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1998 Abstract: MOLECULAR GENETICS OF PANCREATIC CANCER. RJ Bold, DB Evans, KR Hess, AM Grau, F Sinicrope, KR Cleary, PJ Chiao, JL Abbruzzese, The University of Texas M. D. Anderson Cancer Center, Houston, TX. 25

Abstracts
1998 Digestive Disease Week

#2317

MOLECULAR GENETICS OF PANCREATIC CANCER. RJ Bold, DB Evans, KR Hess, AM Grau, F Sinicrope, KR Cleary, PJ Chiao, JL Abbruzzese, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

INTRODUCTION: Adenocarcinoma of the pancreas has been associated with a number of genetic mutations, including alterations of the tumor-suppressor gene p53, the anti-apoptotic gene bcl-2 and the K-ras oncogene. We sought to determine the impact of mutations in p53 or K-ras, or overexpression of bcl-2 on recurrence and survival in patients who received multimodality therapy including pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma.

METHODS: Clinical, surgical and standard pathologic information was available for 104 patients who underwent multimodality therapy including PD during a 6 year time period. Mutations in the K-ras gene were detected by tumor DNA amplification from either paraffin-embedded or frozen tissue followed by mutant-enriched PCR with subsequent DNA cloning and sequencing. Expression levels of p53 (mutant status is associated with overexpression) and bcl-2 proteins were determined by immunohistochemical staining of paraffin-embedded tissue. Recurrence and survival were measured from the time of tissue diagnosis and statistical analysis performed by Kaplan-Meier estimates and Cox proportional hazards regression.

RESULTS: Median survival of the 104 patients was 23 months with a 2-year survival of 47%. Genetic analysis was available for K-ras in 75 patients and immunohistochemical results available for p53 in 75 and for bcl-2 in 76. Negative predictors of tumor recurrence were: K-ras mutation (p=0.0035), poorly differentiated histology (p=0.025), and presence of lymph node metastases (p=0.0039). The tumor status of neither p53 nor bcl-2 was predictive of recurrence or survival, although mutation of the p53 gene was predictive of bcl-2 overexpression (p=0.046). In a multivariate analysis, mutation of the K-ras gene was the most significant predictor of tumor recurrence (p=0.0035) and poor survival (p=0.014).

CONCLUSIONS: Mutation of the K-ras gene is associated with early tumor recurrence and short survival. In contrast to results with other solid tumors, mutation of the p53 gene or overexpression of the bcl-2 gene had no impact on survival duration. Molecular genotyping of potentially resectable pancreatic cancer can predict patient outcome. Such findings support ongoing efforts to develop novel therapeutic strategies directed at important molecular targets.

Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.



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