title: Circulating tumor cells as prognostic markers in neuroendocrine tumors.
abstract: OBJECTIVE
  To determine the prognostic significance of circulating tumor cells (CTCs) in patients with neuroendocrine cancer.
  
  
  METHODS
  In this single-center prospective study, 176 patients with measurable metastatic neuroendocrine tumors (NETs) were recruited. CTCs were measured using a semiautomated technique based on immunomagnetic separation of epithelial cell adhesion molecule-expressing cells.
  
  
  RESULTS
  Overall, 49% patients had ≥ one CTC, 42% had ≥ two CTCs, and 30% had ≥ five CTCs in 7.5 mL blood. Presence of CTCs was associated with increased burden, increased tumor grade, and elevated serum chromogranin A (CgA). Using a 90-patient training set and 85-patient validation set, we defined a cutoff of < one or ≥ one as the optimal prognostic threshold with respect to progression-free survival (PFS). Applying this threshold, the presence of ≥ one CTC was associated with worse PFS and overall survival (OS; hazard ratios [HRs], 6.6 and 8.0, respectively; both P < .001). In multivariate analysis, CTCs remained significant when other prognostic markers, grade, tumor burden, and CgA were included. Within grades, presence of CTCs was able to define a poor prognostic subgroup. For grade 1, HRs were 5.0 for PFS (P = .017) and 7.2 for OS (P = .023); for grade 2, HRs were 3.5 for PFS (P = .018) and 5.2 for OS (P = .036).
  
  
  CONCLUSIONS
  CTCs are a promising prognostic marker for patients with NETs and should be assessed in the context of clinical trials with defined tumor subtypes and therapy.
authors.affiliation: University College London (UCL) Cancer Institute, London, United Kingdom.
authors.forename: Mohid S
authors.initials: MS
authors.lastname: Khan
authors.forename: Amy
authors.initials: A
authors.lastname: Kirkwood
authors.forename: Theodora
authors.initials: T
authors.lastname: Tsigani
authors.forename: Jorge
authors.initials: J
authors.lastname: Garcia-Hernandez
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Martyn E
authors.initials: ME
authors.lastname: Caplin
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002469:Cell Separation; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000097:blood* / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor