Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420–0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.

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A novel genomic rearrangement signature to predict poor survival among women with high grade serous ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.5509 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 5509-5509

Author(s):

Robert Tyler Hillman ◽

Karen H. Lu ◽

Phillip Andrew Futreal

Keyword(s):

Ovarian Cancer ◽

Cohort Analysis ◽

Group Versus ◽

Hazard Ratio ◽

Genomic Rearrangement ◽

High Grade ◽

Serous Ovarian Cancer ◽

Poor Survival ◽

High Group ◽

Platinum Based Chemotherapy

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]

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