Plasma and Serum Levels of Tissue Inhibitor of Metalloproteinases-1 Are Associated with Prognosis in Node-negative Breast Cancer

Abstract

The tumor level of TIMP-1 has been suggested as a new prognostic marker in breast cancer. The purpose of this study was to investigate whether TIMP-1 also carries prognostic information when measured in blood as this is a much more preferable material compared with tumor extracts. Using ELISA, TIMP-1 was measured in prospectively collected preoperative plasma and serum samples from 519 patients with primary breast cancer, and the measurements were related to patient outcome. The median age of the patients was 58 years (range, 38 -80 years), and the median follow-up time was 1043 days (range, 300 -1630 days). Plasma and serum TIMP-1 measurements correlated significantly with each other with a Pearson correlation coefficient of 0.75 (p < 0.0001). For univariate survival analysis, patients were divided into quartiles according to increasing TIMP-1 levels (Q1-Q4). Analysis of all patients showed that high TIMP-1 plasma levels were significantly associated with a shorter disease-free survival. Subgroup analysis showed that plasma TIMP-1 significantly predicted the prognosis of node-negative patients but not of node-positive patients. Importantly plasma TIMP-1 was able to further stratify low risk node-negative patients. High serum TIMP-1 levels were associated with a shorter disease-free survival; however, the association was not statistically significant. In contrast, serum TIMP-1 significantly predicted the prognosis of node-negative and low risk patients. In multivariate survival analysis of node-negative patients including all the classical prognostic parameters, plasma TIMP-1 remained significantly associated with prognosis when comparing Q1 with Q2 and Q4. Serum TIMP-1 remained significant when comparing Q1 with Q4. Taken together, this study is to our knowledge the first large prospective study suggesting that TIMP-1 carries independent prognostic information when measured in blood, especially plasma. This was especially true in the node-

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

“…As a final remark, it should be mentioned, as emphasized in the introduction, that a number of previous studies have demonstrated that tumor tissue levels of TIMP-1 as well as TIMP-1 measured in blood carry prognostic information in primary breast cancer [7][8][9][10][11]. It is important to be aware of the various limitations in prognostic studies where endpoints such as recurrencefree survival and overall survival are used.…”

“…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].…”

Biomarkers Predicting Outcome in Patients with Advanced Renal Cell Carcinoma: Results from Sorafenib Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial

“…High serum VEGF-165 (the predominant isoform of VEGF-A in circulation) levels have also been associated with tumor stage, tumor grade, and poor prognosis in RCC (30). Elevated levels of tumor and/or plasma TIMP-1 are associated with poor survival prognosis in a number of tumor types [colorectal (31,32), gastric (33), breast (34)(35)(36), ovarian (37), and lung (38) cancers]. In a number of these studies, plasma TIMP-1 was an independent prognostic factor upon multivariable analysis.…”

Survival Outcomes According to TIMP1 and EGFR Expression in Heavily Treated Patients with Advanced Non-small Cell Lung Cancer who Received Biweekly Irinotecan Plus Bevacizumab

“…Such effects are likely mediated by their direct binding to cell-surface receptors and subsequent signaling activation, including the mitogen-activated protein kinase and the cyclic adenosine 3',5'-monophosphate-protein kinase A (PKA) pathways (14,15). TIMP1 has been extensively studied in recent years as a promising prognostic marker in colorectal, endometrial and breast cancer (16)(17)(18)(19)(20)(21)(22). Recently, Spindler et al showed that TIMP1 has a potential role as a prognostic biomarker in patients with metastatic colorectal cancer treated with cetuximab and irinotecan.…”