title: Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracyclin based therapy: influenced by the HER2- and Topoisomerase IIalpha-status of the primary tumor?
abstract: OBJECTIVE
  The presence of isolated tumor cells in the bone marrow (ITC-BM) is an independent prognostic factor in all stages of breast cancer. Both the expression/amplification of human epithelial growth factor receptor 2 (HER2) and Topoisomerase IIalpha (TOP IIa), a key enzyme of DNA replication and main target of anthracyclins, in breast cancer tissue seem to have predictive value regarding the effectiveness of systemic therapies.
  
  
  METHODS
  To investigate the correlation between these factors and their influence on clinical outcome, tumor tissue of 54 patients who were screened for ITC-BM before and after anthracyclin-based chemotherapy (abCTX) was examined for HER2 and TOP IIa by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).
  
  
  RESULTS
  By IHC, 31% of the tumors showed positive for HER2 (2+/3+), 14.6% were amplified in FISH. TOP IIa expression (>50%) was found in 13/53 patients (25%), FISH was positive in 5/47 cases (11%). TOP IIa amplification was not seen in cases without HER2 amplification, five of the seven HER2 amplified cases also were amplified for TOP IIa (71% co-amplification). Forty-three patients had adjuvant, seven neo-adjuvant, four palliative abCTX. ITC-BM were present in 24% of patients before and 31% after CTX. Patients with HER2 (IHC, P = 0.29) and TOP IIa (FISH, P = 0.16) positive tumors tended to stay or become negative in BM status after abCTX and vice versa. After a median follow-up of 44 months (6-127), none of the factors reached significance for overall survival. Yet, patients with HER2 (P = 0.16) and TOP IIa (P = 0.09) positive tumors showed a trend towards prolonged disease-free survival. Remarkably, none of the TOP IIa FISH-positive patients developed distant metastases (P = 0.099) or died (P = 0.19) after CTX so far.
  
  
  CONCLUSIONS
  HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.
authors.affiliation: I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universität, Maistrasse 11, 80337 Munich, Germany. Christian.Schindlbeck@med.uni-muenchen.de
authors.forename: C
authors.initials: C
authors.lastname: Schindlbeck
authors.forename: W
authors.initials: W
authors.lastname: Janni
authors.forename: N
authors.initials: N
authors.lastname: Shabani
authors.forename: A
authors.initials: A
authors.lastname: Kornmeier
authors.forename: B
authors.initials: B
authors.lastname: Rack
authors.forename: D
authors.initials: D
authors.lastname: Rjosk
authors.forename: B
authors.initials: B
authors.lastname: Gerber
authors.forename: S
authors.initials: S
authors.lastname: Braun
authors.forename: H
authors.initials: H
authors.lastname: Sommer
authors.forename: K
authors.initials: K
authors.lastname: Friese
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001853:Bone Marrow / Q000473:pathology*; D019046:Bone Marrow Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012307:Risk Factors
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases