Abstract
BackgroundTo identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer.Patients and MethodsSurgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR. Gene expression normalized to reference genes was categorized as lower or higher than the median, and association with relapse sites was analyzed based on 5-year relapse-free survival.ResultsHematogenous, lymph node, and peritoneal recurrence developed in 72, 105, and 138 of the 829 patients, respectively; hazard ratios were 0.79 (95% confidential interval: 0.54–1.16), 0.51 (0.31–0.82), and 0.60 (0.42–0.84), respectively. Expression of platelet/endothelial cell adhesion molecule 1 (PECAM1) and topoisomerase II alpha (TOP2A) was strongly correlated with hematogenous recurrence and peritoneal recurrence, respectively (false discovery rate = 7.7×10−5 and 0.002, respectively). Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence (false discovery rate = 0.34). Relapse-free survival was worse in patients expressing high levels of PECAM1 (hazard ratio = 2.37, 1.65–3.41), TOP2A (hazard ratio = 2.35, 1.55–3.57), or GGH (hazard ratio = 1.87, 1.13–3.08), respectively. A multivariate analysis revealed that these were stronger independent risk factors than tumor histological type.ConclusionIn patients with stage II/III gastric cancer, TOP2A, GGH, and PECAM1 levels in primary tumors are linked to high risk of hematogenous, lymph node, and peritoneal recurrence, respectively.
Highlights
Despite a decreasing trend, gastric cancer remains the most common malignancy of the gastrointestinal tract in Japan and the second most common cause of cancer-related death worldwide
Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence
Relapse-free survival was worse in patients expressing high levels of PECAM1, TOP2A, or gamma-glutamyl hydrolase (GGH)
Summary
Gastric cancer remains the most common malignancy of the gastrointestinal tract in Japan and the second most common cause of cancer-related death worldwide. Gene expression profiles associated with cancer metastasis have been extensively studied using genome-wide approaches such as DNA microarray [5,6,7,8,9] and have been used to predict peritoneal relapse after curative surgery for gastric cancer [10]. An eight-gene Gastric Cancer Prognostic Score has been developed to identify patients with stage II gastric cancer who are at high risk of recurrence after surgery regardless of adjuvant treatment [11]. To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer
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