Prognostic and predictive significance of VEGF and TNFα levels in ascites of patients with epithelial ovarian cancer. Correlation with lymphocytes subpopulations

Background

Cytokines regulate immune response and have been associated with prognosis in epithelial ovarian cancer (EOC) patients. Specific lymphocytic subpopulations may also affect response to treatment and outcomes. Study of immunoregulatory factors in ascites may be more relevant than in blood. We have previously shown that the levels of Vascular Endothelial Growth Factor (VEGF) and Tumor Necrosis Factor alpha (TNFα) in ascites from EOC patients correlated with specific lymphocytic subpopulations and with survival. We now report our confirmatory study in a larger series.

Methods

Ascites was collected from 105 patients with EOC, prior to frontline chemotherapy. Soluble VEGF and TNFα levels were determined by standard ELISA methods. Flow cytometric analysis was used to determine lymphocytic subpopulations. Surface expression of CD3, CD8, CD4, CD56, CD45, HLA-DR, and CD127 using fluorescence activated cell scanning (FACS) was analyzed. Median was used as a cut-off for all analyzed parameters.

Results

VEGF levels in ascites were inversely correlated with HLA-DR expressing (marker of activation) CD4 and CD8 lymphocytes. No correlation was found between TNFα levels and lymphocytic subpopulations. Among patients receiving frontline chemotherapy, TNFα levels above median were correlated with platinum sensitivity (P = 0.005). High TNFα levels, low number of Natural Killer (NK)(CD3-CD56+) cells and optimal debulking surgery were associated with improved Progression Free Survival (PFS) and Overall Survival (OS). In multivariable analysis, only high TNFα levels retained its statistical significance for both PFS (HR 0.49, 95% CI 0.27-0.93) and OS (HR 0.51, 95%CI 0.27-0.98).

Conclusions

TNFα levels in ascites holds promise as a biomarker in EOC, but further validation is necessary. Our results support our previous in vitro findings showing an immunosuppressive effect of VEGF on ascitic lymphocytes form EOC patients. This indicates that immunological parameters may be of value as predictive markers for response to anti-angiogenic therapy.

Clinical trial identification

Legal entity responsible for the study

National and Kapodistrian University of Athens

Funding

National and Kapodistrian University of Athens

Disclosure

M. Liontos, E. Kostouros: Janssen. F. Zagouri: Honoraria from Novartis and Roche. K. Koutsoukos: Honoraria from Roche, Novartis and Genesis pharma. E. Terpos: Honoraria: Celgene, Amgen, Janssen-Cilag, Novartis, Takeda Pharmaceuticals, Roche, Medtronic. M. Dimopoulos: Honoraria from Celgene, Janssen and Takeda. A. Bamias: Roche, Amgen and Janssen. All other authors have declared no conflicts of interest.