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p27^Kip1 Expression Is Associated with Clinical Outcome in Advanced Epithelial Ovarian Cancer: Multivariate Analysis¹

Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [V. M., B. P., S. L., J. P., A. G.]; Department of Obstetrics and Gynecology, Catholic University, Rome 00168, Italy [G. F., F. F., S. M., G. S.]; and Department of Surgical Pathology, Catholic University, Rome 00168, Italy [G. Z.]

	ABSTRACT

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Few biological parameters have been shown to have a prognostic role in patients with advanced ovarian cancer. p27^Kip1 is a cyclin-dependent kinase inhibitor, and its loss may contribute to tumor progression. We determined whether p27^Kip1 protein expression in advanced ovarian cancer could be associated with prognosis. p27^Kip1 status was assessed by immunohistochemical analysis of tissue sections from primary tumors of 99 patients with stages III–IV ovarian carcinoma and was analyzed in relation to clinicopathological variables, time to progression (TTP), and overall survival (OS). p27^Kip1 expression was detected in 47 (47%) of the 99 patients. p27 expression did not correlate with any of the classical clinicopathological parameters. Loss of p27 protein was significantly associated with a short TTP (P = 0.0004) and decreased OS (P = 0.0302). The 5-year TTP rate in p27-positive patients was 50% versus 11% in p27-negative patients. p27-positive cases showed a 5-year OS rate of 53% compared with 43% of p27-negative cases. In multivariate analysis, p27 expression was an independent predictor of progression of disease (P = 0.0009) and survival (P = 0.0032) when considered together with stage of disease, presence of ascites, and residual tumor at surgery. Loss of p27^Kip1 conferred poor prognosis independently of proliferative index, as assessed by proliferating cell nuclear antigen immunostaining. p27 immunoreactivity can be used to predict progression of disease and survival in patients with advanced epithelial ovarian cancer and therefore may represent a new prognostic marker.

	INTRODUCTION

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Ovarian cancer is the most common gynecological malignancy causing fatality in Western countries and constitutes the fifth leading cause of female cancer death (1) . Over 70% of women present with an advanced stage of disease at the time of diagnosis, and despite cytoreductive surgery and the effectiveness of platinum-based chemotherapy, tumors progress in most patients, becoming resistant to chemotherapy (2) . Traditional clinicopathological criteria used to predict clinical outcome are largely inadequate. Thus, the characterization of biological prognostic factors that may help in identifying patients with different clinical outcomes would greatly facilitate management of disease. The p53 tumor suppressor gene has been suggested to play an important role in influencing tumor cell sensitivity to chemotherapy in "in vitro" models as well as in clinical settings (3 , 4) .

Recently, much attention has been focused on the potential prognostic role of cell cycle inhibitors in ovarian cancer. In particular, p27^Kip1 is a cdk³ inhibitor that regulates progression from G₁ into S-phase by inhibiting a variety of cyclin-cdk complexes, including cyclin D-cdk4, cyclin E-cdk2, and cyclin A-cdk2 (5) . The p27^Kip1 gene is located on chromosome 12p and, unlike the genes encoding INK4 family members, is rarely affected by structural alterations in human cancer (6) .

Several studies have demonstrated that loss of p27^Kip1 protein is associated with progression in various malignancies (7, 8, 9, 10, 11, 12) . In ovarian cancer, we and others (13, 14, 15) have shown previously that loss of p27 protein is a frequent event in primary epithelial ovarian carcinomas but not in benign and low malignant potential ovarian tumors. However, conflicting data about the possible prognostic role of p27 status in advanced ovarian cancer patients have been reported (16 , 17) .

The objective of this study was to examine the value of p27^Kip1 protein in predicting prognosis in a large cohort of uniformly treated patients with stages III–IV epithelial ovarian cancer, followed up over a long period of time. The correlation with response to chemotherapy, PCNA, and p53 status was also investigated.

	MATERIALS AND METHODS

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Patients.
The study included 99 primary advanced epithelial ovarian cancer patients who underwent surgical resection in the Department of Gynecology of the Catholic University of Rome. Patients had stage III/IV disease according to the Fédération Internationale des Gynaecologistes et Obstetristes staging system. Histological classification of tumors was carried out according to the WHO system (18) , and tumors were graded as well (G1), moderately (G2), and poorly differentiated (G3). Although several cutoff values of residual volume tumor have been proposed, it has been reported that gradual gradations of residual disease can affect ovarian cancer prognosis (19) . Our patient population was divided into two groups according to the extent of residual disease at first surgery; 58 patients had 2 cm residual disease, whereas 41 patients had >2 cm residual disease at surgery. Patient characteristics, collected by retrospective chart reviews, are shown in Table 1 . Chemotherapy was instituted 2–3 weeks after surgery. All patients received four to six cycles of cisplatin-containing regimens (total cisplatin dose, at least 400 mg/m²). Gynecological examination, abdominopelvic ultrasonography, CA-125 assay, and radiological investigations, if necessary, were performed monthly for the clinical assessment of response, which was recorded according to WHO criteria (18) . Approximately 28 days after the last course, clinical complete responders underwent second-look laparoscopy. In laparoscopy-negative cases, second-look laparotomy was performed for the assessment of pathological response. During laparotomy and after peritoneal washings and careful inspection of the abdominal cavity, biopsy of all suspicious lesions was performed, and in the case of no evidence of disease, at least 20 random biopsies were taken. Patients who initially had only an explorative laparotomy underwent a second laparotomy if clinically responsive to chemotherapy, and a second cytoreduction was attempted. Follow-up examinations were performed every 3 months.

