Originally published as JCO Early Release 10.1200/JCO.2007.15.4336 on April 28 2008

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lipton, A. Articles by Carney, W. Search for Related Content PubMed PubMed Citation Articles by Lipton, A. Articles by Carney, W. Social Bookmarking                            What's this?

Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer

Allan Lipton, Kim Leitzel, Hilary A. Chaudri-Ross, Dean B. Evans, Suhail M. Ali, Laurence Demers, Peter Hamer, Sheryl Brown-Shimer, Karen Pierce, Victor Gaur, Walter Carney

From the Penn State University, Hershey Medical Center, Hershey; Lebanon VAMC, Lebanon, PA; Oncogene Science Biomarker Group/Siemens Medical Solutions Diagnostics, Cambridge, MA; Oncology Business Unit, Novartis Pharma AG; and Oncology Research, Novartis Institutes for BioMedical Research Basel, Basel, Switzerland

Corresponding author: Allen Lipton, MD, Penn State University, Hershey Medical Center, Hematology/Oncology, 500 University Dr, Hershey, PA, United States, 17033; e-mail: alipton{at}psu.edu

Purpose To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen.

Patients and Methods Five hundred twenty-two patients estrogen receptor–positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay.

Results Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone.

Conclusion Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.

published online ahead of print at www.jco.org on April 28, 2008

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?