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Title: | Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer. | Authors: | Horvath L.G.;Yu J.;Huang Y.;Jia S.;Kohli M.;Azad A.A.;Fettke H.;Kwan E.M.;Docanto M.M.;Bukczynska P.;Ng N.;Graham L.-J.K.;Mahon K.;Hauser C.;Tan W.;Wang X.H.;Zhao Z.;Zheng T.;Zhou K.;Du P. | Monash Health Department(s): | Oncology | Institution: | (Fettke, Kwan, Docanto, Azad) Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia (Kwan) Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia (Bukczynska, Ng, Hauser) Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia (Ng) Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia (Graham, Mahon, Horvath) Medical Oncology, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia (Mahon, Horvath) University of Sydney, Sydney, New South Wales, Australia (Mahon, Horvath) Garvan Institute of Medical Research, Sydney, New South Wales, Australia (Tan) Department of Oncology, Mayo Clinic, Jacksonville, FL, United States (Wang, Zhao, Zheng, Zhou, Du, Yu, Jia) Predicine Inc., Hayward, CA, United States (Huang) Huidu Medical Sciences, Shanghai, China (Kohli) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Centre and Research Institute, Tampa, FL, United States (Horvath) Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (Azad) Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia (Azad) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia | Issue Date: | 9-Aug-2020 | Copyright year: | 2020 | Publisher: | Elsevier B.V. | Place of publication: | Netherlands | Publication information: | European Urology. 78 (2) (pp 173-180), 2020. Date of Publication: August 2020. | Journal: | European Urology | Abstract: | Background: The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy. Objective(s): To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes. Design, setting, and participants: We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube. Outcome measurements and statistical analysis: Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations. Results and limitations: Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs >=2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs >=2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period. Conclusion(s): We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC. Patient Summary: In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer. We demonstrated, in two independent metastatic castration-resistant prostate cancer (mCRPC) cohorts, that simultaneous profiling of androgen receptor (AR) cell-free DNA and RNA aberrations provides important prognostic information in patients with mCRPC. Profiling of circulating AR aberrations may be of high clinical value, especially with increasing use of AR-targeted therapies earlier in the prostate cancer disease course.Copyright © 2020 European Association of Urology | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1016/j.eururo.2020.03.044 | PubMed URL: | 32487321 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32487321] | ISSN: | 0302-2838 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/29172 | Type: | Article | Subjects: | cancer radiotherapy *castration resistant prostate cancer/di [Diagnosis] *castration resistant prostate cancer/dt [Drug Therapy] *castration resistant prostate cancer/rt [Radiotherapy] *clinical outcome cohort analysis copy number variation *DNA fingerprinting follow up gene expression hazard ratio high throughput sequencing human Kaplan Meier method *liquid biopsy male middle aged overall survival priority journal progression free survival proportional hazards model prospective study *RNA fingerprinting somatic mutation validation study very elderly abiraterone/dt [Drug Therapy] abiraterone/pv [Special Situation for Pharmacovigilance] *androgen receptor/ec [Endogenous Compound] androgen receptor antagonist/dt [Drug Therapy] androgen receptor antagonist/pv [Special Situation for Pharmacovigilance] cabazitaxel/dt [Drug Therapy] cabazitaxel/pv [Special Situation for Pharmacovigilance] *cell free nucleic acid/ec [Endogenous Compound] docetaxel/dt [Drug Therapy] docetaxel/pv [Special Situation for Pharmacovigilance] enzalutamide/dt [Drug Therapy] enzalutamide/pv [Special Situation for Pharmacovigilance] prostate specific antigen/ec [Endogenous Compound] taxane derivative/dt [Drug Therapy] taxane derivative/pv [Special Situation for Pharmacovigilance] major clinical study adult aged article cancer radiotherapy castration resistant prostate cancer copy number variation DNA fingerprinting gene expression hazard ratio high throughput sequencing Kaplan Meier method liquid biopsy progression free survival proportional hazards RNA fingerprinting somatic mutation validation study very elderly abiraterone androgen receptor androgen receptor antagonist cabazitaxel cell free nucleic acid docetaxel enzalutamide prostate specific antigen taxane derivative aged gene expression hazard ratio high throughput sequencing human Kaplan Meier method *liquid biopsy major clinical study male middle aged overall survival priority journal progression free survival proportional hazards model prospective study *RNA fingerprinting somatic mutation validation study adult very elderly aged Article cancer radiotherapy *castration resistant prostate cancer / *diagnosis / *drug therapy / *radiotherapy *clinical outcome cohort analysis copy number variation *DNA fingerprinting follow up |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional or survey) |
Appears in Collections: | Articles |
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