Targeted Molecular Profiling of Circulating Cell-Free DNA in Patients With Gastroesophageal Adenocarcinoma.

Abstract

We sought to characterize the genomic landscape of gastroesophageal adenocarcinoma (GEA) using next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA), compare the genomic profile to tissue NGS, and determine the association of circulating tumor DNA (ctDNA) detection with clinical outcomes. In this prospective biospecimen-collection study (2017-2022), cfDNA was analyzed using a clinically validated 129-gene tumor-informed NGS assay Memorial Sloan Kettering-Analysis of Circulating cfDNA to Evaluate Somatic Status (MSK-ACCESS); tissue-NGS was performed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. In total, 169 patients with GEA underwent baseline molecular profiling of cfDNA; 93 had localized disease, 55 had untreated metastatic disease, and 21 had progressive metastatic disease. The frequency of the most common alterations was similar between platforms, although copy-number alterations were detected less frequently in plasma than in tissue (10% <i>v</i> 40%; <i>P</i> < .001). Matched-tumor NGS was conducted in 154 patients (91%). Baseline ctDNA detection and on-treatment clearance were associated with improved overall survival and recurrence-free survival in patients with localized disease and progression-free survival in patients with metastatic disease. Baseline ctDNA detection was a stronger predictor of overall survival than American Joint Committee on Cancer (AJCC) clinical stage and positively predicted lymph node metastasis in 87% of cases. Trends in variant allele fractions correlated with pathologic responses to neoadjuvant therapy more closely than fluorodeoxyglucose-positron emission tomography standard uptake values. Persistence or resurgence of ctDNA was associated with worse survival and forecasted recurrent disease a median of 7 months sooner than imaging. cfDNA analysis using MSK-ACCESS in patients with GEA is a valuable adjunctive clinical tool that enhances molecular profiling, prognostication, treatment response assessment, and detection of recurrent disease in conjunction with tissue NGS, imaging, and AJCC clinical staging criteria.