Cytokine profiling of ascites at primary surgery identifies an interaction of tumor necrosis factor-α and interleukin-6 in predicting reduced progression-free survival in epithelial ovarian cancer

Abstract

Objectives Epithelial ovarian cancer (EOC) typically presents with advanced disease. Even with optimal debulking and response to adjuvant chemotherapy, the majority of patients will have disease relapse. We evaluated cytokine and chemokine profiles in ascites at primary surgery as biomarkers for progression-free survival (PFS) and overall survival (OS) in patients with advanced EOC. Methods Retrospective analysis of patients (n =70) who underwent surgery at Roswell Park Cancer Institute between 2002-12, followed by platinum-based chemotherapy. Results The mean age at diagnosis was 61.8 years, 85.3% had serous EOC, and 95.7% had stage IIIB, IIIC, or IV disease. Univariate analysis showed that ascites levels of tumor necrosis factor (TNF)-α were associated with reduced PFS after primary surgery. Although the ascites concentration of interleukin (IL)-6 was not by itself predictive of PFS, we found that stratifying patients by high TNF-α and high IL-6 levels identified a sub-group of patients at high risk for rapid disease relapse. This effect was largely independent of clinical prognostic variables. Conclusions The combination of high TNF-α and high IL-6 ascites levels at primary surgery predicts worse PFS in patients with advanced EOC. These results suggest an interaction between ascites TNF-α and IL-6 in driving tumor progression and resistance to chemotherapy in advanced EOC, and raise the potential for pre-treatment ascites levels of these cytokines as prognostic biomarkers. This study involved a small sample of patients and was an exploratory analysis; therefore, findings require validation in a larger independent cohort.

Impact of ascites volume on clinical outcomes in ovarian cancer: A cohort study

“…We observed that the combination of high levels of IL-6 and TNF-α in ascites of patients with newly diagnosed epithelial ovarian cancer predicted worse outcome [28]; however, this was a small single-center study, and cytokine profiling from other centers have produced different results [29]. In addition to stimulating thrombocytosis, IL-6 within the tumor microenvironment can have broad effects on tumor, inflammatory, and non-immune stromal cells, including increasing endothelial cell permeability that drives ascites generation [30].…”

Metabolomic characterization of experimental ovarian cancer ascitic fluid

“…Prognostic factors for advanced epithelial ovarian cancer principally rely on age, performance status, residual tumor volume following primary surgery, and tumor histology (Kolomeyevskaya et al 2015). It has been shown that substantial variability in progression-free survival exists among women with similar disease stage (Kolomeyevskaya et al 2015).…”

“…It has been shown that substantial variability in progression-free survival exists among women with similar disease stage (Kolomeyevskaya et al 2015). The accessibility of ascites composition could provide an opportunity to identify prognostic and treatment-monitor markers (Ahmed and Stenvers 2013).…”

“…The combined measurement of CA125 and CYFRA21-1 in fluid assisted in detecting all ovarian cancer and papillary serous carcinoma of the peritoneum (Trape et al 2015). Other studies have examined cytokines as predictive factor, showing an interaction between ascites TNF-α and IL-6 in driving tumor progression and resistance to chemotherapy in advanced epithelial ovarian cancer (Kolomeyevskaya et al 2015). NMR derived biomarkers of ascites can provide companion diagnostics of ovarian cancer, and enhance our understanding of the biochemical and metabolic changes associated with ovarian cancer, and with ascites formation.…”

Redefining the origin and evolution of ovarian cancer: a hormonal connection

“…Indeed, cytokines present in the post-ovulatory ovaries such as IL-6, IL-8, CCL2/MCP-1 and CCL5/RANTES have been demonstrated to modulate ovarian cancer (Freedman et al 2004). These factors have been shown to induce in vitro growth of ovarian cancer cell lines, induce expression of angiogenic factors such as VEGF and inversely correlate with patient survival (Kolomeyevskaya et al 2015, So et al 2015, Eichten et al 2016.…”