title: The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients.
abstract: BACKGROUND
  The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods.
  
  
  METHODS
  We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow-up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously-developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies.
  
  
  RESULTS
  CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P < 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P < 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low-risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes.
  
  
  CONCLUSIONS
  These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Molloy
authors.forename: Astrid J
authors.initials: AJ
authors.lastname: Bosma
authors.forename: Lars O
authors.initials: LO
authors.lastname: Baumbusch
authors.forename: Marit
authors.initials: M
authors.lastname: Synnestvedt
authors.forename: Elin
authors.initials: E
authors.lastname: Borgen
authors.forename: Hege Giercksky
authors.initials: HG
authors.lastname: Russnes
authors.forename: Ellen
authors.initials: E
authors.lastname: Schlichting
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van't Veer
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells; D001943:Breast Neoplasms / Q000175:diagnosis / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis