The Relationship of Molecular Markers of p53 Function and Angiogenesis to Prognosis of Stage I Epithelial Ovarian Cancer

Abstract

Purpose: Multiple angiogenic factors may influence tumor progression and metastasis. Several are modified by the p53 gene. We sought to identify molecular markers for high-risk stage I epithelial ovarian cancers. Experimental Design: Seventy-seven consecutive stage I epithelial ovarian cancers were evaluated for p53, CD31 microvessel density, thrombospondin-1, vascular endothelial growth factor (VEGF), p21 immunohistochemical staining, and p53 gene mutations. Molecular marker impact upon disease-specific survival, disease recurrence, and distant recurrence was evaluated with Cox regression. Results:There were 12 deaths from disease.Twelve of the 77 tumors contained p53 mutationsö 10 missense and 3 null (one tumor had two mutations). Fesddration Internationale des Gynaecologistes et Obstetristes substage (IA/IB versus IC; P < 0.001) and VEGF staining (P = 0.02) were significant in bivariate models with relationship to disease-specific survival. Stage (P = 0.0004), grade (P = 0.008), histology (P = 0.0025), p53 dysfunction (positive stain and/or mutation; P = 0.048), and microvessel density (P = 0.04) were significant in bivariate models with relationship to time to recurrence. In multivariate analyses among stage IC patients, failure to receive chemotherapy and microvessel density were associated with disease-specific survival, time to recurrence, and time to distant recurrence with hazard ratios of 4.8 to 44.1. Conclusions: The p53-dependent molecular markers of angiogenesis are of limited utility in developing a clinical strategy for postoperative management of stage I ovarian carcinoma. Microvessel density impacts survival and metastasis for high-risk stage IC disease. Adjuvant chemotherapy is necessary, but not sufficient, for cure of high-risk stage I epithelial ovarian cancers.

Antiangiogenic drugs in ovarian cancer

“…Several retrospective clinical studies in ovarian cancer have also demonstrated that intratumoral VEGF and VEGFR-2 expression and the carriage of VEGF gene polymorphisms associated with an increased VEGF excretion are independent poor prognostic factors (Shen et al, 2000;Goodheart et al, 2005;Hefler et al, 2007).…”

Effect of the combination of a cyclooxygenase-1 selective inhibitor and taxol on proliferation, apoptosis and angiogenesis of ovarian cancer in vivo

“…Studies showed that VEGF-positive tissue was associated with a high MVD expression, whereas VEGF-negative tissue demonstrated a low expression of MVD, indicating a positive correlation between VEGF and MVD (36,37). The increase of MVD, an indirect marker of intense tumor vascularization, increases blood volume (38), and increased MVD is known to be associated with both evolution of disease and survival (39)(40)(41). Our results indicated that SC-560 and/or taxol therapy caused a marked reduction in MVD compared with vehicle-treated control, and the combination therapy revealed a synergistic effect on the inhibition of MVD.…”

Role of vascular endothelial growth factor inhibitors in the treatment of gynecologic malignancies

“…Often this relationship to clinical outcome has been found to be independent of important clinical and pathologic prognostic factors. 13,14,[16][17][18][19][20][21][22] In addition VEGF has demonstrated prognostic value [23][24][25] in accordance with its known functional relationship to angiogenesis. In addition to correlative clinical studies cited above, pre-clinical investigations have provided a strong rationale for clinical trials of anti-VEGF therapeutics in gynecologic malignancies.…”