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© 1999 American Society for Clinical Oncology Clinical Significance of Apoptosis-Related Factors p53, Mdm2, and Bcl-2 in Advanced Ovarian CancerFrom the Departments of Gynecologic Oncology and Pathology, The Norwegian Radium Hospital, Montebello, Oslo, Norway. Address reprint requests to M. Baekelandt, MD, Department of Gynecologic Oncology, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
PURPOSE: To investigate the prognostic and predictive relevance of p53, Mdm2, and Bcl-2 protein expression in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsy specimens from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for expression of p53, Mdm2, and Bcl-2 proteins. Both uni- and multivariate analyses of prognostic factors were performed, and correlations with classical clinicopathologic parameters and response to chemotherapy were examined. RESULTS: Forty-nine percent and 39% of cases were considered positive for expression of p53 and Bcl-2, respectively. p53 expression was correlated with loss of histologic differentiation and Bcl-2 expression with smaller residual disease after primary surgery. The absence of p53 expression and the presence of Bcl-2 expression were associated with improved survival but not with overall response to chemotherapy, although a positive correlation was found between Bcl-2 expression and the possibility of obtaining a completely negative second-look laparotomy. Expression of Mdm2 was found in 17% of cases. Although correlations were found with known favorable clinicopathologic factors, no prognostic significance was demonstrated for Mdm2 in this patient group. In multivariate analyses, histologic type, degree of differentiation, residual disease, and p53 alone or combined with Bcl-2 expression were found to be independently associated with overall survival. CONCLUSION: p53, and especially the combination of p53 and Bcl-2 expression data, represents an independent prognostic predictor in stage III ovarian cancer. Despite their role in the apoptotic process, p53 and Bcl-2 do not seem to be clinically useful predictors of response to combination chemotherapy in these patients.
OVARIAN CANCER IS the second most common and most fatal of the gynecologic malignancies. Approximately two thirds of the patients present with advanced-stage disease (stage III or IV) at diagnosis. The majority of cases will initially respond to cytostatic drug treatment, but long-term survival and cure rates are still disappointingly low because of the development of drug resistance.1 It seems that all known cytostatic drugs kill cancer cells predominantly through apoptosis, a mechanistically driven form of cell death that is distinct from necrosis.2 Apoptosis, as a "final common pathway of cell kill," is situated downstream from other possible drug resistance mechanisms, which implies that an impaired ability of cancer cells to undergo apoptosis might be a critical factor in explaining clinical pleiotropic drug resistance.3 Different endogenous regulators of the apoptotic process have been described,4 among which the p53 tumor suppressor gene and the Bcl-2 family of apoptosis regulators are the most prominent. The p53 protein is a transcription factor, possessing sequence-specific DNA-binding activity that can activate the transcription of genes carrying a target element within their promotor or repress the transcription of genes that lack such an element. This leads to the expression of specific genes necessary for the inhibition of cell growth and the induction of apoptosis. Mutation of the p53 gene is one of the most frequently occurring genetic alterations in a wide variety of human cancers.5 Loss of wild-type p53 function can lead to uncontrolled growth of DNA-damaged cells. The level of wild-type p53 protein present in nontransformed cells is low, because of the short half-life of the native protein. Many of the mutant p53 proteins are more stable and can be detected in solid tumor tissue by immunohistochemical techniques. Evidence exists that inactivation of p53 enhances sensitivity to chemotherapy, but in vitro studies have also shown contradictory results.6 The protein product of the mdm2 gene, the human homolog of an amplified murine gene (murine double minute 2), has been shown to form complexes with wild-type p53, thereby abolishing its growth-suppressing properties. Its amplification has been confirmed in soft tissue sarcomas and gliomas7,8 but seems to be rare in carcinomas. Bcl-2 belongs to an ever-expanding family of pro- and antiapoptotic proteins, able to form homo- and heterodimers. Bcl-2 itself has been shown to enhance cell survival by inhibiting apoptosis induced under a wide variety of circumstances.4 Transfection of the bcl-2 gene into cell lines has been shown to confer increased resistance to a variety of cytostatic drugs.9 In the present study, a large cohort of patients with stage III ovarian cancer, uniformly treated with the same drug combination, was examined for aberrant expression of p53, Mdm2, and Bcl-2 proteins. Furthermore, we wanted to correlate protein alterations with clinicopathologic variables and examine whether these alterations provide prognostic information. In addition, we examined whether increased p53 and Bcl-2 protein expression has any predictive value with regard to drug sensitivity in the clinical setting.
