BACKGROUND: To validate the clinical utility of a previously identified circulating tumor DNA methylation marker (meth-ctDNA) panel for disease detection and survival outcomes, meth-ctDNA markers were compared to PSA levels and PSMA PET/CT findings in men with different stages of prostate cancer (PCa). METHODS: 122 PCa patients who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT and plasma sampling (03/2019-08/2021) were analyzed. cfDNA was extracted, and a panel of 8 individual meth-ctDNA markers was queried. PET scans were qualitatively and quantitatively assessed. PSA and meth-ctDNA markers were compared to PET findings, and their relative prognostic value was evaluated. RESULTS: PSA discriminated best between negative and tumor-indicative PET scans in all (AUC 0.77) and hormone-sensitive (hsPC) patients (0.737). In castration-resistant PCa (CRPC), the meth-ctDNA marker KLF8 performed best (AUC 0.824). CHST11 differentiated best between non- and metastatic scans (AUC 0.705) overall, KLF8 best in hsPC and CRPC (AUC 0.662, 0.85). Several meth-ctDNA markers correlated low to moderate with the tumor volume in all (5/8) and CRPC patients (6/8), while PSA levels correlated moderately to strongly with the tumor volume in all groups (all p < 0.001). CRPC overall survival was independently associated with LDAH and PSA (p = 0.0168, p < 0.001). CONCLUSION: The studied meth-ctDNA markers are promising for the minimally-invasive detection and prognostication of CRPC but do not allow for clinical characterization of hsPC. Prospective studies are warranted for their use in therapy response and outcome prediction in CRPC and potential incremental value for PCa monitoring in PSA-low settings.

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Clinical Institute of Pathology Department for Experimental and Laboratory Animal Pathology Medical University of Vienna Vienna Austria

Comprehensive Cancer Center Medical University Vienna Vienna Austria

Department of Molecular Biology Umeå University Umeå Sweden

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology and Andrology University Hospital Krems Krems Austria

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Nuclear Medicine Department of Biomedical Imaging and Image Guided Therapy Medical University of Vienna Vienna Austria

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Karl Landsteiner University of Health Sciences Krems Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

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