Elevated plasma tissue inhibitor of metalloproteinase‐1 level predicts decreased response and survival in metastatic breast cancer

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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. Cancer 2007. © 2007 American Cancer Society.