Background: Circulating tumor cells (CTCs) are cells that have shed into the vasculature or lymphatics from a primary tumor and are carried around the body in the blood circulation. The CTCs constitute seeds for the subsequent growth of additional tumors (metastases) in distant organs, a mechanism that is responsible for the vast majority of cancer-related deaths. Circulating-tumor DNA (ctDNA) includes DNA which derives from tumor necrosis or apoptosis; therefore, CTCs may potentially represent more precise tumor status compared to ctDNA. There have been few reports to assess the genomic concordance between ctDNA and CTCs in cancer patients. In addition, genomic analysis of ctDNA would find novel mechanism of resistance to anti-EGFR monoclonal antibody (mAb) in metastatic colorectal cancer (mCRC). RAS mutations in ctDNA are considered to be one of mechanism of resistance to anti-EGFR mAb in RAS wild-type mCRC. However, there is no data regarding CTCs when mCRC patients acquires resistance to anti-EGFR mAb. Methods: This translational study prospectively recruits patients with advanced/metastatic gastrointestinal and pancreatobiliary cancers (esophageal, gastric, pancreatic, biliary tract and colorectal cancers) who receive systemic chemotherapy in first- or second-line and mCRC with RAS wild-type tumors treated with anti-EGFR mAb in any lines, at St. Marianna University School of Medicine Hospital. We accumulate the clinical data regarding patients’ characteristics, treatment, and survival time. The primary objective is to evaluate genomic markers and concordance with ctDNA and CTCs in patients with advanced/metastatic gastrointestinal and pancreatobiliary cancers. Then, this study approaches to assess which biomarkers can predict clinical outcome more accurately. Secondary objectives include evaluating association between genomic status in ctDNA and clinical outcomes; association between genomic status in CTCs and clinical outcomes; comparing genomic change between ctDNA and CTCs in RAS wild-type mCRC patients treated with anti-EGFR mAb. Blood draw of total 10mL is performed for analyses of ctDNA and CTCs at 3 time points, pre-treatment of chemotherapy, 4 weeks after treatment start, and disease progression. Blood of 5mL is processed with CTCs enrichment using the CD-PRIME system (Clinomics Inc.) and remaining 5mL is used for the plasma preparation. Genomic alterations are measured using the customized cancer panel which allows the detection of mutations in 51 actionable genes. This study will enroll 70 patients with willing to undergo blood draws. Accrual is starting in May 2019. Clinical trial information: UMIN000036681.