-grade serous ovarian cancer (HGSOC) are usually treated with paclitaxel and carboplatin; however, predictive markers for this drug combination are poorly defined.
Methods
Tumor samples from 71 consecutive HGSOC patients, who received neoadjuvant chemotherapy with paclitaxel and carboplatin, were subjected to molecular analysis.
Results
BRCA1/2 germline mutation carriers (n = 22) had longer treatment-free interval (TFI) than non-carriers (n = 49) (9.5 months vs. 3.8 months; P = 0.007). Fifty-one HGSOCs had sufficient quality of tumor DNA for the next-generation sequencing (NGS) analysis. These tumors were examined by the SeqCap EZ CNV/LOH Backbone Design 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 showed a high number of evenly spread chromosomal breaks, which 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 HDR scoring system [Telli et al., 2016], 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 of the chromosome 8, while this event was significantly 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 paclitaxel plus carboplatin.
Conclusions
This study describes a cost-efficient method of detecting the BRCAness phenotype, which is compatible with the laboratory-scale NGS equipment. Some molecular predictors allow the identification of potential non-responders to paclitaxel plus carboplatin, who may need to be considered for other treatment options.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work has been supported by the Russian Science Foundation (grant 19-75-10062).
Disclosure
All authors have declared no conflicts of interest.