bcl-2 and p 53 Expression in Resectable Pancreatic Adenocarcinomas : Association with Clinical Outcome 1

The bcl-2 proto-oncogene and the p53 tumor suppressor gene are important determinants of tumor cell susceptibility to apoptosis. bcl-2 and mutant p53 proteins inhibit apoptosis in vitro and can provide prognostic information in certain tumor types. We analyzed bcl-2 and p53 expression in archival pancreatic (ii 35) and ampullary (n = 6) adenocarcinomas, resected for cure, and their relationship to overall survival. Patients were treated with 5-fluorouracil and irradiation either pre(ii = 21) or postoperatively (ii = 15); 5 patients received surgery alone. Using specific monoclonal antibodies, cytoplasmic bcl-2 and nuclear p53 proteins were detected in 22 of 40 (55%) and 20 of 37 (54%) tumors, respectively. No relationship was found between bcl-2 and p53 expression. Neither bcl-2 nor p53 correlated with histological response to preoperative chemoradiation. Lymph node involvement predicted poor overall survival (P 0.02). A trend toward improved survival was seen in well-differentiated (P = 0.08) tumors and in those with increased bcl-2 expression (P = 0.06). p53 expression was not related to clinical outcome. In a multivariate analysis, nodal status was the single most important predictor of overall survival. Of note, the combined variable of bcl-2 expression and histological grade was a stronger prognostic variable than nodal status alone. Unlike nodal status, these features can potentially be evaluated in preoperative biopsy specimens. Received 5/10/96: revised 9/1 1/96: accepted 10/2/96. I Supported in part by grants from the Glaxo Institute for Digestive Health (to F. A. S.) and the Physician’s Referral Service (to J. L. A. and D. B. E.). F. A. S. is a recipient of an American Cancer Society Career Development Award. 2 To whom requests for reprints should be addressed, at Department of Gastrointestinal Medical Oncology and Digestive Disease. M. D. Anderson Cancer Center. Box 78. 15 15 Holcombe Boulevard. Houston, TX 77030. Phone: (713) 792-2828: Fax: (713) 745-1 163. INTRODUCTION Pancreatic carcinoma is the fifth most common cause of cancer-related death in the United States ( I ). Prognosis in this disease remains extremely poor ( 1 ). Pancreatic adenocarcinomas are characterized by molecular genetic alterations that accumulate during neoplastic progression. Reported genetic abnormabities in pancreatic carcinomas include K-ra.s (2-4) and P53 (4-9) gene mutations and deletions of the p! 6 (MSTI ) gene ( 10). The clinical relevance of these genetic alterations is as yet undetermined: however, correlation of patient outcome with molecular markers may allow the selection of patients more likely to benefit from anticancer treatment. Evidence indicates that the bd-2 proto-oncogene and the p53 gene regulate the process of apoptosis or programmed cell death ( I 1 , I 2). Susceptibility to apoptosis appears to be a critical determinant of tumor cell sensitivity to anticancer drugs and irradiation ( I 1). The hd-2 proto-oncogene encodes a M 25.000 integral membrane protein that has been shown to protect cells from apoptosis under a variety of experimental conditions (reviewed in Ref. I 2). In transfection experiments. bcl-2 confers resistance to apoptotic stimuli, including multiple anticancer drugs and irradiation (12, 13). The bel-2 protein has been detected in normal tissues, including glandular cells, lymphoid tissues, and organized epithelia (14). In normal human epithelia, hcl-2 expression is restricted to the basal layer, where it is believed to protect stem cells from apoptosis (14). We ( 15) and others (16) have shown that bel-2 overexpression and loss of topographic restriction occurs coincident with neoplastic transformation in coborectal inucosa, suggesting that abnormal bcl-2 expression is an early event in coborectal tumorigenesis. Deregulated bel-2 expression has been detected in several solid tumors and, paradoxicably. has been associated with improved survival in colon (17-19). breast (20-22), ovarian (23). and non-small cell lung carcinomas (24). However, to date, no studies of bcl-2 expression in pancreatic carcinoma have been reported. The wt3 p53 protein transcriptionally activates specific genes necessary for cell cycle arrest and can also induce apoptosis (25). Loss of p53 function by mutation is associated with inhibition of apoptotic cell death (26). In a transgenie mouse model of brain tumorigenesis, loss of wt p53 function was associated with a decrease in apoptosis and rapid tumor progression (27). In a variety of human cancers, accumulation of mutant p53 proteins has been shown to be a marker of poor prognosis (28). Furthermore, transplanted murine fibrosarcomas containing an inactive p53 gene contained few ap()ptotic cells and were resistant to anticancer drugs. whereas those with wt p53 had a high propcrtion of apopResearch. on July 14, 2017. © 1996 American Association for Cancer clincancerres.aacrjournals. org Downloaded from Table 1 Study characteristics