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Detection of Tumor-Specific Mutations in Circulating, Cell-Free DNA: Potential for a Biomarker in Esophageal Adenocarcinoma
*Matthew Egyud1, *Jennifer Jackson1, *Emiko Yamada1, *Anders Stahlberg2, *Virginia Litle1, *Tony Godfrey1
1Boston Medical Center, Boston, MA;2University of Gothenburg, Gothenburg, Sweden

Objective: The goal of this study is to determine if Esophageal Adenocarcinoma (EAC) can be diagnosed from, or treatment response monitored with blood-based tests to detect circulating tumor DNA. Studies have detected tumor-specific DNA in plasma, which raises the possibility of “liquid biopsies” using mutated tumor DNA as a diagnostic and prognostic biomarker. We developed a novel approach using molecular barcodes to detect mutant alleles with frequencies below 1%, and are using this to evaluate liquid biopsy for diagnosis and treatment monitoring of esophageal adenocarcinoma.
Design: Cohort Study - DNA from patients with EAC was sequenced using targeted gene panels to identify tumor mutations. Assays with molecular barcodes were designed to identify these mutations in plasma, and sequencing libraries subsequently prepared and analyzed.
Setting: General community
Patients: Patients with pathologic evidence of EAC were identified for study. 66 patients with various stages of disease consented to participate. One set had blood collected at a single time point (n=32). A second set undergoing neoadjuvant therapy followed by potential surgery had blood collected longitudinally across treatment (n=34). Tumor samples were obtained via biopsy or surgical resection.
Interventions: N/A
Main Outcome Measures: Identification, from plasma DNA, of mutations of interest found in the primary tumor.
Results: Tumor Mutations were identified in 32 patients. Of 18 analyzed to date, tumor mutations were identified in 7 plasma samples, with two patients demonstrating multiple mutant alleles. All mutations were present below 0.5% frequency.
Conclusions: Tumor DNA can be detected in plasma of patients with EAC using ultra-sensitive sequencing. Possible applications include prognostication in early stage patients and rapid monitoring of therapeutic response and recurrence. Further work to evaluate this is ongoing.


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