title: Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma.
abstract: BACKGROUND
  Using cytokeratin (CK) as a histogenetic marker of epithelial tumor cells in the bone marrow of patients with primary breast carcinoma, a subgroup of patients with decreased survival can be identified. This study was designed to evaluate the frequency and prognostic relevance of such cells in patients with recurrent breast carcinoma.
  
  
  METHODS
  Bone marrow aspirates from 65 patients were analyzed immunocytochemically for the presence of CK positive cells. A quantitative immunoassay with monoclonal anti-CK antibody A45-B/B3 was used and 2 x 10(6) bone marrow cells per patient were evaluated. For prognostic evaluation the authors calculated a cutoff value of micrometastatic tumor cells by analogy to classification and regression tree (CART) analysis. Patients were monitored prospectively for a median of 37 months (range, 11-63 months).
  
  
  RESULTS
  Bone marrow micrometastases were present in 5 of 32 patients (16%) with locoregional recurrence and in 24 of 33 patients (73%) with distant recurrence. The bone marrow status yielded no prognostic indication for patients with locoregional recurrence. In contrast, a cutoff value of 2.5 tumor cells per 1 million bone marrow cells analyzed (2.5 x 10(-6) tumor cells) correlated with a significantly different prognosis for women with distant disease. Patients with metastatic disease and a micrometastatic tumor load of > 2.5 x 10(-6) tumor cells survived for a mean of 6 months (95% confidence interval [95% CI], 2.0-9.1) compared with 17 months (95% CI, 11.6-22.0) for patients with < or = 2.5 x 10(-6) tumor cells (P < 0.0001). Multivariate analysis, allowing for hormone receptor status, disease free interval prior to recurrence, manifestation site of metastases, age, and micrometastases in bone marrow, revealed that bone marrow involvement was an independent risk factor, with a hazard ratio of 7.4 (95% CI, 1.6-13.3) for disease-related death.
  
  
  CONCLUSIONS
  An increased number of micrometastases identified in the bone marrow of patients with metastatic breast carcinoma represents an independent prognostic factor that may influence future therapeutic strategies for patients with metastatic breast carcinoma.
authors.affiliation: I. Frauenklinik, Klinikum Innenstadt, Ludwig-Maximilians-Universtiitaet, Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Janni
authors.forename: S
authors.initials: S
authors.lastname: Gastroph
authors.forename: F
authors.initials: F
authors.lastname: Hepp
authors.forename: C
authors.initials: C
authors.lastname: Kentenich
authors.forename: D
authors.initials: D
authors.lastname: Rjosk
authors.forename: C
authors.initials: C
authors.lastname: Schindlbeck
authors.forename: T
authors.initials: T
authors.lastname: Dimpfl
authors.forename: H
authors.initials: H
authors.lastname: Sommer
authors.forename: S
authors.initials: S
authors.lastname: Braun
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000032:analysis; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology*; D009364:Neoplasm Recurrence, Local; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D007633:Keratins