Tumor-informed liquid biopsy in predicting recurrence in patients with operable gastroesophageal adenocarcinoma: The LIQUID study.

4067 Background: Gastroesophageal cancers (GEC) shows high recurrence rates after curative surgery with or without perioperative/adjuvant chemotherapy. Pathological stage is currently the only prognostic tool, but its accuracy should be improved. Liquid biopsy, analyzing circulating tumor DNA (ctDNA), offers a non-invasive method to detect molecular residual disease (MRD) and monitor disease status. The LIQUID study aimed to evaluate the prognostic utility of liquid biopsy in GC patients, for whom observational studies are still scarce. Methods: This single-institutional study enrolled patients with resectable GC treated or not with perioperative/adjuvant chemotherapy. Liquid biopsies were collected before neoadjuvant chemotherapy (optional), pre- and post-surgery (minimum 2 weeks interval) and every six months during follow-up, until disease progression or the last follow-up for alive and progression-free patients. MRD analysis was performed using a clinical trial assay based on the tumor-informed ctDNA assay FoundationOne®Tracker, which identified somatic mutations by tissue comprehensive genomic profiling and tracked them in patients’ plasma samples. Results: Between December 2019 and February 2024, 119 patients were enrolled. Of these, 40 were excluded due to screen failure (mostly peritoneal disease at surgery), and 27 due to technical failure (n = 18) or loss to follow-up (n = 9), leaving 52 patients (median 4 timepoints per patient) for analysis. Median age was 70 years (range: 23–86), with 55.8% male, and 86.5% of tumors located in the stomach. Pathological staging revealed pT0 (3.8%), pT1 (21.2%), pT2 (21.2%), pT3 (34.6%), and pT4 (19.2%) tumors, with nodal involvement in 69.6%. Additionally, 51.9% and 46.2% of patients received neoadjuvant or adjuvant treatment respectively, and 32.7% experienced peritoneal relapse. ctDNA presence was not significantly associated with known clinico-pathological baseline risk factors, except for postoperative N-stage ( p = 0.04 ). With a median follow-up of 49.0 months (IQR 30.6 -54.0), post-surgery MRD+ patients had a significantly worse relapse-free survival (RFS) than those with ctDNA- (13.2 months vs not reached; HR 2.81 95% CI 1.23-6.45; p = 0.011 ). Similar results were observed in longitudinal ctDNA monitoring, (RFS 16.3 months for ctDNA+ vs not reached for ctDNA-; HR 2.70, 95% CI 1.22–5.97, p = 0.011 ). Notably, absence of ctDNA after completing the treatment plan (post-surgery or adjuvant therapy) or clearance/seroreversion after treatment were associated with significantly longer RFS ( p = 0.001 and p = 0.036 , respectively). Conclusions: Post-surgical landmark and longitudinal ctDNA detection demonstrates robust evidence of MRD and identifies GC patients at high risk of relapse. These findings support ctDNA as a valuable tool for postoperative surveillance and early intervention strategies in GEC.