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Impact of E2F-1 Expression on Clinical Outcome of Gastric Adenocarcinoma Patients with Adjuvant Chemoradiation Therapy

Authors' Affiliations: ¹ Division of Hematology-Oncology, Departments of ² Surgery, ³ Radiation Oncology, and ⁴ Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Requests for reprints: Won Ki Kang, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong Kangnam-gu, Seoul, 135-710 Korea. Phone: 82-2-3410-3451; Fax: 82-2-3410-0041; E-mail: wkkang{at}smc.samsung.co.kr.

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 R₀-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 R₀-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 (M₀) patients (P < 0.001). TS immunopositivity did 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.