The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma - Prognostic and therapeutic implications

BACKGROUND. Vascular endothelial growth factor (VEGF) is an important endot helial cell mitogen associated with increased angiogenesis and aggressive t umor behavior, Its stimulating effect on endothelial cells basically is dep endent on the presence of specific VEGF receptors, such as the flk-1(KDR) r eceptor. This study investigates the roles of VEGF and of a functionally in tact angiogenic pathway "VEGF/flk-1 (KDR)," in patients with endometrial ca rcinoma and their significance in prognosis and therapy. METHODS. A series of 121 endometrial carcinomas were studied. The expressio n of VEGF by endometrial tumor cells was assessed using the monoclonal anti body (MoAb) VG1. VEGF/KDR complexes on tumor endothelium or activated micro vessel density (aMVD) were identified using the MoAb 11B5. In addition, the standard microvessel density (sMVD) was assessed with anti-CD31. In all tu mors, the alkaline phosphatase/antialkaline phosphatase technique was emplo yed. A Fisher exact test or an unpaired, two-tailed t test was used for tes ting correlations between categoric tumor variables, whereas a log-rank tes t was used to determine statistical differences between life tables. A Cox proportional hazards model was used to assess the effect of tumor variables on overall survival. RESULTS. Cytoplasmic VEGF expression in > 50% of tumor cells was associated significantly with aMVD (P < 0.0001) and with sMVD (P < 0.003). In univari ate survival analysis, VEGF (P = 0.0002), aMVD (P = 0.001), and sMVD (P = 0 .0009) were significant prognostic variables. Equally important were the hi stologic parameters tumor type (P = 0.03), tumor grade (P = 0.003), and dis ease stage (P < 0.0001). In multivariate analysis, disease stage was the mo st important independent prognostic factor (P < 0.0001), followed by VEGF/K DR (P < 0.01), and VEGF (P < 0.04). Furthermore, VEGF and VEGF/KDR were the only independent prognostic variables for patients with Stage I endometrio id adenocarcinoma. CONCLUSIONS. sMVD and the angiogenic factor VEGF are important indicators o f a poor prognosis in patients with endometrial carcinoma. VEGF/KDR complex es define a subgroup of patients with endometrial carcinoma with an even wo rse prognosis. (C) 2001 American Cancer Society.