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

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 prospec- tively collected preoperative plasma and serum samples from 519 patients with primary breast cancer, and the measurements were related to patient outcome. The me- dian 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 meas- urements 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 dis- ease-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 mul- tivariate survival analysis of node-negative patients in- cluding all the classical prognostic parameters, plasma TIMP-1 remained significantly associated with prognosis when comparing Q1 with Q2 and Q4. Serum TIMP-1 re- mained significant when comparing Q1 with Q4. Taken together, this study is to our knowledge the first large prospective study suggesting that TIMP-1 carries inde- pendent prognostic information when measured in blood, especially plasma. This was especially true in the node- negative group of patients and in patients already defined as low risk patients using the currently available prognos- tic parameters. Molecular & Cellular Proteomics 7: 424-430, 2008. First line treatment of patients diagnosed with primary breast cancer is surgical removal of the tumor with or without adjuvant radiotherapy. Subsequently patients may be offered adjuvant systemic therapy depending on a prognostic evalu- ation. Today prognosis is estimated using both classical prog- nostic parameters (lymph node status, tumor size, grade of malignancy, and age) as well as HER2/neu gene expression (1). In addition, estrogen/progesterone receptor status is used by some as a predictive factor and by others as a prognostic and predictive factor. Axillary lymph node status is currently recognized as the best clinical discriminate between a good and poor prognosis. Based on these prognostic factors pa- tients are allocated to different risk groups, i.e. low risk, inter- mediate risk, or high risk group. Patients in the low risk group are offered minimal or no adjuvant therapy following removal of the primary tumor. In contrast, intermediate risk and high risk patients are recommended adjuvant systemic therapy. Unfortunately it is becoming increasingly clear that the cur- rently available prognostic parameters are relatively inade- quate to precisely define the prognosis of individual patients (2). In this regard, a substantial proportion of breast cancer patients allocated to the intermediate risk or high risk group are given adjuvant therapy although they are not in need of this treatment. These patients are therefore overtreated. Also some patients who are allocated to the low risk group and therefore do not receive adjuvant therapy do nevertheless experience recurrence of the disease, and these patients are therefore undertreated. Thus, additional prognostic markers, which can be used either alone or in combination with the traditional markers, need to be identified to ensure a more precise stratification and thereby a more effective manage- ment of breast cancer patients.