Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease prog
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RESEARCH
Open Access
Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression Edmund Lau1,2†, Patrick McCoy1†, Fairleigh Reeves1†, Ken Chow1, Michael Clarkson1, Edmond M. Kwan3,4, Kate Packwood5, Helen Northen5, Miao He5, Zoya Kingsbury5, Stefano Mangiola6, Michael Kerger7, Marc A. Furrer8,9, Helen Crowe7, Anthony J. Costello7, David J. McBride5, Mark T. Ross5, Bernard Pope1,2,3,10, Christopher M. Hovens1 and Niall M. Corcoran1,7,8,11,12*
Abstract Background: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Methods: We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2–4.8, p = 0.014). Conclusions: CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
* Correspondence: [email protected] † Edmund Lau, Patrick McCoy and Fairleigh Reeves contributed equally to this work. 1 Department of Surgery, University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia 7 Australian Prostate Cancer Centre, North Melbourne, VIC 3195, Australia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and in
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