To develop a risk classifier using urine-derived extracellular vesicle RNA (UEV-RNA) capable of providing diagnostic information of disease status prior to biopsy, and prognostic information for men on active surveillance (AS).
Post-digital rectal examination UEV-RNA expression profiles from urine (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based Continuation-Ratio model was built to generate four Prostate-Urine-Risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico Low-risk (PUR-2), Intermediate-risk (PUR-3), and High-risk (PUR-4) PCa. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation.
Each PUR signature was significantly associated with its corresponding clinical category (p<0.001). PUR-4 status predicted the presence of clinically significant Intermediate or High-risk disease, AUC = 0.77 (95% CI: 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n=87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (p<0.001; IQR HR = 2.86, 95% CI:1.83-4.47). PUR-4, when utilised continuously, dichotomised patient groups with differential progression rates of 10% and 60% five years post-urine collection (p<0.001, HR = 8.23, 95% CI:3.26-20.81).
UEV-RNA can provide diagnostic information of aggressive PCa prior to biopsy, and prognostic information for men on AS. PUR represents a new & versatile biomarker that could result in substantial alterations to current treatment of PCa patients. This article is protected by copyright. All rights reserved.
BJU international. 2019 May 20 [Epub ahead of print]
Shea P Connell, Marcel Hanna, Frank McCarthy, Rachel Hurst, Martyn Webb, Helen Curley, Helen Walker, Rob Mills, Richard Y Ball, Martin G Sanda, Kathryn L Pellegrini, Dattatraya Patil, Antoinette S Perry, Jack Schalken, Hardev Pandha, Hayley Whitaker, Nening Dennis, Christine Stuttle, Ian G Mills, Ingrid Guldvik, Movember GAP1 Urine Biomarker Consortium , Chris Parker, Daniel S Brewer, Colin S Cooper, Jeremy Clark
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK., The Institute of Cancer Research, Sutton, Surrey, UK., Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, Norfolk, UK., Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., School of Biology and Environmental Science, Science West, University College Dublin, Dublin 4, Ireland., Nijmegen Medical Centre, Radboud University Medical Centre, Nijmegen, The Netherlands., Faculty of Health and Medical Sciences, The University of Surrey, Guildford, UK., Molecular Diagnostics and Therapeutics Group, University College London, Gower Street, London, UK., School of Medicine, Dentistry and Biomedical Sciences, Institute for Health Sciences, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK., Centre for Molecular Medicine, University of Oslo, Oslo, Norway., The Royal Marsden Hospital, Sutton, Surrey, UK.