Impact of E2F-1 expression on clinical outcome of gastric adenocarcinoma patients with adjuvant chemoradiation therapy

Purpose: There are no reliable prognostic markers that identify gastric cancer patients who may benefit from adjuvant chemoradiation therapy. E2F-1 was shown to be associated with radiosensitivity and chemosensitivity in certain tumor types. Therefore, we analyzed expression and prognostic significance of E2F-1 along with thymidylate synthase (TS) in R-0-resected gastric adenocarcinoma patients, who underwent adjuvant chemoradiation therapy with 5-fluorouracil (5-FU) and leucovorin. Experimental Design: The chemosensitivity to 5 - FU and radiosensitivity were tested in three E2F-1 - overexpressed gastric cancer cell lines in vitro. The expressions of TS and E2F-1 were analyzed in 467 R-0-resected primary gastric cancer patients, who received adjuvant chemoradiation therapy with 5-FU and leucovorin using tissue microarray. Results: The E2F-1 immunopositivity rate was 22.2% (103 of 465 samples) with a cutoff value of 5% immunoreactivity, whereas the TS-positive expression occurred in 19.0% of the 463 tumors tested. Using stepwise Cox proportional hazards regression modeling, multivariate analyses showed that the E2F-1 immunopositivity predicted more favorable survival as compared with the E2F-1 immunonegativity with borderline statistical significance [P = 0.050, hazard ratio (HR) = 0.702, 95% confidence interval, 0.487,1.013]. However, the E2F-1 immunopositivity did not retain its statistical significance at multivariate analysis for predicting disease-free survival (data not shown, P = 0.270), but stage was the only influential factor for disease-free survival in stages IB to IV (M-0) patients (P < 0.001).TS immunopositivityclid not influence survival (P = 0.459) or disease-free survival (P = 0.447). Conclusion: E2F-1 is a potentially novel independent prognostic factor that may identify gastric cancer patients who will likely benefit from adjuvant chemoradiation therapy following curative resection.