title: High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients.
abstract: Exosomes arise from viable cancer cells and may reflect a different biology than circulating cell-free DNA (cfDNA) shed from dying tissues. We compare exosome-derived DNA (exoDNA) to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC).
  
  
  
  Patient samples were obtained between 2003 and 2010, with clinically annotated follow up to 2015. Droplet digital PCR was performed on exoDNA and cfDNA for sensitive detection of KRAS mutants at codons 12/13. A cumulative series of 263 individuals were studied, including a discovery cohort of 142 individuals: 68 PDAC patients of all stages; 20 PDAC patients initially staged with localized disease, with blood drawn after resection for curative intent; and 54 age-matched healthy controls. A validation cohort of 121 individuals (39 cancer patients and 82 healthy controls) was studied to validate KRAS detection rates in early-stage PDAC patients. Primary outcome was circulating KRAS status as detected by droplet digital PCR. Secondary outcomes were disease-free and overall survival.
  
  
  
  KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Higher exoKRAS MAFs were associated with decreased disease-free survival in patients with localized disease. In the validation cohort, mutant KRAS exoDNA was detected in 43.6% of early-stage PDAC patients and 20% of healthy controls.
  
  
  
  Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: K
authors.initials: K
authors.lastname: Allenson
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: J
authors.initials: J
authors.lastname: Castillo
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.|Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: F A
authors.initials: FA
authors.lastname: San Lucas
authors.affiliation: Genetic Epidemiology Group International Agency for Research on Cancer, Lyon, France.
authors.forename: G
authors.initials: G
authors.lastname: Scelo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: D U
authors.initials: DU
authors.lastname: Kim
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: G
authors.initials: G
authors.lastname: Davis
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kumar
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: M
authors.initials: M
authors.lastname: Katz
authors.affiliation: Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Foretova
authors.affiliation: Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia.
authors.forename: E
authors.initials: E
authors.lastname: Fabianova
authors.affiliation: Institute of Public Health and Preventive Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Holcatova
authors.affiliation: Department of Preventive Medicine, Palacky University of Medicine, Olomouc, Czech Republic.|Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Janout
authors.affiliation: Department of Investigational Cancer Therapeutics and the Institute for Personalized Cancer Therapy, Houston, USA.
authors.forename: F
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Section of Experimental Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA
authors.forename: P
authors.initials: P
authors.lastname: Gascoyne
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: I
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: G
authors.initials: G
authors.lastname: Varadhachary
authors.affiliation: Genetic Epidemiology Group International Agency for Research on Cancer, Lyon, France.
authors.forename: P
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hanash
authors.affiliation: Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.|Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: A
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.|Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: H
authors.initials: H
authors.lastname: Alvarez
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D018572:Disease-Free Survival; D055088:Early Detection of Cancer / Q000379:methods*; D055354:Exosomes / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; circulating tumor DNA; exosome; liquid biopsy; pancreatic cancer