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

Authors' Affiliations: ¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; Departments of ² Pathology and ³ Biostatistics, Holden Comprehensive Cancer Center, University of Iowa Hospital and Clinics, Iowa City, Iowa; and ⁴ Oncotech Incorporated, Irvine, California

Requests for reprints: Michael J. Goodheart, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4630JCP, Iowa City, IA 52242. Phone: 319-356-2015; Fax: 319-353-8363; E-mail: michael-goodheart{at}uiowa.edu.

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.

Key Words: p53 • molecular markers • stage I epithelial ovarian cancer • prognosis

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