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Prognostic Significance of p53 Mutation and p53 Overexpression in Advanced Epithelial Ovarian Cancer: A Gynecologic Oncology Group Study

Laura Havrilesky, Kathleen M. Darcy, Hasnah Hamdan, Roger L. Priore, Jorge Leon, Jeffrey Bell, Andrew Berchuck

From the Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Quest Diagnostics Nichols Institute, San Juan Capistrano, CA; and the Ohio State University, Division of Gynecologic Oncology, Riverside Methodist Hospital, Columbus, OH.

Address reprint requests to GOG Administrative Office, Four Penn Center, Suite 1020, 1600 John F. Kennedy Blvd, Philadelphia, PA 19103.

Purpose: The prognostic significance of p53 mutations and overexpression in advanced epithelial ovarian cancers was examined in primary tumors from 125 patients participating in a Gynecologic Oncology Group randomized phase III treatment protocol.

Patients and Methods: Mutational analysis of p53 was performed in RNA or genomic DNA extracted from frozen tumor. An immunohistochemistry assay was used to detect p53 overexpression in fixed tumor.

Results: There were 81 patients (74%) with a single mutation, three patients (3%) with two mutations, and 25 patients (23%) lacking a mutation in exons 2 to 11 of p53. Although most mutations occurred within exons 5 to 8, mutations outside this region were observed in 11% of patients. A mutation in exons 2 to 11 of p53 was associated with a short-term improvement in overall survival and progression-free survival. Adjusted Cox modeling demonstrated a 70% reduction in risk of death (P = .014) and a 60% reduction in risk of disease progression (P = .014) for women with such mutations. However, these striking risk reductions increased over time (P < .02) and eventually disappeared with longer follow-up. Overexpression of p53 was observed in 55 patients (100%) with only missense mutation(s), seven patients (32%) with truncation mutations, and eight patients (40%) lacking a mutation in exons 2 to 11. Overexpression of p53 was associated with tumor grade but not with patient outcome.

Conclusion: Alterations in p53 are a common event in advanced epithelial ovarian cancer. A mutation in p53, but not overexpression of p53, is associated with a short-term survival benefit. Additional studies are required to define the roles that p53 plays in regulating therapeutic responsiveness and patient outcome.

This study was supported by National Cancer Institute (Bethesda, MD) grants of the Gynecologic Oncology Group (GOG) Administrative Office (No. CA 27469), GOG Tissue Bank (No. CA 27469), and the GOG Statistical and Data Center (No. CA 37517).

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