Assessment of methylated BCAT1 and IKZF1 circulating tumor DNA as a prognostic biomarker in esophagogastric adenocarcinomas

Esophagogastric adenocarcinomas have poor survival, and accurate prognosis assessment is required to guide appropriate treatment. Pre-treatment planning can be challenging and would benefit from non-invasive prognostic tools. Methylated circulating tumor DNA (ctDNA) has prognostic value in colorectal cancer. The aim of the study was to evaluate the prognostic value of methylated ctDNA biomarkers in esophageal and gastric cancers. Circulating cell free DNA, isolated from plasma collected prior to treatment from 122 patients diagnosed with esophagogastric cancer was assayed for methylated BCAT1 and IKZF1. Test positivity was assessed against clinicopathological features, and prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) were investigated with Cox regression analysis. Methylated BCAT1/IKZF1 DNA was detected in 54.9% (67/122) of patients following a diagnosis of esophagogastric cancer. Advanced disease had higher detection rates, with a significant association between test positivity and pathological node-positive disease (odds ratio [OR] for pN2: 5.63, 95% CI 1.27-24.86, P = 0.02), and metastatic disease (OR 4.92, 95% CI 1.94-12.47, P < 0.01). A positive ctDNA result at diagnosis was associated with worse RFS for individuals considered in remission (hazard ratio [HR] 4.49, 95% CI 1.48-13.67, P < 0.01), and a worse OS in all patients (HR 3.64, 95% CI 1.73-7.68, P < 0.01), independent of stage and other clinical variables, compared to a negative ctDNA result. Detection of circulating methylated BCAT1/IKZF1 DNA is a promising prognostic biomarker in esophagogastric cancers. Prospective studies are warranted to investigate the utility of methylated BCAT1/IKZF1 for monitoring treatment response and for risk stratification to guide adjuvant therapeutic decisions.