Intratumoral Ral-binding protein 1 (RalBP1) expression as a potential predictor of bevacizumab treatment efficacy in patients with ovarian cancer.

5576 Background: The anti-VEGF antibody bevacizumab (Bev) has become part of the first-line treatment of patients with advanced ovarian cancer (OC) due to its significant impact on progression-free survival (PFS). However, a significant effect on overall survival (OS) was not demonstrated. In this context, we hypothesized that the stress-responsive multidrug transporter and modulator of neovascularization Ral-binding protein 1 (RalBP1) might be prognostic for patient survival and stratify patients according to their predicted Bev response. Methods: Tissue samples from 554 patients with epithelial OC were obtained during first-line cytoreductive surgery at the Department of Obstetrics and Gynecology, University Hospital, LMU Munich, between 2003 and 2021. RalBP1 immunohistochemical staining was quantified using a mean staining intensity score (MSIS, 1-3) and a cut-off was defined as 2.5. Correlationbetween MSIS and clinicopathologic data was assessed using two-sample t-tests. Additional correlation measures included Spearman’s correlation, Chi 2 -test and ANOVA. PFS and OS were visualized by Kaplan-Meier curves and significant differences determined by Wilcoxon. Cox regression models were used for multivariate analysis. Results: RalBP1 was present in the cytosol of almost all OC cells (RalBP1-low: n= 385, RalBP1-high: n= 169) and independent of histopathologic subtype or grading. Patients with elevated intratumoral RalBP1 expression showed significantly improved median PFS (73.5 vs. 35.8 months, HR=0.62, p=0.033) and median OS (120.1 vs. 71.7 months, HR=0.56, p=0.007) after complete tumor debulking and platin-based adjuvant chemotherapy (n=155). In a comprehensive multivariate analysis, RalBP1 expression levels emerged as an independent prognostic marker for both OS (HR=0.67, p=0.031) and PFS (HR=0.72, p=0.033). Interestingly, in the subgroup of all patients that received an adjuvant platinum-based chemotherapy (n=351), the RalBP1–low patient status was shown to be a predictive factor for response to Bev therapy for both PFS (median 26.4 vs. 18.1 months, HR=0.94, p=0.036) and OS (median 63.4 vs. 49.3 months, HR=0.72, p=0.041). Conclusions: RALBP1 may serve as a prognostic biomarker for OC patients, helping to identify those who are likely to benefit not only in PFS but also in OS following Bev therapy. Its tumor biological role remains a matter of current investigations.