Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with few biomarkers to inform treatment selection or patient prognosis. Methylation profiles of plasma circulating tumour DNA (ctDNA) accurately reflect tumour methylomes and may reveal novel biomarkers of mCRPC.
To establish a novel mCRPC-associated methylation signature for detection of ctDNA, we performed plasma methylome profiling on 27 mCRPC patients and 10 controls (cohort 1). Signature-based ctDNA detection was evaluated across prostate cancer (PC) disease stages using an internal cohort of 93 PC patients and 8 controls (cohort 2), and an external cohort of 115 PC patients (cohort 3).
We established a 48-region methylation signature (cfMeCaP) capable of highly sensitive detection of ctDNA in mCRPC (100%, 84% and 95% in cohorts 1, 2 and 3, respectively). cfMeCaP methylation at mCRPC diagnosis was associated with poor progression-free survival (PFS) and overall survival in all three cohorts (p < 0.005), independent of routine clinical variables. Persistent serial detection of ctDNA using cfMeCaP was strongly associated with rapid mCRPC treatment failure (median PFS 4.4 vs. 65.5 months; p < 0.0001), while no detection predicted continued treatment response.
These results highlight cfMeCaP as a promising non-invasive biomarker for prognostication in mCRPC.
British journal of cancer. 2026 Apr 10 [Epub ahead of print]
Karoline Kondrup, Laura Iisager, Paul Vinu Salachan, Maibritt Nørgaard, Philippe Lamy, Rosalind Eeles, Torben Frøstrup Hansen, Palle Jörn Sloth Osther, Ahmed Hussein Zedan, Michael Borre, Karina Dalsgaard Sørensen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., The Institute of Cancer Research, London, UK., Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. .