Y. Muneoka1, H. Ichikawa1, S. Kosugi2, T. Hanyu1, T. Ishikawa1, Y. Kano1, N. Sudo1, M. Nemoto1, Y. Shimada1, M. Nagahashi1, J. Sakata1, T. Kobayashi1, H. Kameyama1, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Uonuma Institute Of Community Medicine, Niigata University, Medical And Dental Hospital,Department Of Digestive And General Surgery,Niigata, NIIGATA, Japan
Introduction: NAD(P)H:quinone oxidoreductase-1 (NQO1) is an antioxidant protein. Low expression of NQO1 contributes to high response to anticancer agents, particularly to oxidative stress inducers such as cisplatin (CDDP) or 5-fluorouracil (5-FU) in malignant tumors. It was reported that NQO1 expression is constitutively reduced in non-neoplastic esophageal squamous epithelium of patients with single nucleotide polymorphism of NQO1 (C609T). The aim of this study is to elucidate the clinical significance of NQO1 expression in the non-neoplastic squamous epithelium of patients with esophageal squamous cell carcinoma (ESCC) who underwent preoperative chemotherapy with CDDP and 5-FU (CF) followed by a radical esophagectomy.
Methods: We retrospectively analyzed the cases of 43 patients who underwent preoperative chemotherapy with CF followed by a radical esophagectomy for ESCC between 2001 and 2012. NQO1 expression in non-neoplastic squamous epithelium of the surgically resected specimens were examined by immunohistochemistry. The expression was defined as negative when basal cells and vascular endothelial cells were not stained with anti-NQO1 antibody. We analyzed the associations between NQO1 expression and the patient demographics, tumor characteristics, histological response to CF therapy, and relapse-free survival. The median follow-up period of the relapse-free patients was 51 months.
Results: Twenty-two patients (51%) had non-neoplastic squamous epithelium with negative NQO1 expression (NQO1-negative patients). No histological evidence of primary tumor or pathological T1 (pT1) tumor was more frequent in NQO1-negative patients than in NQO1-positive patients (41% vs. 5%; P < 0.01). Overall, downstaging of the primary tumor was achieved in 46% of NQO1-negative patients and in 10% of NQO1-positive patients (P = 0.02). There was no significant difference in the histological response to preoperative CF therapy between the two groups. The three-year relapse-free survival of NQO1-negative patients was significantly better than that of NQO1-positive patients (76% vs. 48%, P = 0.02). Other significant prognostic factors were pT, pN, and lymphovascular invasion in a univariate analysis. Multivariate analysis demonstrated that negative NQO1 expression (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.10-0.92; P = 0.04) and lymphovascular invasion (HR, 4.39; 95%CI, 1.43-13.5; P = 0.04) were independent prognostic factors.
Conclusion: NQO1 expression in non-neoplastic squamous epithelium of ESCC patients could be a promising biomarker to predict treatment outcomes after preoperative CF therapy followed by a radical esophagectomy.