PREDICTIVE MARKERS OF TREATMENT RESPONSE TO 5-FU AND GEMCITABINE IN PANCREATIC CANCER

Abstract

Introduction: The RTOG 9704 prospective multicenter randomized adjuvant treatment trial demonstrated that the addition of gemcitabine to postoperative adjuvant 5-FU chemoradiation therapy improves survival in patients with pancreatic adenocarcinoma. Thymidylate synthase (TS) thymidine phosphorylase (TP) and methylenetetrahydrofolate reductase (MTHFR) are key enzymes in the metabolism of folate and 5-fluorouracil. Human equilibrative nucleoside transporter (hENT1) is involved in gemcitabine transport into cells. Retrospective studies in pancreatic cancer suggest that these markers may have prognostic and predictive value. We aim to study protein expression and polymorphisms of these markers in resected tumors from patients participating in the RTOG 9704 trial. Methods: A Tissue Microarray was constructed using 3 separate cores from 225 resected pancreatic tumors. Immunohistochemistry was performed to define TS, TP and hENT1 protein expression. TS promoter genotype (2 or 3 tandem repeats) and MTHFR genotype (C667T) was assessed using tumor DNA. Correlations between protein expression or genotype and prognostic or predictive factors were sought, by unconditional logistic regression analysis. Results: High TS nuclear expression, TP cytoplasmic expression, TP nuclear expression and TP stromal expression is seen in 30%, 86%, 65% and 92% of cases. There are statistically significant associations between higher pathologic grade and high expression of TP nuclear (p = 0.05) and TP cytoplasmic (p = 0.02). There is a trend towards nodal status and high TP nuclear marker levels (p = 0.09). The frequencies of TS promoter tandem repeat 2R/2R, 2R/3R and 3R/3R are 27%, 33%, and 38%. There is a non-significant trend towards 3R/3R TS genotype and high TS protein expression. 22% of cases had no expression of hENT1, compared with 38% with high expression. The frequencies of the MTHFR 667CC, 667CT, and 667TT genotypes are 48.8%, 41.1%, and 10.1%, respectively. 27.6% of patients with either 667CC or 667CT vs. 8.3% of patients with 667TT are early T stage (p = 0.12). Correlation analysis with treatment outcome and toxicity for this trial will be presented. Conclusions: This is the first study to analyze prognostic and predictive markers in a prospective randomized pancreatic cancer clinical trial. There is limited association between TS or TP protein expression and tumor demographic factors. There is a trend towards correlation between TS genotype 3R/3R and high TS protein expression in pancreatic cancer. MTHFR TT genotype was more likely to be associated with advanced T stage and may be associated with disease progression. The majority of tumors expressed hENT1. These markers may serve as useful predictors markers of response and toxicity in pancreatic cancer treatment.