Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study

SIMPLE SUMMARY: The possibility to identify, with appropriate biomarkers, patients that might mostly benefit from any given treatment is the basis of personalized oncology. Cancer biomarkers should be properly identified and validated on a large number of patients possibly enrolled in dedicated clinical trials. Here, we report the first molecular results of the MITO16A-ManGo-OV2 phase IV trial that was specifically designed to identify prognostic biomarkers of survival in epithelial ovarian cancer patients treated in first line with carboplatin-paclitaxel plus Bevacizumab (NCT01706120), a treatment for which validated predictive or prognostic biomarkers are still lacking. With this work we propose not only novel possible biomarkers for Bevacizumab-treated patients but also a way through which they can be properly collected, analyzed and statistically evaluated in the frame of large multicenter clinical trials. ABSTRACT: Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.