Abstract
5561 Background: The REZOLVE clinical trial investigated the effect of administering bevacizumab via the intraperitoneal route to reduce re-accumulation of ascites in patients with ovarian cancer who were not suitable for further chemotherapy. Plasma and ascites were collected throughout for translational research. Ascites contains cell-free DNA (cfDNA), a large proportion of which is tumour derived (ctDNA). There is increasing interest in cfDNA in plasma, yet little is known of it in ascites. Objectives: To compare cfDNA in ascites and plasma in terms of total concentration, tumour proportion and endothelial-cell derived (ec-cfDNA) proportion and investigate their association with clinical outcomes (paracentesis-free interval, overall survival) and CA125 level. Methods: Longitudinal plasma and ascites samples were collected from 20/24 participants and stored at -70°C for up to 8.5 years. cfDNA was extracted from 0.3-1 mL fluid using conventional protocols. Standard and methylation-specific PCR was used to measure total cfDNA, ctDNA and ec-cfDNA. Values were correlated with time to paracentesis pre- and post-bevacizumab treatment (the primary trial outcome) as well as overall survival, using log-rank tests. Relationships with clinical CA125 levels were tested by Pearson’s correlation coefficient. Comparisons between plasma and ascites used non-parametric analyses. Results: cfDNA was detected in all samples, with higher yield in ascites (average 669 ng/mL) than plasma (average 75 ng/mL, p<0.0001). ctDNA was detected in 30/32 (94%) ascites samples and 37/56 (68%) plasma samples. ctDNA was detected in plasma and/or ascites from each patient at at least 1 time point. ctDNA proportion was higher in ascites than plasma (p<0.0001) and ec-cfDNA proportion was higher in plasma than ascites (p=0.002). High ctDNA (>75%) in ascites at baseline was associated with significantly shorter paracentesis-free interval (median interval 47.5 versus 84 days, hazard ratio (HR) 2.21, 95% confidence interval (CI) 0.85 to 5.73, p=0.039). ctDNA presence in plasma at baseline was unfavourable for survival (median survival 56 versus 242 days, HR 3.21, 95% CI 1.15 to 9.00, p=0.008). A significant positive correlation was observed between ctDNA proportion in plasma and CA125 level measured within 7 days (p=0.0006). No difference in total cfDNA, ctDNA nor ec-cfDNA was observed between participants who were bevacizumab responders and non-responders in the trial. Conclusions: Sufficient cfDNA was obtained from plasma and ascites to perform qPCR for three biomarkers. Ascites was found to contain proportionately more ctDNA, while plasma contained more ec-cfDNA. The early evidence presented here supports the potential value of cfDNA biomarkers in plasma and ascites, however incorporation of their collection in future clinical trials will allow further investigation.
Published Version
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