title: Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment.
abstract: BACKGROUND
  Disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (BC) patients are a promising surrogate marker of micrometastatic spread and an independent predictor of poor prognosis for disease-free survival (DFS) and overall survival (OS). The present study aims to analyze DTCs as an independent prognostic factor for DFS/OS in tumor biology and bisphosphonate treatment.
  
  
  METHODS
  A total of 504 patients with operable primary BC and a median observation time of 72.3 months [lower quartile (LQ) 58.1; upper quartile (UQ) 82.8] have been included. DTCs were detected via immunohistochemistry as MUC-1 positive cells in the BM of 59.13 % (298 of 504) of the patients. The immunophenotyping of cancer cells was achieved immunohistochemically as well.
  
  
  RESULTS
  For luminal A/B carcinoma patients, we observed a significant benefit of BM DTC negativity with respect to DFS (luminal A, P = 0.0498; luminal B, P = 0.0224). In triple-negative patients, DTC-negative BM was associated with a longer OS (P = 0.0326). In a multivariate Cox survival analysis relating to DFS and OS, the DTC status was identified as an independent prognostic factor for DFS in luminal A/B BC (P = 0.0071). A multivariate Cox survival analysis among DTC-positive patients with luminal immunophenotype showed bisphosphonate application (P = 0.0326) to be an independent prognostic factor for DFS.
  
  
  CONCLUSIONS
  The findings of our multivariate analyses reveal BM DTC positivity as an independent risk factor for DFS particularly in luminal A/B BC patients. This might be a novel criterion for the identification of candidates most likely to benefit from additional adjuvant therapy possibly including bisphosphonates.
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stefanovic
authors.affiliation: CGG-Clinic Mannheim, Mannheim, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Diel
authors.affiliation: Department of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sinn
authors.affiliation: Institute of Medical Biometry and Informatics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Englert
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Hennigs
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Mayer
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wallwiener
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Blumenstein
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Golatta
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heil
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rom
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schuetz
authors.affiliation: Breast Unit, Department of Gynecology and Obstetrics, Heidelberg University Hospital, Heidelberg, Germany. christoph.domschke@med.uni-heidelberg.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Domschke
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004164:Diphosphonates; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human