Early Circulating Tumor DNA Dynamics Predict Overall Survival in Solid Tumors: A Landscape Assessment

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PURPOSE Circulating tumor DNA (ctDNA) is an emerging biomarker for early, minimally invasive treatment response assessment, but heterogenous sampling schedules, assay methods, and molecular response (MR) definitions have slowed progress toward regulatory acceptance of ctDNA reductions as an early end point. METHODS We conducted a landscape assessment of studies evaluating on-treatment ctDNA dynamics within 6 months of therapy initiation and their association with overall survival (OS) or progression-free survival. A total of 162 studies across advanced solid tumors met the inclusion criteria, and four meta-analyses were reviewed separately. We extracted data on cancer type, treatment modality, ctDNA collection timing, assay methodology, and MR definitions to characterize methodological patterns across studies. RESULTS Among the 76 studies reporting hazard ratios for on-treatment ctDNA dynamics and associations with OS, all but one demonstrated a positive association between ctDNA reductions and improved OS, independent of cancer type, treatment modality, assay platform, or MR definition. Most studies collected ctDNA between 3 and 8 weeks after treatment initiation or at the start of cycle 2 or 3, and next-generation sequencing was the predominant assay used. Although ctDNA clearance yielded the strongest associations, ≥50% decrease and any decrease in ctDNA from baseline were also consistently prognostic, whereas increases in ctDNA were associated with poorer OS. Additionally, all four meta-analyses reported significant associations between ctDNA decrease or clearance and improved OS. CONCLUSION Early reductions in ctDNA are associated with improved OS across diverse tumor types and therapeutic contexts, underscoring the robustness of ctDNA dynamics as a prognostic biomarker in clinical trials. Standardization of collection timing, MR thresholds, and assay approaches will be essential for advancing on-treatment ctDNA reductions toward regulatory qualification as an early end point.

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