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Clinical Research 11: Breast Cancer

Abstract #3589

Elevated serum levels of TIMP-1 and HER-2/neu in metastatic breast cancer patients (MBC) may be valuable in guiding targeted therapies

Oncogene Science/Bayer HealthCare, Cambridge, MA, Penn State/Hershey Medical Center, Hershey, PA, Lebanon VA Medical Center, Lebanon, PA, Novartis Pharmaceuticals AG, Basel, Switzerland

The search for new biomarkers in various cancers is becoming a vital area of cancer research. The use of more than one marker may provide additional information compared to any single marker. The use of circulating sera markers allows the researcher to collect samples in a less invasive fashion and to monitor the progress of the patients disease. We measured the circulating levels of HER-2/neu and tissue inhibitor of metalloproteinase-1 (TIMP-1) in pretreatment samples from 600 post-menopausal metastatic breast cancer (MBC) patients. These patients were part of a trial examining the efficacy of first-line treatment comparing letrozole to tamoxifen. A panel of 50 serum samples from normal, healthy post-menopausal women was analyzed in order to establish a cutoff value for the TIMP-1 marker. Cutoff value, calculated as the mean + 2 standard deviations (SD) for the normal, healthy population, was determined to be 454 ng/mL for TIMP-1. For serum HER-2/neu, the well-established cutoff value of 15 ng/mL was used. These cutoff values were then used to determine the percentage of MBC patients that had elevated levels of TIMP-1 and serum HER-2/neu. This study found a sizeable percentage of patients whose pretreatment serum showed elevations of one or both of the circulating markers. Specifically, there were 26% of the patients who showed an elevation of TIMP-1 levels and 31% showed elevated serum HER-2/neu levels. More specifically, of the 187 samples that were elevated for serum HER-2/neu, 68 (36%) were elevated for TIMP-1. Of the 416 samples that showed normal levels of serum HER-2/neu, 85 (20%) were elevated for TIMP-1. Therefore, 11% of the total samples showed elevations of both HER-2/neu and TIMP-1. In a previous study (ECCO 2001), we presented data showing that in MBC patients treated with second-line hormone therapy, 34% had elevated uPA serum levels. This increase of uPA seen in pretreatment serum samples was statistically significant for TTP and OS. Markers such as uPA and TIMP-1 that are associated with tissue degradation during metastasis may be valuable for selecting patients for new classes of protease inhibitor therapies. In addition, the use of serum markers as diagnostic tests, which allow monitoring of the patient’s response may allow for a more efficacious use of targeted cancer therapies. Elevation of both uPA and the inhibitor TIMP-1 imply that proteolytic systems have become activated, which could contribute to an increased metastatic potential. Since estrogen receptor-positive (ER+) MBC patients derive greater benefit from letrozole than tamoxifen, and HER-2/neu positive patients benefit from the anti-HER-2/neu therapy trastuzumab, it may be valuable to select ER+ patients with elevated uPA and TIMP-1 levels to receive combination therapy with letrozole and anti-TIMP-1 and uPA-targeted therapy.