title: Clodronate treatment influences MMP-2 associated outcome in node positive breast cancer.
abstract: OBJECTIVE
  Serum postoperative matrix metalloproteinase 2 (MMP-2) level is a predictor of outcome in node positive breast cancer and can be used to stratify patients into low and high risk groups. Our aim was to determine how clodronate treatment influences MMP-2 associated clinical outcome.
  
  
  METHODS
  Women with primary node-positive breast cancer were randomized to control group or to receive oral clodronate for 3 years. Adjuvant chemo- or endocrine therapy was given to all patients. The follow-up time for all patients was 5 years. MMP-2 and MMP-9 levels were quantitatively measured from the serum of 252 patients before and after 1 year clodronate treatment using enzyme-linked immunoassays.
  
  
  RESULTS
  In clodronate-treated patients, postoperative MMP-2 levels did not predict 5-year disease-free survival or overall survival (DFS, in low MMP-2 group (<5.32 ng/ml, median) 53% versus in high MMP-2 group (>median) 63%, p=NS; OS, 68% versus 63%, p=NS). When the patients were grouped according to serum MMP-2 levels, survival rates among patients with low MMP-levels were better in control than clodronate treated patients (DFS, 82% versus 53%, p = 0.003; OS, 91% versus 68%, p=0.014). Among patients with high serum MMP-2 levels, no significant difference in DFS or OS was found between control and clodronate groups. In multivariate analysis of low risk patients, independent predictors for DFS were treatment, age, nodal and PgR status, and those for OS treatment together with nodal and ER status. During 12 months follow-up, MMP-2 levels increased significantly more in clodonate receiving patients than in controls (p = 0.002). In comparison, when the patients were grouped according to MMP-9 levels, clodronate also impaired DFS among patients with low MMP-9 levels (82% versus 53%, p = 0.02), but no influence on OS was observed (83% versus 70%, p = 0.09).
  
  
  CONCLUSIONS
  Clodronate interferes with the prognostic value of serum MMP-2. Clodronate has a negative impact on outcome among patients with low serum MMP-2 and MMP-9 levels, while no such influence is observed among patients with high MMP-2 and MMP-9 levels.
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN-00029, Helsinki, Finland. sirpa.leppa@hus.fi
authors.forename: S
authors.initials: S
authors.lastname: Leppä
authors.forename: T
authors.initials: T
authors.lastname: Saarto
authors.forename: L
authors.initials: L
authors.lastname: Vehmanen
authors.forename: C
authors.initials: C
authors.lastname: Blomqvist
authors.forename: I
authors.initials: I
authors.lastname: Elomaa
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000097:blood* / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000187:drug effects; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate
chemical_list: D000963:Antimetabolites; D014408:Biomarkers, Tumor; D004002:Clodronic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9