Longitudinal Analysis of Circulating Tumor DNA and Detection of Tumor Genomic Alterations Using Liquid Biopsy in Patients with Locally Advanced Esophagogastric Carcinoma

Abstract

For locally advanced esophageal (E), esophagogastric junction (EGJ), and gastric (G) carcinoma, the standard treatment is neoadjuvant chemoradiotherapy followed by surgery. The curative goal is to control the tumor locally, prevent regional recurrence, and prevent or delay metastatic progression. Up to one-third of patients will achieve complete pathologic response rate (pCR) under this treatment. Yet disease recurrence can occur in one-third of patients after definitive treatment. Our study provides real-world longitudinal data of liquid biopsy to analyze circulating tumor deoxyribonucleotide acid (ctDNA) for minimal residual disease (MRD) as an informative marker for early therapeutic response, detectable disease, and risk for recurrence. Furthermore, the liquid biopsy reveals variable tumor-specific sequence alterations. A total of 8 patients with newly diagnosed locoregional esophagogastric cancers were evaluated with non-invasive plasma sample, collected at baseline, post-neoadjuvant chemoradiation, post-surgery, and serially as disease surveillance. Bespoke mPCR-NGS assay measured the ctDNA-based MRD levels and identified a comprehensive tumor-specific genomic profile. The primary outcome is assay recurrence compared to radiologic disease recurrence, defined as radiologic confirmed disease. Exploratory endpoints are used to examine the profile of tumor. Baseline ctDNA levels were detected in 8 newly diagnosed patients. Longitudinal testing showed a decrease in ctDNA in 4 patients and residual disease in 2 patients after the start of neoadjuvant therapy. 1 patient demonstrated pCR in conjunction with ctDNA clearance. Clearance of ctDNA may correlate to a favorable pCR and indicate a lower risk of relapse, guiding the strategy for adjuvant treatment. Personalized, tumor-informed sequence alterations of the 8 patients revealed a high frequency in TP53 alterations, which occurs early during development in esophagogastric cancer. This prospective study seeks to validate the application of ctDNA surveillance and tumor molecular alterations in a larger cohort after 5 years.