Comprehensive cytokine, chemokine and immune marker evaluation in plasma samples of primary, non-metastatic high grade serous ovarian cancer patients to estimate outcome and platinum resistance

Background: Ovarian cancer (OC) still has the highest mortality rate of all gynecological malignancies, diagnosed mostly at advanced stages, resulting in a generally poor outcome. Radical tumor debulking, followed by platinum-based chemotherapy with/without bevacizumab and with/without PARP inhibitors is the standard of care in advanced OC. However, the majority of patients will ultimately relapse due to the development of platinum resistance. Efforts to apply immunotherapy has been less successful, however, immunologic processes play an important role in tumorigenesis and therapy response. Little is known about immune-marker, cytokine and chemokine expression in OC. In view of biomarker research to identify patients at high risk for relapse, we here determined cytokine/chemokine/immune-related marker levels in blood samples of primary, non-metastatic, high grade serous (HGS) OC patients before and after therapy to estimate their value with regard to progression-free survival (PFS), overall survival (OS) and platinum resistance. Patients and Methods: Plasma samples of 53 HGSOC patients were collected prior (n=53) and following platinum-based chemotherapy (n=27) with/without bevacizumab. Cytokine/chemokine/immune-related marker levels were quantified using the Olink Target 48 Cytokine panel and Immune Surveillance Panel (LuminoDx, San Diego, USA), which includes total 89 immune-related proteins and requires only one μL of sample. Results were correlated between cytokine/chemokine/immune related marker levels and PFS and OS using the Cox proportional hazards model and Log-rank test as well as platinum resistance applying the student`s t-test. Results: Associations between cytokine/chemokine/immune-related marker levels and patient outcomes were evaluated using Cox proportional hazards models. At baseline, lower IL19 levels and higher FASLG and CEACAM5 levels were significantly associated with an improved PFS (p<0.01). Lower IL17A, IL19, VEGFA, IL27 and higher FASLG levels were significantly associated with a longer OS (p<0.01). Decreases in FASLG and CEACAM5 levels over the course of treatment correlated with a longer PFS while increasing VEGFA levels were significantly associated with a longer OS. Additionally, high baseline IL19 and IL6 levels and low CXCL12 and IL18 levels were significantly associated with the development of platinum resistance (p<0.05). IL19 was the only marker demonstrating statistical significance (p<0.05) for both, PFS and platinum resistance. Conclusion: Here we demonstrate the potential value of cytokine, chemokine and immune-related marker plasma levels to better estimate PFS, OS as well as platinum resistance in HGSOC. These prognostic and predictive markers may be further developed into clinical assays to support patient management.