Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer

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.