title: Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer.
abstract: OBJECTIVE
  The use of circulating tumor cells (CTC) as a prognostic marker in metastatic breast cancer (MBC) has been well established. However, their efficacy and accuracy are still under scrutiny mainly because of methods of their enrichment and identification. We hypothesized that circulating miRNAs can predict the CTC status of patients with MBC, and tested for the same. Furthermore, we aimed at establishing a panel of circulating miRNAs capable of differentiating MBC cases from healthy controls.
  
  
  METHODS
  Circulating miRNAs from plasma of CTC-positive and CTC-negative patients with MBC, and healthy controls, were profiled by TaqMan Human MicroRNA arrays. Candidates from the initial screen were validated in an extended cohort of 269 individuals (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls).
  
  
  RESULTS
  CTC-positive had significantly higher levels of miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 than CTC-negative MBC and controls (P < 0.00001), whereas miR-768-3p was present in lower amounts in MBC cases (P < 0.05). miR-200b was singled out as the best marker for distinguishing CTC-positive from CTC-negative patients (AUC 0.88). We identified combinations of miRNAs for differentiating MBC cases from controls (AUC 0.95 for CTC-positive; AUC 0.78 for CTC-negative). Combinations of miRNAs and miR-200b alone were found to be promising prognostic marker for progression-free and overall survival.
  
  
  CONCLUSIONS
  This is the first study to document the capacity of circulating miRNAs to indicate CTC status and their potential as prognostic markers in patients with MBC.
authors.affiliation: Molecular Epidemiology, Division of Biostatistics, German Cancer Research Center, DKFZ, Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, National Center for Tumor Diseases, University of Heidelberg, Hamburg, Germany. d.madhavan@dkfz.de
authors.forename: Dharanija
authors.initials: D
authors.lastname: Madhavan
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Markus
authors.initials: M
authors.lastname: Wallwiener
authors.forename: Katarina
authors.initials: K
authors.lastname: Cuk
authors.forename: Caroline
authors.initials: C
authors.lastname: Modugno
authors.forename: Martina
authors.initials: M
authors.lastname: Scharpff
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Jörg
authors.initials: J
authors.lastname: Heil
authors.forename: Andrey
authors.initials: A
authors.lastname: Turchinovich
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002452:Cell Count; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011379:Prognosis; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs