5509 Background: Resistance to platinum-based chemotherapy is a major cause of disease progression and mortality among women with high grade serous ovarian cancer (HGSOC). It is not known whether patterns of genomic rearrangement are predictive of clinical outcome in HGSOC. Methods: This was a retrospective cohort analysis of whole genome sequences from 80 HGSOC tumors. Genomic rearrangements were identified and categorized by size and type (inversion, duplication, deletion, or translocation). Non-negative matrix factorization was then used to extract rearrangement signatures. Wilcoxon rank-sum test was used for comparison of continuous variables. Univariate and multivariate analyses were performed using Cox proportional hazards models. Results: A rearrangement signature characterized by 10 kilobase to 10 megabase duplications and deletions was identified. The median overall survival (OS) was 22.5 months (95% CI, 20.1 to 33.5 months) in the Sig-High group versus 46.0 months (95% CI, 27.7 to 80.6 months) in the Sig-Low group (hazard ratio, 2.13; 95% CI, 1.27 to 3.55; P=0.004). Exploration of clinical variables showed a significantly higher median signature contribution in platinum-resistant disease than platinum-sensitive disease (20.0% vs 9.1%, p=0.007). Multivariate analysis showed a hazard ratio for death of 2.1 associated with the Sig-High group (Table). Validation of this signature was performed using HGSOC copy number data from the Cancer Genome Atlas. In this cohort, the median OS was 38.8 months (95% CI, 36.7 to 44.5 months) in the Sig-High group versus 49.5 months (95% CI, 45.2 to 56.3 months) in the Sig-Low group (hazard ratio, 1.44; 95% CI, 1.14 to 1.82; P=0.024). Conclusions: A genomic rearrangement signature is associated with chemoresistance and poor prognosis in HGSOC. Prediction of poor survival outcomes could allow early identification of women who may be candidates for clinical trials. [Table: see text]
Genomic Rearrangement Signatures and Clinical Outcomes in High-Grade Serous Ovarian Cancer
