title: Microsatellite instability predicts poor short-term survival in patients with advanced breast cancer after high-dose chemotherapy and autologous stem-cell transplantation.
abstract: OBJECTIVE
  The purpose is to define molecular prognostic factors in patients with advanced breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).
  
  
  METHODS
  Thirty-nine patients with breast cancer and extensive lymph node (level III) and/or systemic metastases from a prospective single-center study of sequential HDCT/ASCT were studied. Microsatellite analysis was performed after laser microdissection using 15 markers selected for sensitive detection of microsatellite instability (MSI) in breast cancer. Exons 5-9 of the P53 gene were directly sequenced. Expression of P53, HER-2/neu, and the mismatch repair proteins hMSH2 and hMLH1 was evaluated by immunohistochemistry.
  
  
  RESULTS
  MSI of at least three markers was detected in 13 of 39 patients (33%) and was predominantly found at tetranucleotide markers. All MSI-positive tumors showed normal expression of hMSH2 and hMLH1. Complete sequence analysis of exons 5-9 of the P53 gene was successful in 34 cases; 18% (n = 6) revealed a mutation. Overexpression of HER-2/neu and P53 was observed in 7 (22%) and 12 (46%) of 26 evaluated cases, respectively. The presence of MSI strongly correlated with shorter overall survival (OS; P = 0.0004) and progression-free survival (PFS; P = 0.02). None of the other investigated clinical or molecular factors correlated with OS in univariate analyses, with the exception of menopausal status and previous adjuvant chemotherapy. Testing various multivariate Cox regression models, MSI remained a highly significant, independent, and adverse risk factor for OS.
  
  
  CONCLUSIONS
  MSI is frequent in advanced breast cancer and could be an indicator of chemotherapy resistance and poor prognosis in breast cancer patients treated with HDCT/ASCT.
authors.affiliation: Departments of Pathology and Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Albrecht
authors.initials: A
authors.lastname: Reichle
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Georg
authors.initials: G
authors.lastname: Röckelein
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.forename: Hagen
authors.initials: H
authors.lastname: Blaszyk
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstädter
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005091:Exons; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008593:Menopause; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D033581:Stem Cell Transplantation; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases