title: Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.
abstract: 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.
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Perkins
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: Lorna
authors.initials: L
authors.lastname: Pope
authors.forename: Amy M
authors.initials: AM
authors.lastname: Cassidy
authors.forename: Juliet P
authors.initials: JP
authors.lastname: Dukes
authors.forename: Ruth
authors.initials: R
authors.lastname: Riisnaes
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
authors.forename: Susana
authors.initials: S
authors.lastname: Miranda
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Katie A
authors.initials: KA
authors.lastname: Denholm
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez De Castro
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000368:Aged; D004247:DNA / Q000097:blood* / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D055815:Young Adult
chemical_list: D004247:DNA