Vascular Endothelial Growth Factor Expression in Ovarian Cancer: A Model for Targeted Use of Novel Therapies? Timothy J. Duncan, 1 Ahmad Al-Attar, 1 Phil Rolland, 1 Ian V. Scott, 4 Suha Deen, 2 David T.Y. Liu, 3 Ian Spendlove, 1 and Lindy G. Durrant 1 Abstract Purpose: Angiogenesis has a vital role in tumor growth and metastasis, and vascular endothelial growth factor (VEGF) represents a potent cytokine in this process. However, the influence of VEGF in ovarian cancer remains controversial. Interest has focused on the use of antiangiogenic drugs in ovarian cancer. This study aims to establish the pattern of expression and effect on prognosis of VEGF in a large population of ovarian cancer patients and to potentially identify a cohort in whom antiangiogenic therapy is appropriate. Experimental Design: Using a tissue microarray of 339 primary ovarian cancers, the expression of VEGF was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors and survival was studied. Results: Tumors expressing high levels of VEGF had significantly poorer survival (P = 0.04). Factors shown to predict prognosis independently of each other were age, International Federa- tion of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. VEGF was independently predictive of prognosis on multivariate analysis (P = 0.02). There was no correlation between VEGF and any clinicopathologic variable. High expression of VEGF was seen in only 7% of the tumors, suggesting that the role of antiangiogenic drugs may be limited to a small subset of patients. Conclusion: High VEGF expression occurs in a small proportion of ovarian cancers, and this independently predicts poor prognosis. The small percentage of tumors with high levels of VEGF activity suggests that the role of bevacizumab may potentially be limited to a few patients; these patients could be targeted by molecular profiling. Ovarian cancer is the leading cause of death from gynecologic malignancies. As symptoms are vague and nonspecific, these tumors often present at an advanced stage. Developments in chemotherapy and surgical techniques have had minimal effect on patient survival over the last few decades (1). Tumor stage and residual tumor mass, following primary cytoreductive surgery, have been shown to most reliably predict outcomes in patients with ovarian cancer (2) but offer no information with regard to the potential sensitivity to molecular ‘‘targeted’’ therapy. Investigation of novel prognostic markers offers an insight into the mechanisms of tumor development and suggests potential avenues for the develop- ment of new therapeutic agents particularly through the use of monoclonal antibody therapies. Angiogenesis has been established as a vital component in the mechanisms involved in tumor growth and metastasis (3, 4). The angiogenic potential of tumors can be assessed by microvessel density. Earlier studies illustrated the importance of angiogenesis in tumor development, with microvessel density directly correlating with a poor prognosis in ovarian (5) and other tumors (6, 7). Vascular endothelial growth factor (VEGF) is a multifunc- tional cytokine that stimulates angiogenesis and increases microvascular permeability through binding to specific recep- tors expressed on vascular endothelial cells (8, 9). Although VEGF is produced by several tumors and hypoxic tissues (10), its receptors are expressed primarily by endothelial cells. It has been shown to have a crucial role in neovascular formation in tumors, providing nourishment for the highly metabolic tumor cells as well as providing access to the host vasculature (11). Studies have suggested a specific role for VEGF in various phases of ovarian carcinogenesis, with effects on tumor growth and neovascularization seen in animal models and in humans (12, 13). Higher levels of VEGF are shown in ovarian carcinomas when compared with normal ovaries (14, 15). Recent interest has focused on the use of antiangiogenic drugs in an attempt to inhibit the protumor effects of VEGF and other such cytokines. These studies have shown some antitumor effects but have shown significant side effects. Imaging, Diagnosis, Prognosis Authors’Affiliations: 1 Academic and Clinical Department of Oncology, University of Nottingham; 2 Division of Histopathology and 3 Department of Obstetrics and Gynaecology, University Hospitals Nottingham, Nottingham, United Kingdom and 4 Department of Obstetrics and Gynaecology, Derby City General Hospital, Derby, United Kingdom Received 8/1/07; revised 1/27/08; accepted 2/7/08. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Lindy G. Durrant, Institute of Infections and Immunity, University of Nottingham, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Phone: 44-115-82-31862; Fax: 44-115- 82-31849/44-121-353-1482; E-mail: lindy.durrant@nottingham.ac.uk. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1888 www.aacrjournals.org Clin Cancer Res 2008;14(10) May 15, 2008 3030 Research. on May 23, 2020. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from