Differential expression and prognostic value of ERCC1 and thymidylate synthase in resected gastric adenocarcinoma

• Type of Material: Article
• Authors: Malcolm H. Squires, Emory University; Sarah B. Fisher, Emory University; Kevin E. Fisher, Emory University; Sameer H. Patel, Emory University; David Kooby, Emory University; Bassel El-Rayes, Emory University; Charles Staley, Emory University; Alton Farris III, Emory University; Shishir Maithel, Emory University
• Language: English
• Date: 2013-09-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 American Cancer Society.
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.28175
• Title of Journal or Parent Work: Cancer
• ISSN: 0008-543X
• Volume: 119
• Issue: 17
• Start Page: 3242
• End Page: 3250
• Grant/Funding Information: This study is supported in part by the Katz Foundation.; Dr. Fisher is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.
• Keywords: CELL LUNG-CANCER; DNA-REPAIR; CAPECITABINE; Life Sciences & Biomedicine; ERCC1; biomarkers; CROSS-COMPLEMENTING GENE-1; CHEMOTHERAPY; GROWTH-FACTOR RECEPTOR; PLUS CISPLATIN; thymidylate synthase; SURGERY; gastric adenocarcinoma; Science & Technology; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER-1; REDUCTASE SUBUNIT M2; Oncology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology; Health Sciences, Oncology

Abstract

Background: Excision repair cross-complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are associated with overall survival (OS) in several malignancies. Their expression patterns and prognostic value in resected gastric adenocarcinoma (GAC) are not known. Methods: In total, 109 patients who underwent resection for GAC between January 2000 and June 2011 had tissue available for analysis. The primary objective was to assess for the differential expression of ERCC1 and TS using immunohistochemistry. The secondary objective was to assess for the association between OS and the expression of ERCC1 and TS. Results: The median follow-up was 21.2 months, and the median OS was 28.8 months. Resected GAC exhibited differential expression of ERCC1 (high expression, 23%; n = 25) and TS (high expression, 43%; n = 47). ERCC1 and TS expression were not associated with OS. In a subset analysis of patients who received chemotherapy (n = 73), high ERCC1 expression was associated with decreased OS (16.7 months vs 53.8 months; P = 0.03). After controlling for known adverse pathologic features, high ERCC1 expression persisted as a negative prognostic factor in multivariate Cox regression analysis (hazard ratio, 2.5; 95% confidence interval, 1.03-6.0; P =.04). Conversely, in patients who underwent resection only (n = 35), high ERCC1 expression demonstrated a trend toward improved OS (40.4 months vs 12.7 months; P =.10); a positive prognostic influence also was present on multivariate analysis (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P =.03). Conclusions: Resected GAC exhibited differential expression of TS and ERCC1. Among all patients, ERCC1 and TS expression levels were not associated with OS. High ERCC1 tumor expression was associated with decreased OS in the patients who received chemotherapy but was associated with increased OS in those who underwent surgery alone. ERCC1 expression had prognostic value in resected gastric cancer, and further investigation is warranted.