Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients

William K. Oh, Roberto Vargas, Susanna Jacobus, Kim Leitzel, Meredith M. Regan, Peter Hamer, Karen Pierce, Sheryl Brown-Shimer, Walter Carney, Suhail M. Ali, Philip W. Kantoff, Allan Lipton

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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 â102 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.

Original languageEnglish (US)
Pages (from-to)517-525
Number of pages9
JournalCancer
Volume117
Issue number3
DOIs
StatePublished - Feb 1 2011

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Oh, W. K., Vargas, R., Jacobus, S., Leitzel, K., Regan, M. M., Hamer, P., Pierce, K., Brown-Shimer, S., Carney, W., Ali, S. M., Kantoff, P. W., & Lipton, A. (2011). Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients. Cancer, 117(3), 517-525. https://doi.org/10.1002/cncr.25394