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 ¼ 50 women) were 201 AE 86 ng/mL mean AE standard deviation (range, 49-455 ng/ mL). The upper limit of normal was defined as the mean AE 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 1 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 ¼ .03). The time to progression (TTP) (84 days vs 174 days; P < .0001) and overall survival (141 days vs 860 days; P ¼ .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 ¼ .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.

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

“…Tissue inhibitor of metalloproteinases-1 (TIMP-1) has proven to be a promising marker in breast cancer carrying both prognostic [7][8][9][10][11] and, as shown more recently, predictive information [12][13][14][15]. For example, our laboratory has previously demonstrated that high primary tumor tissue levels of TIMP-1 were significantly associated with a poor response to the most frequently used chemotherapeutic drugs in metastatic breast cancer [14].…”

Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

“…The natural-occurring endogenous inhibitor of MMP-9 is tissue inhibitor of metalloproteinase-1 (TIMP-1) (9). Similar to MMPs, the role of TIMPs in cancer is reported contradictory and both tumor-protective and tumor-enhancing properties have been reported (10)(11)(12)(13). In breast cancer patients, high tumor and serum levels of TIMP-1 have been associated with decreased response to chemotherapy and decreased survival, suggesting a detrimental effect of TIMP-1 (14)(15)(16).…”

Efeitos morfológicos, histológicos e moleculares dos moduladores seletivos dos receptores de estrogênios tamoxifeno e raloxifeno na prevenção primária de tumores mamários quimicamente induzidos em ratas

“…Níveis altos de MMP e Timp3 estão relacionados com casos de pior prognóstico e maior risco de metástase em câncer de mama (Jinga et al, 2006;Lipton et al, 2007;Vizoso et al, 2007). Obtivemos maior expressão de Timp3 no grupo tamoxifeno em relação ao DMBA (Tabela 8).…”

“…Obtivemos maior expressão de Timp3 no grupo tamoxifeno em relação ao DMBA (Tabela 8). Essa alta expressão de Timp poderia estar relacionada com diminuição da resposta ao tratamento anti-hormonal, comprovando nossos resultados (Lipton et al, 2007).…”

“…al., 2004a(Buck et. al., , 2004bRyden et al, 2005aRyden et al, , 2005bCreighton et al, 2006;Kuske et al, 2006;Nakamura et al, 2006;Lehnes et al, 2007;Lipton et al, 2007).…”