Rutika Mehta, Samuel Rivero‐Hinojosa, Farshid Dayyani, Jenifer Ferguson, Bushra Shariff, V. Aushev, Griffin Budde, J. Bryce Ortiz, Giby V. George, Shruti Sharma, Adham A. Jurdi, Minetta C. Liu, Ronald Drengler, Samuel J. Klempner
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.