Clinical validity of circulating tumor DNA as a diagnostic biomarker for prostate cancer: a systematic review

Current diagnostic pathways for prostate cancer (PCa) have unsatisfactory specificity and rely heavily on magnetic resonance imaging, underscoring the need for novel diagnostic biomarkers. This article provides a systematic review of the evidence on using blood-derived cell-free DNA (cfDNA)-based biomarkers for PCa diagnosis. A structured review was conducted according to the PRISMA guidelines. Original peer-reviewed research articles published before August 2025 were identified from PubMed/Medline, Web of Science, and Embase using keyword combinations concerning PCa, cfDNA, and diagnostic test performance. Studies that compared blood-derived cfDNA-based diagnostic biomarkers in men with and without PCa were included. Fifty-nine articles were identified and analyzed. Most articles reported qualitative cfDNA assays relying on PCR (N=37) or next generation sequencing (NGS; N=10). Diagnostic test performance improved for aggressive and metastatic PCa. However, evidence regarding clinical validity in localized disease is scarce, particularly for NGS-based methods (3 studies). GSTP1 promoter hypermethylation, the most frequently investigated biomarker, showed an average sensitivity and specificity of 35.1% and 91.2%, respectively, for the detection of localized PCa. Overall, circulating tumor DNA represents a promising diagnostic biomarker for PCa early detection. High-quality discovery and validation research in the intended-use setting are essential to fully understand clinical validity and utility.