Circulating tumor DNA is clinically advanced in oncology, but its value differs between molecular residual disease assessment after curative-intent treatment and multicancer early detection in asymptomatic populations.

To evaluate clinical effectiveness, actionability, and certainty of evidence for ctDNA-based MRD strategies and cfDNA- or ctDNA-based MCED pathways.

The review followed PRISMA 2020 and PRISMA-S. Databases and trial registries were searched through July 2026. Two reviewers independently screened records, extracted data, and assessed risk of bias.

Twenty-nine completed reports representing 25 study programs were included. Selected MRD trials demonstrated clinical utility when test results were linked to defined treatment decisions.

ctDNA has demonstrated clinical utility in selected MRD settings. In many other tumors it remains primarily prognostic, and broad MCED implementation is premature.