title: Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients.
abstract: BACKGROUND
  Tissue inhibitor of metalloproteinase-1 (TIMP-1) has paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of matrix metalloproteinases and apoptosis as well as promotion of angiogenesis and tumor growth. Elevated TIMP-1 levels have been associated with a poorer prognosis in multiple cancers.
  
  
  METHODS
  Ethylenediaminetetraacetic acid plasma TIMP-1 was determined in 362 castration-resistant prostate cancer (PC) patients using a TIMP-1 enzyme-linked immunosorbent assay. All patients with castration-resistant PC and available plasma were identified from an institutional database. Overall survival was analyzed using the Kaplan-Meier method and Cox modeling on plasma TIMP-1 tertiles.
  
  
  RESULTS
  Patients were evaluated in pilot (n = 60) and primary (n = 302) sets. Median follow-up from diagnosis was 5.8 and 6.6 years, respectively. Median plasma TIMP-1 levels were 335 and 183 ng/mL in the pilot and primary sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP-1 in both datasets (P<.001). For the primary cohort, hazard ratio of (HR) death and median survival by plasma TIMP-1 tertile levels were: low, HR 1.0, 43 months; middle, HR 1.7, 27 months; high, HR 2.4, 19 months. In the primary set, significant covariates in the adjusted Cox regression model were: TIMP-1 level (mid or high vs low tertile), prostate-specific antigen (>20 vs ≤20 ng/mL), alkaline phosphatase (>102 vs ≤102 U/L), Eastern Cooperative Oncology Group performance status (1 + vs 0), and Gleason score (7 or 8 vs ≤6).
  
  
  CONCLUSIONS
  Elevated plasma TIMP-1 levels predicted decreased survival in metastatic castration-resistant PC patients, independent of known prognostic markers.
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. william.oh@mssm.edu
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Roberto
authors.initials: R
authors.lastname: Vargas
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobus
authors.forename: Kim
authors.initials: K
authors.lastname: Leitzel
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Peter
authors.initials: P
authors.lastname: Hamer
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.forename: Sheryl
authors.initials: S
authors.lastname: Brown-Shimer
authors.forename: Walter
authors.initials: W
authors.lastname: Carney
authors.forename: Suhail M
authors.initials: SM
authors.lastname: Ali
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
mesh_terms: D000368:Aged; D002369:Castration; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1