Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers

Abstract

BackgroundPlatinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC.MethodsA total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival < 6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients.ResultsMedian ascites levels of IL-6, IL-10 and osteoprotegerin (OPG) were significantly higher in women with advanced serous EOC than in controls (P ≤ 0.012). There were no significant difference in the median ascites levels of leptin, soluble urokinase plasminogen activator receptor (suPAR) and CCL18 among serous EOC women and controls. In Receiver Operator curve (ROC) analysis, IL-6, IL-10 and OPG had a high area under the curve value of 0.905, 0.832 and 0.825 respectively for distinguishing EOC from benign controls. ROC analysis of individual cytokines revealed low discriminating potential to stratify patients according to their sensitivity to first-line treatment. The combination of biomarkers with the highest discriminating potential was with CA125 and leptin (AUC = 0.936, 95 % CI: 0.894–0.978).ConclusionIL-6 was found to be strongly associated with advanced serous EOC and could be used in combination with serum CA125 to discriminate benign and EOC. Furthermore, the combination of serum CA125 and ascites leptin was a strong predictor of clinical resistance to first-line therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1511-7) contains supplementary material, which is available to authorized users.

Ascites modulates cancer cell behavior, contributing to tumor heterogeneity in ovarian cancer

“…These factors cumulatively contribute to creating a pro‐inflammatory and immunosuppressive tumor microenvironment . Among these factors, IL‐6 and IL‐10 have received the most attention due to their correlation with poor prognosis and response to therapy …”

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

“…Patients with EOC and higher IFN-γ expression levels in ascites have shorter disease-free progression and overall survival [54]. Measuring cytokines in ascites may also provide a novel approach to discriminate patients with intrinsic resistance to irst-line therapy [55]. The authors found that the combination of serum CA125 and ascites leptin levels was a strong predictor of clinical resistance to irst-line therapy.…”

Ascitic Fluid in Ovarian Carcinoma – From Pathophysiology to the Treatment

“…The concentration of these proinflammatoy cytokines in ascites is 40-500 folds greater than in serum. IL-6 may be secreted in ovarian cancer cells, tumor-associated macrophages, and peritoneal mesothelial cells, which have the highest potential for secretion of this interleukin [68,69].…”