Patients and Samples Tumor tissue was obtained at first surgery in 185 previously untreated patients with International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer. This patient cohort consisted of all patients consecutively included at the Department of Gynecologic Oncology, Norwegian Radium Hospital, in a multicenter trial on consolidation treatment after second-look laparotomy in stage III ovarian cancer patients. Selection criteria were patient age less than 71 years, Karnofsky index of at least 60, histologically verified and previously untreated stage III epithelial ovarian cancer, and serum creatinine level of less than 115 µmol/L. All patients were treated between January 1988 and May 1993. The median age was 54 years (range, 21 to 70 years). Histologic slides were reviewed by one pathologist (J.M.N.) who had no knowledge of the clinical data. Histologic classification was performed with the criteria defined by the World Health Organization.10 After surgery, a standard regimen containing cisplatin (50 mg/m2 every 4 weeks) and epirubicin (50 mg/m2 every 4 weeks) was used. Second-look laparotomy was performed in 149 of 185 patients. In 35 cases, no second-look laparotomy was performed because of clinically evident disease progression, and one patient preferred not to undergo the procedure. To assess response, reports from first surgery and second-look laparotomy were reviewed and all tumor measurements were compared. Complete pathologic response was defined as the disappearance of all tumor at second-look laparotomy, with all biopsy specimens and peritoneal washings negative for tumor cells. Microscopic residual disease was defined as the disappearance of all macroscopic tumor lesions but the presence of tumor cells in one or more biopsy specimens or peritoneal washings. Partial response was defined as a 50% or more decrease in size of all bidimensionally measured tumor lesions. Stable disease was either a decrease in size of less than 50% or an increase in size of less than 25% of one or more measured tumor lesions. Progressive disease was defined as either a 25% or more increase in the size of one or more clinically measured lesions or the appearance of new disease manifestations or a 25% increase in size of one or more tumor lesions at second-look laparotomy. Response was not assessable in 10 cases, in nine because the patient had no macroscopic residual tumor after first surgery and in one because of patient refusal to undergo the second-look procedure. All patients were followed up until death or August 1998. Follow-up information was collected from the medical records, and no patients were lost to follow-up. The median follow-up time for patients still alive was 77 months (range, 65 to 121 months). A detailed description of patient characteristics is given in Table 1.
Immunohistochemistry
Statistical Analysis
Differences in proportions were evaluated by the
Immunohistochemistry Ninety (49%) of 185 cases were considered positive for p53 protein expression (16 cases [9%] with between 5% and 50% of tumor cells having nuclear staining and 74 cases [40%] with more than 50% of cells stained) (Fig 1A). Ninety-five cases (51%) were considered negative (65 [35%] had no positive cells and in 30 [16%] less than 5% of cells were stained).
Thirty-one cases (17%) showed nuclear staining for Mdm2 protein (Fig 1B). In one tumor, 5% to 50% of cells were immunoreactive for Mdm2, whereas the other positive specimens were characterized by only rare Mdm2-positive nuclei (< 5% of cells). A correlation was found between Mdm2 and p53 expression (P = .001), but only when any degree of immunostaining for p53 was considered to be positive. Twenty-eight of the Mdm2-positive cases were p53 protein–positive, whereas three Mdm2-positive cases had no p53 protein immunoreactivity. Of the 185 specimens, 73 (39%) were considered positive for Bcl-2. Fifty-four (29%) showed cytoplasmic immunoreactivity in between 5% and 50% of cells and 19 (10%) showed cytoplasmic immunoreactivity in more than 50% of cells (Fig 1C). One hundred twelve cases (61%) were negative, with 79 (43%) having no positive cells and 33 (18%) having less than 5% of cells stained.
Clinicopathologic Correlations
No straightforward correlations could be demonstrated between p53 and/or Mdm2 or Bcl-2 expression and response to chemotherapy, as measured by second-look laparotomy after four cycles of treatment and as grouped as in Table 1. Only when the analysis was repeated, and response was defined as complete pathologic response versus any other finding at second-look laparotomy, could an association be found between Bcl-2 positivity and a negative result at second-look laparotomy (P = .037).
Analysis of Survival In univariate analysis, age below or over the median (P = .0192), FIGO substage (P < .0001), histologic type (P = .0066), differentiation grade (P < .0001), ascites (P = .0003), residual disease (P < .0001), p53 expression (P = .0017), and Bcl-2 expression (P = .0021) correlated significantly with survival (Figs 2 and 3).
The results of the multivariate survival analysis, incorporating the variables that reached significance in univariate analysis and using corrected survival as end point, is shown in Table 3. In the final model, only histologic type, degree of differentiation, residual tumor status, and p53 expression retained independent prognostic significance. When progression-free survival was used as an end point, only residual disease status, degree of differentiation, and the presence of ascites were of independent significance (data not shown).
When studying the univariate survival data, a clear pattern of prognostic significance was found, with lack of p53 expression and presence of Bcl-2 expression as good risk factors. We therefore constructed a new variable, considering a combination of p53 and Bcl-2 expression for each case. This resulted in three distinct risk groups: group I, with patients without (-) p53 expression (p53-) but with (+) Bcl-2 expression (Bcl-2+); group II, with patients either p53- and Bcl-2- or p53+ and Bcl-2+; and group III, with patients p53+ and Bcl-2-. When a log-rank analysis was performed for the new variable, a P value of .00003 was found, ie, the prognostic power of either factor alone increased considerably (Fig 4). We then replaced p53 and Bcl-2 as separate variables with the new, combined variable and performed a new multivariate survival analysis. The resulting model is shown in Table 4. The model then retained residual disease, differentiation grade, presence of ascites, and the combination of p53 and Bcl-2 as independent prognostic factors.
Patients with advanced ovarian cancer are still being faced with disappointingly low long-term survival rates. Eventually, most patients will succumb to the disease, which by then will have become drug-resistant. We report here on our data on p53, Mdm2, and Bcl-2 expression in a large cohort of patients with stage III ovarian cancer, all of whom were treated and followed up in a uniform fashion. The proportion of p53 protein–positive tumors (49%) found in the present analysis is in accordance with other studies.13-15 The immunohistochemical technique detects stabilized p53 protein, a stabilization that can be the result of a mutation in the p53 gene or of an interaction between p53 protein and other cellular proteins, such as Mdm2. Missense mutations in the p53 gene most often result in a protein detectable by immunohistochemistry, whereas null mutations, which result in stop codons and shortened proteins, often may not be detectable by this method.16 Most p53 mutations in ovarian cancer are missense mutations, and a close correlation between p53 immunoreactivity and p53 mutation has been demonstrated previously.17 In our material, p53 protein positivity correlated with loss of differentiation, a finding similar to that in previous studies.13,14,18,19 We found no correlations with any other clinicopathologic factors. The significance of Mdm2 in ovarian cancer has been reported in only a few articles, and the relatively low prevalence of Mdm2 expression found in our work (17%) is in accordance with other studies20,21 but in contrast to the study by Tanner et al.22 In their study, mdm2 mRNA and not protein expression was investigated, which could help explain the contradictory results. In a previous study from the Norwegian Radium Hospital, 347 stage I ovarian cancers and 27 borderline ovarian tumors were examined, and a frequency of Mdm2 expression of 12% was found.23 In the present study, the majority of Mdm2-positive cases also demonstrated some degree of p53 immunoreactivity, also in agreement with findings in early-stage ovarian cancer.23 It has been shown that the expression of the mdm2 gene product is positively regulated by high levels of the p53 protein,24 and it is possible that some of the p53 mutants are able to induce Mdm2 protein expression. Mdm2 protein can in turn reverse cell-cycle arrest induced by p53, either by binding to the p53 protein and stabilizing it,25 as indicated by our work, or by promoting a rapid degeneration of p53.26 It has been postulated that mdm2 gene amplification generally is a late and secondary event during tumor evolution in ovarian cancer.21 As to its clinical significance, our observations support the view that Mdm2 protein expression is a relatively rare event in advanced ovarian cancer20 and has no prognostic significance. To our knowledge, the present study is the largest to date to report on the significance of Bcl-2 expression in ovarian cancer with use of a multivariate analysis of prognostic factors. The prevalence of Bcl-2 positivity in our material (39%) is in accordance with previous studies.13,27-30 We found Bcl-2 to be related to residual disease status after first surgery, with the biologically more aggressive tumors (those that are most difficult to debulk optimally) having less Bcl-2 expression. p53 is one of the known regulators of Bcl-2 expression in vitro,9 but we could not confirm any correlation between p53 and Bcl-2 expression. One of the aims of this study was to identify factors that could predict response to the chemotherapy given. Both p53 and Bcl-2 are major players in the regulation of apoptosis, and some in vitro studies have shown that expression of Bcl-2 protein or mutant p53 can confer relative resistance to cisplatin.28,31 In one clinical study,32 a significant