Prognostic Significance of Circulating Tumor DNA Mutations in Gastrointestinal Stromal Tumors: A Systematic Review and Meta-analysis Based on Time-To-Event Data.

Abstract

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the digestive tract, most commonly originating in the stomach or small intestine, and driven by activating mutations in the KIT or PDGFRA genes. Liquid biopsy has emerged as a promising, minimally invasive technique to detect and monitor circulating tumor DNA (ctDNA), offering real-time insights into tumor dynamics and treatment response. Specifically, detecting KIT/PDGFRA mutations in ctDNA may aid in assessing prognosis, therapeutic response, and resistance. However, the clinical utility of this approach remains unclear. To address this, we conducted a systematic review and meta-analysis to evaluate the prognostic relevance of ctDNA mutations in GIST patients by comparing survival outcomes between those with KIT/PDGFRA mutations and those with wild-type profiles or no detectable ctDNA.

Methods: A comprehensive systematic search was performed in the PubMed, Scopus, and Web of Science databases to identify studies evaluating overall survival (OS) at different time points in patients with GIST, stratified by ctDNA status (ctDNA-negative vs. ctDNA-positive). Hazard ratios (HRs) were extracted or calculated, and Kaplan-Meier curves were reconstructed using an adjusted Cox proportional hazards model, with 95% confidence intervals (CIs). A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using RStudio software, version 4.2.3.

Results: This study included seven eligible studies comprising a total of 2024 histologically confirmed GIST patients, of whom 1610 were classified as ctDNA-positive and 414 had no detectable ctDNA mutations. OS at different time points was consistently more favorable in the ctDNA-negative group compared to the ctDNA-positive group (reference). The pooled hazard ratios (HR) were as follows: at 1year, HR 0.91 (95% CI: 0.89-0.93; p < 0.01; I² = 0%); at 2years, HR 0.85 (95% CI: 0.83-0.88; p < 0.01; I² = 20%); at 3years, HR 0.77 (95% CI: 0.74-0.81; p < 0.01; I² = 28.2%); and at 5years, HR 0.63 (95% CI: 0.54-0.73; p < 0.01; I² = 70.8%). At maximum follow-up (mean follow-up of 7.5months), OS showed a 49% reduction in survival in the ctDNA-positive group (HR 0.51; 95% CI: 0.40-0.64; p < 0.01; I² = 79.9%). Additionally, in a pooled analysis of Kaplan-Meier data from patients with the KIT exon 11 (KIT11) mutation, the adjusted Cox proportional hazards model estimated an HR of 0.66 (95% CI: 0.49-0.89; p = 0.007), favoring the ctDNA-positive group.

Conclusion: This meta-analysis highlights the potential of ctDNA as a prognostic biomarker in GIST, showing that its presence is consistently associated with poorer survival outcomes across mutational subtypes. These findings support the integration of ctDNA analysis into clinical practice as a minimally invasive tool for disease monitoring, contributing to more personalized and precise management of GIST patients.