Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.
Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely deri...
Guardado en:
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Public Library of Science (PLoS)
2012
|
Materias: | |
Acceso en línea: | https://doaj.org/article/3dec2081d85c4d8ca5a5e0e4c2fc16a1 |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:3dec2081d85c4d8ca5a5e0e4c2fc16a1 |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:3dec2081d85c4d8ca5a5e0e4c2fc16a12021-11-18T08:09:51ZMulti-purpose utility of circulating plasma DNA testing in patients with advanced cancers.1932-620310.1371/journal.pone.0047020https://doaj.org/article/3dec2081d85c4d8ca5a5e0e4c2fc16a12012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23144797/?tool=EBIhttps://doaj.org/toc/1932-6203Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.Geraldine PerkinsTimothy A YapLorna PopeAmy M CassidyJuliet P DukesRuth RiisnaesChristophe MassardPhilippe A CassierSusana MirandaJeremy ClarkKatie A DenholmKhin ThwayDavid Gonzalez De CastroGerhardt AttardL Rhoda MolifeStan B KayeUdai BanerjiJohann S de BonoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e47020 (2012) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
Medicine R Science Q |
spellingShingle |
Medicine R Science Q Geraldine Perkins Timothy A Yap Lorna Pope Amy M Cassidy Juliet P Dukes Ruth Riisnaes Christophe Massard Philippe A Cassier Susana Miranda Jeremy Clark Katie A Denholm Khin Thway David Gonzalez De Castro Gerhardt Attard L Rhoda Molife Stan B Kaye Udai Banerji Johann S de Bono Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
description |
Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted. |
format |
article |
author |
Geraldine Perkins Timothy A Yap Lorna Pope Amy M Cassidy Juliet P Dukes Ruth Riisnaes Christophe Massard Philippe A Cassier Susana Miranda Jeremy Clark Katie A Denholm Khin Thway David Gonzalez De Castro Gerhardt Attard L Rhoda Molife Stan B Kaye Udai Banerji Johann S de Bono |
author_facet |
Geraldine Perkins Timothy A Yap Lorna Pope Amy M Cassidy Juliet P Dukes Ruth Riisnaes Christophe Massard Philippe A Cassier Susana Miranda Jeremy Clark Katie A Denholm Khin Thway David Gonzalez De Castro Gerhardt Attard L Rhoda Molife Stan B Kaye Udai Banerji Johann S de Bono |
author_sort |
Geraldine Perkins |
title |
Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
title_short |
Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
title_full |
Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
title_fullStr |
Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
title_full_unstemmed |
Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. |
title_sort |
multi-purpose utility of circulating plasma dna testing in patients with advanced cancers. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doaj.org/article/3dec2081d85c4d8ca5a5e0e4c2fc16a1 |
work_keys_str_mv |
AT geraldineperkins multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT timothyayap multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT lornapope multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT amymcassidy multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT julietpdukes multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT ruthriisnaes multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT christophemassard multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT philippeacassier multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT susanamiranda multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT jeremyclark multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT katieadenholm multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT khinthway multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT davidgonzalezdecastro multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT gerhardtattard multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT lrhodamolife multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT stanbkaye multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT udaibanerji multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers AT johannsdebono multipurposeutilityofcirculatingplasmadnatestinginpatientswithadvancedcancers |
_version_ |
1718422100761378816 |