Journal Article

Monitoring treatment response using an ultra-sensitive ctDNA assay in advanced esophagogastric cancer patients

Ravi, Neeraja, Chen, Richard O., Abbott, Charles W., Strickler, John H., Uronis, Hope, Navarro, Fábio C. P., Nixon, Andrew B., McDaniel, Lee, Brady, J. Christopher, Jia, Jingquan, Boyle, Sean M., Howard, Lauren E., Niedzwiecki, Donna, Zhou, Katherine I., Liu, Yingmiao

2026

Overview

To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables earlier prediction of treatment response and detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. A total of 24 patients were evaluated, and all were ctDNA-positive at baseline. ctDNA levels varied from 406,067 down to 1.5 parts per million (PPM) with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, p = 7.3 × 10 ). Lack of early molecular response (50% or greater decrease in ctDNA levels at first available time point after 30 days, C2D1 or C4D1) was associated with worse overall survival (OS) (HR 4.5, 95% CI 1.2-16.7, p = 0.02) and progression-free survival (PFS) (HR 10.4, 95% CI 2.2-49.8, p = 0.003). Lack of molecular clearance of ctDNA was associated with worse OS (HR 7.1, 95% CI 1.6-31.7, p = 0.01) and PFS (HR 19.9, 95% CI 2.5-158.2, p = 0.005). Molecular progression (ctDNA increase) preceded imaging-derived progression by a median lead time of 65 days. These results suggest that ultra-sensitive liquid biopsy approaches could improve treatment decision-making for mEGC patients receiving chemotherapy and immunotherapy.