Circulating tumor DNA-guided response evaluation in patients with previously treated gastroesophageal adenocarcinoma

Abstract Background Systemic treatment offers only modest survival benefits in previously treated metastatic gastroesophageal adenocarcinoma (GEA). Treatment monitoring using imaging-based response assessments are often delayed and imprecise, highlighting the need for biomarkers to guide early treatment decisions. We evaluated the value of circulating tumor DNA (ctDNA) for prognosis, patient selection, and on-treatment monitoring in patients with previously treated GEA. Methods This retrospective study aimed to investigate whether baseline ctDNA levels and early ctDNA changes assessed by ctDNA-RECIST were associated with survival outcomes in a randomized Phase 2 trial comparing trifluridine-tipiracil plus bevacizumab or trifluridine-tipiracil alone. Plasma samples were collected at baseline and during treatment (weeks 4 and 8). ctDNA was quantified by a tumor-agnostic methylation-specific digital droplet PCR (ddPCR) assay. Results Plasma samples were available in 86 patients out of a total of 103 patients included in the trial. Patients with the highest baseline ctDNA levels (top 20%, n = 18) had significantly shorter progression-free survival (PFS; median 1.8 vs. 4.6 months; HR 2.2, p = 0.005) and overall survival (OS; median 5.5 vs. 9.9 months; HR 2.2, p = 0.004) compared to those with lower levels. Early progression by ctDNA at four weeks (HR 2.4, p = 0.003) and at eight weeks by radiological assessment (HR 2.9, p = 0.001) were both associated with inferior OS. Conclusions ctDNA is a strong prognostic biomarker in refractory GEA. High baseline levels and early increases identify patients unlikely to benefit from treatment. Prospective validation is needed, but ctDNA monitoring may enable earlier therapeutic decision-making in clinical practice.