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This pilot study assessed the incidence and significance of circulating tumor cells (CTCs) in Western patients treated with first-line chemotherapy for advanced esophagogastric cancers. The CellSearch system was used. In 44% of patients, ≥ 2 CTCs were detected and appeared to be associated with lower response and shorter survival. CTCs in esophagogastric cancer are clinically relevant and worthy of further investigation.Circulating tumor cells (CTCs) have been found to be of clinical utility in predicting response to treatment and prognosis in several malignancies. Less is known of the prevalence and clinical relevance of CTCs in esophagogastric adenocarcinoma, with the available data arising from heterogeneous patient populations using varied detection methods.A pilot study was undertaken to assess the prevalence of CTCs in patients with advanced esophageal or gastric adenocarcinoma. Patients were eligible if they had advanced disease and either had received no prior therapy or had progressed after prior chemotherapy. Blood samples for CTC analysis were obtained at baseline and during the course of treatment. The CellSearch immunomagnetic CTC detection platform was used.Twenty-two patients with metastatic esophageal or gastric adenocarcinoma were enrolled. Eighteen received first-line EOX (epirubicin/oxaliplatin/capecitabine) chemotherapy (± panitumumab) and had baseline samples suitable for CTC analysis. At baseline, ≥ 2 CTCs were detected in 8 patients (44%). Overall tumor response rate was 60% in patients with < 2 CTCs and 37.5% in patients with ≥ 2 CTCs. Median progression-free and overall survival were 6.1 and 10.5 months and 5.2 and 6.1 months in the groups of patients with < 2 CTCs and ≥ 2 CTCs, respectively. The study was prematurely discontinued, owing to the withdrawal of commercial support.The incidence of CTCs in locally advanced or metastatic esophagogastric cancer may be clinically relevant. Investigation of the potential clinical utility of CTCs is warranted in a larger cohort of patients with esophagogastric cancer.