Circulating tumor DNA informs clinical practice in patients with recurrent/metastatic gastroesophageal cancers

Background: Circulating tumor DNA (ctDNA) is a valuable biomarker for assessing treatment response and molecular residual disease. In advanced esophageal and gastric cancer (gastroesophageal cancer [EGC]), ctDNA dynamics remain poorly understood. The authors investigated ctDNA in patients with advanced EGC to evaluate its clinical utility. Methods: This was a multi-institutional, retrospective analysis of 200 patients with recurrent/metastatic EGCs who underwent commercial ctDNA testing using a personalized, tumor-informed assay (Signatera; Natera, Inc.). Patients were divided into cohort A (N = 36; stage I–III with recurrence) or cohort B (N = 164; metastatic at diagnosis). Longitudinal ctDNA dynamics were correlated with clinical and radiographic findings. Results: In cohort A, 31 of 36 patients (86.1%) had ctDNA collected ≤90 days before recurrence; of these, 25 of 31 patients (80.65%) were ctDNA-positive before recurrence. In cohort B, baseline ctDNA was available for 29 of 164 patients (17.68%), and all 29 were ctDNA-positive. Among 52 patients who had on-treatment ctDNA assessments, 62 treatment lines were analyzed (N = 6 in cohort A; N = 46 in cohort B). All who remained ctDNA-negative throughout treatment (Neg-Neg) showed treatment benefit (n = 6 of 6). Those who converted to ctDNA-positive (Neg-Pos) progressed (n = 2 of 2). Among ctDNA-positive patients (Pos-Pos), 27 of 40 (67.5%) showed treatment benefit, whereas 13 of 40 (32.5%) progressed. Patients who cleared ctDNA (Pos-Neg) had favorable outcomes (12 of 14 patients; 85.7%). A decrease >90% in ctDNA levels among Pos-Pos patients was linked to superior progression-fee survival. Grouping treatment lines into favorable (Neg-Neg, Pos-Neg, and Pos-Pos with >90% decrease) versus unfavorable (Neg-Pos and Pos-Pos with a <90% decrease or an increase) had significantly improved progression-free survival in the favorable group (p <.0001). Conclusions: ctDNA dynamics predicted progression and may guide treatment or imaging. ctDNA offers a minimally invasive, cost-effective adjunct to radiographic surveillance.