title: Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer.
abstract: BACKGROUND
  Tissue inhibitors of metalloproteinase (TIMPs) have at least 2 different functions. They inhibit the catalytic activity of matrix metalloproteinases, and they act as growth factors.
  
  
  METHODS
  Pretreatment ethylenediamine tetracetic acid plasma TIMP-1 was assayed from 251 patients who were enrolled in a Phase III, second-line, hormone therapy trial, and from a control group of 50 healthy, postmenopausal women by using the TIMP-1 enzyme-linked immunosorbent assay.
  
  
  RESULTS
  The plasma TIMP-1 levels from the postmenopausal control group (n = 50 women) were 201 +/- 86 ng/mL mean +/- standard deviation (range, 49-455 ng/mL). The upper limit of normal was defined as the mean +/- 2 standard deviations of the control group (373 ng/mL). Patient pretreatment plasma TIMP-1 levels ranged from 70 ng/mL to 982 ng/mL. Plasma TIMP-1 was elevated above the mean + 2 standard deviations of the control group (373 ng/mL) in 19 patients (7.6%). In univariate analysis, patients who had elevated versus normal plasma TIMP-1 levels had a reduced clinical benefit rate (CBR) (16% vs 42%; P = .03). The time to progression (TTP) (84 days vs 174 days; P < .0001) and overall survival (141 days vs 860 days; P = .0001) also were significantly shorter in patients who had elevated TIMP-1 levels. TTP and overall survival also were significantly shorter in patients who had higher TIMP-1 plasma levels when it was analyzed as a continuous variable. In multivariate analysis, elevated plasma TIMP-1 level remained a prognostic factor for reduced overall survival (P < .0001) along with elevated serum HER-2/neu (P < .0001) and the presence of visceral metastases (P = .008).
  
  
  CONCLUSIONS
  Elevated pretreatment plasma levels of TIMP-1 predicted a decreased response to second-line hormone therapy and reduced survival in women with metastatic breast cancer.
authors.affiliation: Department of Hematology-Oncology, Penn State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Suhail M
authors.initials: SM
authors.lastname: Ali
authors.forename: Kim
authors.initials: K
authors.lastname: Leitzel
authors.forename: Laurence
authors.initials: L
authors.lastname: Demers
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Peter
authors.initials: P
authors.lastname: Hamer
authors.forename: Sheryl
authors.initials: S
authors.lastname: Brown-Shimer
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.forename: Walter
authors.initials: W
authors.lastname: Carney
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D017316:Fadrozole / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019290:Megestrol Acetate / Q000627:therapeutic use; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood; D015996:Survival Rate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017316:Fadrozole; D019290:Megestrol Acetate; D018719:Erb-b2 Receptor Tyrosine Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1