Elsevier

Gynecologic Oncology

Volume 111, Issue 3, December 2008, Pages 487-495
Gynecologic Oncology

Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally-resected, advanced stage epithelial ovarian cancers: A Gynecologic Oncology Group study

https://doi.org/10.1016/j.ygyno.2008.08.020Get rights and content

Abstract

Objective

The Gynecologic Oncology Group (GOG) performed a detailed analysis of p53 overexpression in previously-untreated women with invasive early or advanced stage epithelial ovarian cancer (EOC).

Methods

Women were eligible for the study if they provided a tumor block for translational research and participated in either GOG-157, a randomized phase III trial of three versus (vs.) six cycles of paclitaxel + carboplatin in high-risk, early stage EOC, or GOG-111, a randomized phase III trial of cyclophosphamide + cisplatin vs. paclitaxel + cisplatin in suboptimally-resected, advanced stage EOC. The N-terminal DO-7 p53 antibody was used to examine the expression of the major normal and mutant p53-isoforms. p53 overexpression was defined as ≥ 10% tumor cells exhibiting nuclear staining.

Results

p53 was overexpressed in 51% (73/143) and 66% (90/136) of cases in the GOG-157 and GOG-111 cohorts, respectively. In the GOG-157 cohort, p53 overexpression was not associated with any clinical characteristics or overall survival (OS) but was associated with worse progression-free survival (PFS) (logrank test: p = 0.013; unadjusted Cox modeling: p = 0.015). In the GOG-111 cohort, p53 overexpression was associated with GOG performance status (p = 0.018) and grade (p = 0.003), but not with age, stage, cell type or with tumor response and disease status after primary chemotherapy, PFS or OS. Adjusted Cox regression modeling demonstrated that p53 overexpression was not an independent prognostic factor for PFS or OS in either cohort.

Conclusions

p53 overexpression assessed by DO-7 immunostaining is common in early and advanced stage EOC, but has limited prognostic value in women treated with surgical staging and platinum-based combination chemotherapy.

Introduction

Ovarian cancer is the leading cause of cancer-related death among the gynecologic malignancies [1]. It is estimated that 21,650 new cases of ovarian cancer will be diagnosed in the United States in 2008 and that 15,520 women will die from disease [1]. Currently, surgical staging followed by platinum- and taxane-based chemotherapy is the standard of care. Despite impressive initial response rates, the five-year survival rate is 92%, 71%, and 30% for women with localized, regional, and distant disease [1]. Unfortunately, 68% of ovarian cancers are diagnosed with distant disease [1]. Investigators continue to study biomarkers implicated in cancer, malignant progression, metastasis and drug sensitivity with the goal of identifying women with refractory or resistant vs. sensitive disease for whom alternative therapies may be useful.

p53, or TP53, is a multifunctional tumor suppressor that is often altered in ovarian and other cancers [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The p53 gene regulates transcription, DNA repair, cell cycle arrest, differentiation, senescence, genomic instability, apoptosis and survival as well as glucose metabolism, oxidative stress and angiogenesis [3], [4], [5], [6], [7]. Normal cells generally have low levels of p53 protein due to its short half-life. Mutations in p53 often encode proteins that are resistant to degradation, and mutant p53 protein often accumulates in the nucleus of cancer cells. Overexpression of p53 can occur by mutation, altered transcription and translation or post-translational modifications [3], [4], [5], [6], [7], and can be detected using an immunohistochemical method. Currently, alterations in p53 are the most common defects identified in women with epithelial ovarian cancer (EOC). Despite the prevalence of these alterations, overexpression of p53 protein has been inconsistently associated with tumor stage, cell type, grade, progression-free survival (PFS), overall survival (OS), and tumor response, and the value of p53 as an independent prognostic factor for disease progression (DP) and death in women with invasive EOC remains unclear [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42].

Given the inconsistencies in the literature, the Gynecologic Oncology Group (GOG) sought to evaluate the prognostic relevance of p53 overexpression in women with EOC who participated in one of two randomized phase III treatment protocols [43], [44]. Our results using the DO-7 antibody [7], [45], [46] will be discussed in context with the other immunohistochemical studies of p53 overexpression in invasive EOC and the current understanding of the p53 family with its distinct family members and isoforms that exhibit diverse and at times, opposing functions.

Section snippets

Patients

To participate in this study, the women must have provided a formalin-fixed and paraffin-embedded (FFPE) tumor block and participated in GOG-157 or GOG-111. Women on GOG-157 had to have previously-untreated, histologically-confirmed, optimally-resected EOC with stage IA or IB disease that was either clear cell histology or grade 3 disease, or stage IC or II disease independent of histologic subtype and grade, and a GOG performance status below 4 [43]. Women on GOG-111 had to have

High-risk, early stage, epithelial ovarian cancer

Of the 457 women enrolled on GOG-157, 143 (31%) provided archival FFPE primary tumor tissue for translational research. The patient characteristics for the 143 women in this cohort are summarized in Table 1 and are representative of that observed in the entire GOG-157 cohort [43]. At the time of the final analyses, 92 women were alive with no evidence of disease, 13 were alive with DP, 25 had died due to DP, two had died due to treatment, 8 had died due to a reason other than DP or treatment,

Discussion

Mutations in p53 are a common event in ovarian cancer [8], [9], [10], [11], [17], [18], [24], [26], [29], [30], [33], [35], [36], [41] and have been shown to either be associated with OS [24], [29], [33] or response to platinum/paclitaxel based chemotherapy [26], [30], [33] or to not associated with OS [35], [41]. A strong correlation has been observed between a p53 mutation most notably a missense mutation and DO-7 expression of p53 protein [14], [18], [24], [26], [29], [33]. In the study

Conflict of interest statement

The authors declare that there are no conflicts of interest with the exception of Dr. Ilona Linnoila who has ownership of General Electric stock worth less than $15,000.

Acknowledgment

The authors extend special thanks to Dr. Michael Birrer for his role as Study Chair for GOG-9404, coordinating the various aspects of this study of p53 in GOG-157 and GOG-111, and providing insightful comments and suggestions for this study and the manuscript. We also thank Anne Reardon for formatting this manuscript, and Suzanne Baskerville and Dr. Mark Brady for their efforts on GOG-157 and GOG-111. Finally, we would like to thank Dr. Heather Lankes and the GOG Publications Subcommittee for

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    This study was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517), and the Intramural Research Program of the National Cancer Institute of the National Institute of Health. The following Gynecologic Oncology Group (GOG) institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, Wayne State University, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center of Dallas, Indiana University Medical Center, Georgetown University Hospital, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush–Presbyterian–St. Luke's Medical Center, SUNY Downstate Medical Center, University of Kentucky, The Cleveland Clinic Foundation, SUNY at Stony Brook, Washington University School of Medicine, Johns Hopkins Oncology Center, Eastern Pennsylvania Gyn/Onc Center, P.C., Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, and Brookview Research Inc.

    1

    Reprint address: GOG Administrative Office, 1600 JFK Boulevard, Suite 1020 Philadelphia, PA 19103, USA.

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