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

• Published in: Clinical cancer research 2005-05, Vol.11 (10), p.3733-3742
• Main Authors: GOODHEART, Michael J, RITCHIE, Justine M, ROSE, Stephen L, FRUEHAUF, John P, DEYOUNG, Barry R, BULLER, Richard E
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy, Adjuvant; Disease-Free Survival; DNA Mutational Analysis; Female; Female genital diseases; Genes, p53; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Medical sciences; Middle Aged; molecular markers; Neoplasm Metastasis; Neoplasm Recurrence, Local - genetics; Neovascularization, Pathologic; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; p53; Pharmacology. Drug treatments; Prognosis; Regression Analysis; Risk Factors; stage I epithelial ovarian cancer; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0056

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 mutations—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.