title: Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer.
abstract: OBJECTIVE
  Circulating tumor cells (CTCs) may have utility as surrogate biomarkers and "virtual" biopsies. We report the clinical significance and molecular characteristics of CTCs and CTC clusters, termed circulating tumor microemboli (CTM), detected in patients with small-cell lung cancer (SCLC) undergoing standard treatment.
  
  
  METHODS
  Serial blood samples from 97 patients receiving chemotherapy were analyzed using EpCam-based immunomagnetic detection and a filtration-based technique. Proliferation status (Ki67) and apoptotic morphology were examined. Associations of CTC and CTM number with clinical factors and prognosis were determined.
  
  
  RESULTS
  CTCs were present in 85% of patients (77 of 97 patients) and were abundant (mean ± standard deviation = 1,589 ± 5,565). CTM and apoptotic CTCs were correlated with total CTC number and were detected in 32% and 57% of patients, respectively. Pretreatment CTCs, change in CTC number after one cycle of chemotherapy, CTM, and apoptotic CTCs were independent prognostic factors. Overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood and 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P = .002). Subpopulations of apoptotic and of proliferating solitary CTCs were detected, whereas neither were observed within cell clusters (CTM), implicating both protection from anoikis and relative resistance to cytotoxic drugs for cells within CTM.
  
  
  CONCLUSIONS
  Both baseline CTC number and change in CTC number after one cycle of chemotherapy are independent prognostic factors for SCLC. Molecular comparison of CTCs to cells in CTM may provide novel insights into SCLC biology.
authors.affiliation: Paterson Institute for Cancer Research, Wilmslow Rd, Manchester.
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Hou
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Krebs
authors.forename: Lee
authors.initials: L
authors.lastname: Lancashire
authors.forename: Robert
authors.initials: R
authors.lastname: Sloane
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.forename: Rajeeb K
authors.initials: RK
authors.lastname: Swain
authors.forename: Lynsey J C
authors.initials: LJ
authors.lastname: Priest
authors.forename: Alastair
authors.initials: A
authors.lastname: Greystoke
authors.forename: Cong
authors.initials: C
authors.lastname: Zhou
authors.forename: Karen
authors.initials: K
authors.lastname: Morris
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Blackhall
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D018572:Disease-Free Survival; D004617:Embolism / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2