The pattern of staining seen with the p27^Kip1 monoclonal antibody was confirmed on duplicate slides using a polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA). The strong positive immunostaining of lymphocytes, in all of the sections examined, represented an internal positive control for preservation of the p27 antigenicity in tissues. For negative control, PBS was substituted for the primary antibody.

p27 Scoring.
Specificity of p27^Kip1 staining was assessed by preabsorption with the peptide used to generate it. All immunoreactive cells were considered positive. Two pathologists (J. P. and G. Z.) separately evaluated p27 staining. Expression was classified as positive (staining in 5% of cells) or negative (staining in <5% of cells), as described previously (13) . At least 20 high-power fields were chosen randomly, and 2000 cells were counted.

p53 immunohistochemical analysis was performed by using the specific monoclonal antibody for p53 (DO-7; Dako, Carpinteria, CA). Cases were scored as positive (staining in 1% of cells) or negative (absence of staining), as reported previously (4) . Tumors with high and low proliferative index were divided along the median for PCNA, which was 60% of positive cells.

Statistical Analysis.
Fisher’s exact test for proportion and the ² test were used to analyze the distribution of p27-positive and -negative cases according to clinicopathological characteristics. All medians and life tables were computed using the product-limit estimate, and the curves were examined by the log-rank test (20) . Multivariate analysis was performed by the Cox proportional hazards model (21) . TTP and OS were calculated from the date of first surgery to the date of clinical or pathological progression or death. Survival analyses were carried out using SOLO Statistical Software (BMDP Statistical Software, Inc., Los Angeles, CA). All reported Ps are two sided.

	RESULTS

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p27 Protein Expression in Epithelial Ovarian Tumors.
A total of 99 primary epithelial ovarian tumors were evaluated. The majority of tumors displayed heterogeneous p27 expression, whereas only a small group of well-differentiated and poorly differentiated tumors showed present (Fig. 1 A) and decreased or absent p27 expression (Fig. 1 B), respectively. In contrast to normal epithelium, where p27 is mostly localized in the nuclei, in ovarian adenocarcinomas a concomitant weak cytoplasmic staining was also observed in some cases.

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. A, well-differentiated (grade 1) papillary serous carcinoma showing strong nuclear and focal cytoplasmic staining for p27. B, poorly differentiated (grade 3) papillary serous carcinoma negative for p27 (x200).

Patients who responded to chemotherapy were more frequently (53%) p27 positive than cases who did not respond (27%), although no statistical significance was reached (P = 0.089). In the group of optimally cytoreduced patients, cases who achieved complete/partial response to chemotherapy were found to be more frequently p27 positive (62%) than not responding patients (14%; P = 0.035).

The reciprocal relationships among the different clinicopathological features is summarized in Table 2 . A highly significant association was found only between the presence of residual tumor at first surgery >2 cm and stage IV disease (P = 0.004) and the presence of ascites at diagnosis (P = 0.0006).

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Kaplan-Meier curve for TTP (A) and OS (B) in 99 primary ovarian carcinomas stratified according to p27 expression. Loss of p27 expression was significantly associated with progression (P = 0.0004 by log-rank test) and death of disease (P = 0.0302 by log-rank test).

The prognostic role of age at diagnosis, stage, histological grade, presence of ascites, residual tumor, and p27 status were tested in univariate and multivariate analyses for both TTP (Table 3) and OS (Table 4) . Loss of p27 was found to be a strong predictor of a shorter TTP on univariate analysis (RR, 2.63; 95% CI, 1.49–4.47; P = 0.0007). Univariate analysis also showed residual tumor (P = 0.0004) and stage of disease (P = 0.01) to be significantly associated with a short TTP.

Fig. 3 shows TTP (Fig. 3 A) and OS (Fig. 3 B) curves after stratification of patients according to p27 status and residual tumor; the presence of p27-positive immunostaining can identify patients with a better clinical outcome in the subgroup of optimally cytoreduced patients as well as in the subgroup of suboptimally cytoreduced patients.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Probability of progression (A) and survival (B) in 99 patients with stages III–IV ovarian carcinoma as stratified by residual tumor and p27 status. Comparison between the groups by the log-rank test. A: residual tumor (cm) 2, p27-positive (a) versus residual tumor 2, p27-negative (b): P = 0.009; residual tumor (cm) >2, p27-positive (c) versus residual tumor >2, p27-negative (d): P = 0.02; residual tumor (cm) 2, p27-negative (b) versus residual tumor >2, p27-negative (d): P = 0.015. B: residual tumor (cm) 2, p27-positive (a) versus residual tumor >2, p27-positive (c): P = 0.047; residual tumor (cm) 2, p27-positive (a) versus residual tumor >2, p27-negative (d): P = 0.0029. All remaining comparisons are not statistically significant.

	DISCUSSION

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In ovarian cancer, our data extend and confirm preliminary observations by us (13) and others (16) but seem in contrast with a recent study (17) , which found lack of independent prognostic significance of p27 in a series of 185 patients with stage III ovarian cancer. The use of a different antibody, the different cutoff value considered for p27 positivity, and the selected stage of patients (stage III only) in that study may account for the different results from our report. However, in the same study, when a complete loss of p27 protein expression was considered versus any degree of p27 expression, a tendency toward a statistically significant association between p27 positivity and a better clinical outcome was found (17) .

The negative prognostic role of loss of p27 expression is not related to its association with unfavorable clinicopathological features nor biological markers of aggressiveness, such as p53 overexpression, as also reported by Newcomb et al. (16) . Interestingly, there was no correlation (positive or inverse) between p27^Kip1 and PCNA, suggesting that expression of p27^Kip1, as observed previously in other tumors (7 , 24) , is not merely a reflection of low proliferation rate. Moreover, the association between loss of p27 expression and poor survival remained significant after stratification according to residual tumor at first surgery, a parameter that plays a major role in affecting response to chemotherapy and survival (19) . Finally, we demonstrated that loss of p27 expression retained an independent, negative prognostic role also in the multivariate analysis for both TTP and OS. We observed that p27-positive cases showed a higher percentage of response to chemotherapy, especially in the group of patients optimally cytoreduced at first surgery. This finding could justify the apparent closer association between p27 status and TTP with respect to OS, because it is well recognized that TTP more adequately reflects the efficacy of first-line chemotherapy. Platinum-based chemotherapy induces apoptosis in tumor cells, and reduced susceptibility to apoptosis has been proposed as a major mechanism responsible for resistance to chemotherapy (3 , 25) . Recent evidence indicates that p27 overexpression induces apoptosis in several different human cancer cell lines through a p53-independent pathway (26) . Furthermore, in a large series of human breast cancer specimens, p27 levels showed a strong correlation with the apoptotic index and predictive value for the benefits of chemotherapy (27) . It is conceivable that p27 expression may confer sensitivity to apoptosis in a p53-independent manner, thus increasing the sensitivity of ovarian cancer cells to chemotherapeutic agents. Further in vitro and in vivo studies are required to elucidate whether alterations in p27 expression are responsible for the reduced response to chemotherapy in ovarian cancer cells. Moreover, it could be of interest to assess simultaneously other factors, such as the cell cycle control proteins cyclin D1 and cyclin E, which have been postulated to regulate expression levels of p27^Kip1 in a negative regulatory feedback loop (28) .

In summary, in this study, we present evidence for a role of p27 in ovarian cancer patients as an independent prognostic predictor of clinical outcome. Patients with ovarian cancer that show loss of p27 expression are at higher risk of progression and death of disease and may eventually benefit from more aggressive adjuvant therapy. The reliability of p27 as a potential marker in the clinical routine assessment and management of women with advanced ovarian cancer deserves to be further evaluated in long-term follow-up studies.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was partially supported by "Associazione Italiana per la Ricerca sul Cancro" (to S. M.); NIH Grants RO1 CA60999/01A1, PO1-NS36466, and PO1-CA56309; and by a grant from Sbarro Institute for Cancer Research (to A. G.). V. M. is supported by a Fellowship from Consiglio Nazionale delle Ricerche.

² To whom requests for reprints should be addressed, at Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Jefferson Alumni Hall Room 226, 1020 Locust Street, Philadelphia, PA 19107. Phone: (215) 503-0781; Fax: (215) 923-9626; E-mail: agiordan{at}lac.jci.tju.edu

³ The abbreviations used are: cdk, cyclin-dependent kinase; PCNA, proliferating cell nuclear antigen; TTP, time to progression; OS, overall survival; CI, confidence interval; RR, relative risk.

Received 5/22/00; revised 9/27/00; accepted 10/ 2/00.

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