Elevated plasma TIMP-1 and survival in metastatic castration-resistant prostate cancer patients

Abstract

11077 Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in multiple cancers. Methods: EDTA plasma TIMP-1 was determined in 362 metastatic, castration-resistant prostate cancer (CRPC) patients using the TIMP-1 ELISA from Oncogene Science/Siemens Medical Solutions Diagnostics, Cambridge, MA. All patients with CRPC and available plasma were identified from a single institutional database and were studied in test (n=60) and validation (n=302) sets. Median follow-up from diagnosis was 5.8 and 6.6 years, respectively. Approximately 1/3 had received prior chemotherapy and 223 patients (62%) had died. Overall survival was analyzed using the Kaplan-Meier method and Cox modeling on plasma TIMP-1 tertiles. Results: Median plasma TIMP-1 levels were 335 and 183 ng/ml in the test and validation sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP-1 in both datasets (see table). In the validation set, multivariate analysis was performed with known prognostic factors in CRPC; TIMP-1, (high vs. low tertile, HR 2.4, p < 0.001), PSA (>20 vs ≤20 ng/ml), alkaline phosphatase (>102 vs. ≤ 102 U/L), ECOG PS (1+ vs 0) and Gleason score (≥8 vs <8) each remained significant covariates. Conclusions: Elevated plasma TIMP-1 levels predict decreased survival in metastatic CRPC patients, independent of known prognostic markers. Overall survival from the time of blood collection Test Set Validation Set Deaths/ Pts Median (mo) HR (95% CI),p vs. low Deaths/Pts Median (mo) HR (95% CI),p vs. low All patients 27/60 14 All patients 196/302 28 TIMP1 (ng/mL) TIMP1 (ng/mL) Low (<280) 7/20 22 1.0 Low (<159) 42/100 43 1.0 Medium 7/21 14 1.7 Medium 72/103 28 1.7 (1.2-2.5), (280-379) (0.6-4.8) (159-214) p=.007 High 13/19 6 4.5 (1.7-11.7), High 82/99 19 2.4 (1.7-3.5), (>380) p<.01 (>214) p<.001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oncogene Sciences/Siemens Siemens Oncogene Science/Siemens Oncogene Science/Siemens