Abstract
Abstract Background: Targeting ovarian cancer vasculature by humanized VEGFA neutralizing antibody bevacizumab has been demonstrated effective in multiple randomized phase III clinical studies to improve standard chemotherapy in patients with primary (GOG-0218, ICON-7) and recurrent (OCEANS, AURELIA) ovarian cancer. Nevertheless, potential benefits observed in these randomized bevacizumab clinical trials are modest, which has stimulated the search for predictive molecular biomarkers which would identify those women with ovarian cancer who would likely benefit from bevacizumab treatment, while reducing toxicity and expense for those patients who are unlikely to benefit. Methods and Results: In this study, we evaluated prognostic and predictive values of post-surgery, pre-treatment circulating levels of 13 angiogenesis biomarkers (ANG1, ANG2, Tie-2, FGF2, VEGFR1, VEGFR2, VEGFR3, ICAM1, IL8, PDGFC, E-selectin, VEGFA and VEGFC) in 922 plasma samples from GOG-0218 randomized phase III clinical trial. Prognostic and predictive associations of each biomarker with overall survival (OS) and progression-free survival (PFS) were assessed by proportional hazards models on 2.5% winsorized values while adjusting for FIGO stage, initial performance status, and study treatment. Holm-Bonferroni stepwise procedure was used to control the family-wise type I error at 5%.Increased overall risk of first progression or death (PFS) was significantly associated with higher pretreatment levels of IL8, ANG2 or lower levels of VEGFR2. IL8, ANG2 and VEGFR2 were each associated with overall survival also (p<0.0001). However, in predictive analyses, the bevacizumab treatment-related hazard ratios for PFS were not significantly associated with the plasma levels of any of the 13 angiogenesis biomarkers investigated. Conclusions: We provide a comprehensive evaluation of the circulating levels of angiogenesis biomarkers in ovarian cancer. Angiogenesis biomarkers do not exhibit clinically appreciable predictive power for outcome after bevacizumab in ovarian cancer patients, probably due to the complex biology of ovarian cancer. ANG2, IL8 and VEGFR2 are prognostic markers for ovarian cancer and may serve as candidates for targeted therapy. Citation Format: Wei Wei, Mark F. Brady, Tsun-Yee Tsang, Vinod Vathipadiekal, Robert A. Burger, Robert S. Mannel, Parviz Hanjani, Warner K. Huh, Elizabeth M. Swisher, Thomas J. Rutherford, Janos L. Tanyi, Julian C. Schink, Shashikant B. Lele, Paul A. DiSilvestro, Michael J. Birrer. An assessment of the prognostic and predictive associations of 13 angiogenic biomarkers in women with newly diagnosed advanced ovarian cancer treated with chemotherapy with or without bevacizumab. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr PR05.
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