correlation was found between p53 missense mutation and protein accumulation and increased resistance to platinum-based chemotherapy in ovarian cancer. Other studies on both p53 and Bcl-2 expression,28 on p53 gene status,33 and on p53 protein expression34 found no such correlations. In our material, no association was detectable between response to cisplatin-epirubicin combination therapy and p53 protein, further confirming in vitro data on a number of ovarian cancer cell lines.35 There was a trend toward better response in Bcl-2–positive cases, but this correlation only reached statistical significance for patients' possibility of obtaining a complete pathologic response at second-look laparotomy. There is no obvious biologic explanation for this finding, but there is broad acceptance for the view that it is the overall balance between proapoptotic proteins (such as Bax, Bak, and Bad) and antiapoptotic proteins (such as Bcl-2, Bcl-XL, and Mcl-1) that relates to cell survival after DNA damage and less likely the expression of a single one of these proteins.4,36 The determination of Bcl-2 expression at only one point in time is likely to give limited information, considering the highly dynamic nature of the regulation of the bcl-2 family of genes.37 Also, the relative importance of the different complexes formed and pathways used is likely to be tissue-specific. A similar tissue-related specificity might partially explain the conflicting results of studies looking for correlations between p53 expression and resistance to chemotherapy, both in vivo28,32 and in vitro.6,38 Also, p53-defective cells are genetically unstable39 and may gradually acquire additional abnormalities that confer drug resistance. Moreover, there is in vitro evidence that the response of p53-deficient tumor cells may be fundamentally different for various classes of chemotherapeutic agents.33,40 This underscores the importance in clinical studies of putative predictive factors of a clear statement of the type or types of chemotherapy with which patients were treated. We found p53, but not Bcl-2, to be of independent prognostic significance. However, the combination of p53 and Bcl-2 data into three distinct subgroups increased the prognostic significance compared with p53 data alone (Fig 4). Since p53 and Bcl-2 could not predict differences in therapy response but nevertheless were of major prognostic importance, other explanations must be considered beyond their significance for the apoptotic process. Human carcinomas clearly seem to select for p53 missense mutations, which results in the persistence of defective protein in the cancer cells. This most likely means that there is a gain of function, ie, that altered protein may contribute some function that gives the cancer cell a biologic advantage.41 An interesting observation in this regard is that mutant p53 activates transcription of the multidrug resistance mdr-1 gene,42 possibly giving the cell a survival advantage in case of treatment with multidrug resistance phenotype-related chemotherapeutic drugs. It has also been shown that mutant p53 induces expression of vascular endothelial growth factor mRNA, linking p53 to the regulation of tumor angiogenesis.43 Also, p53-positive tumors more frequently seem to express one or more cytokines compared with p53-negative tumors, a relation especially clear for macrophage colony-stimulating factor.44 With regard to Bcl-2, cell line experiments have shown that Bcl-2 expression, depending on the cellular context, can result in a specific and profound growth suppression.45 Bcl-2 has further been shown to delay entry of cells into S phase, and the resulting lower proliferation index may help to explain the favorable prognostic significance of this marker.46 Cell clones with a lower mitotic rate may also acquire complementary genetic defects at a slower pace than clones with a higher mitotic rate, contributing to a more indolent progression.47 Finally, it has also been suggested that Bcl-2 might have a role in the suppression of angiogenesis.48 These observations may contribute to a biologic explanation of our findings. The association of Bcl-2 expression with improved survival in ovarian cancer is in accordance with other studies.13,28 A similar association was found in node-positive breast cancer49 and non–small-cell lung cancer.50 Together, these counterintuitive observations underscore the importance of testing the results of experimental in vitro studies in well-defined and clinically relevant patient groups. In conclusion, none of the factors studied (p53, Mdm2, and Bcl-2) was found to be clinically useful in the prediction of chemotherapy response. In contrast, the combination of p53 and Bcl-2 expression data allowed for a separation of patients into three distinct risk groups and was shown to be a strong independent predictor of cancer-related survival in the cohort of advanced ovarian cancer patients studied.
Supported in part by grants no. 98-132/001 and 95-247/124 from The Norwegian Cancer Society. We thank Ellen Hellesylt, Mette Ingrud, and Liv Inger Håseth for technical assistance.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test, whichever was appropriate. Disease-free and corrected survival rates were calculated using the method of Kaplan and Meier.
) in p53-characterized human ovarian carcinomas. Eur J Cancer 33:2246-2251, 1997
