title: Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients - results from a large single-centre analysis.
abstract: BACKGROUND
  This is the largest single-centre study to determine the prognostic relevance of disseminated tumour cells (DTCs) from the bone marrow (BM) of stage I-III breast cancer patients. Additionally, we aimed to analyse the impact of DTC detection on adjuvant bisphosphonate (BP) treatment efficacy.
  
  
  METHODS
  BM aspirates were collected during primary surgery for early breast cancer (EBC; T1-4, N0-2, M0) at Tuebingen University, Germany, between January 2001 and January 2013. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B-B3) and cytomorphology. We retrospectively estimated the influence of DTC detection and BP treatment on disease-free survival (DFS) and overall survival (OS) using univariate (log-rank test) and multivariate (cox regression) analysis.
  
  
  RESULTS
  BM aspirates were available from 3141 patients. In 803 (26%) of these, DTCs were detectable. As compared to DTC-negative patients, DTC-positive patients more frequently had larger tumors (p<0.001), lymph node involvement (p<0.001), hormonal receptor positive tumours (p<0.001) and HER2-positive tumours (p=0.048). DTC-positive patients were at an increased risk of relapse (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.34-2.25, p<0.001) and death (HR 1.44 95% CI 1.13-1.86, p=0.004). In the multivariate analysis DTCs were an independent predictor of DSF and OS. Additionally, BP treatment had no significant influence on DFS or OS in DTC-negative patients, while it was significantly associated with increased DFS (p<0.001) and OS (p=0.006) in DTC-positive patients.
  
  
  CONCLUSIONS
  These data confirm the clinical validity of DTCs from the BM for prognostication of early breast cancer patients. Further studies are warranted to determine whether DTCs are predictive for adjuvant treatment efficacy using bisphosphonates.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany. Electronic address: andreas.hartkopf@med.uni-tuebingen.de.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Hartkopf
authors.affiliation: Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
authors.forename: Florin-Andrei
authors.initials: FA
authors.lastname: Taran
authors.affiliation: Department of Obstetrics and Gynaecology, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wallwiener
authors.affiliation: Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hahn
authors.affiliation: Department of Obstetrics and Gynaecology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Obstetrics and Gynaecology, Saarland University, Kirrberger Strasse 100, 66424 Homburg, Germany.
authors.forename: Erich-Franz
authors.initials: EF
authors.lastname: Solomayer
authors.affiliation: Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Brucker
authors.affiliation: Department of Obstetrics and Gynaecology, University of Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany.
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Fehm
authors.affiliation: Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
authors.forename: Diethelm
authors.initials: D
authors.lastname: Wallwiener
mesh_terms: D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D004164:Diphosphonates / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D007633:Keratins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: Bisphosphonates; Breast cancer; Disseminated tumour cells; Micrometastasis; Prognosis