Clinical Validity of Circulating Tumor DNA as a Diagnostic Biomarker for Prostate Cancer: A Systematic Review.

Current diagnostic pathways for prostate cancer have unsatisfactory specificity (SPE) 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 prostate cancer diagnosis. A structured review was conducted according to the Preferred Items for Systematic Reviews and Meta-Analyses guidelines. Original peer-reviewed research articles published before August 2025 were identified from PubMed/Medline, Web of Science, and Embase using keyword combinations related to prostate cancer, cfDNA, and diagnostic test performance. Studies that compared blood-derived cfDNA-based diagnostic biomarkers in men with and without prostate cancer 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 prostate cancer. However, evidence about clinical validity in localized disease is scarce, particularly for NGS-based methods (three studies). GSTP1 promoter hypermethylation, the most frequently investigated biomarker, showed an average sensitivity and SPE of 35.1% and 91.2%, respectively, for the detection of localized prostate cancer. Overall, circulating tumor DNA represents a promising diagnostic biomarker for prostate cancer early detection. High-quality discovery and validation research in the intended-use setting are essential to fully understand clinical validity and utility.