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


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.


CONCLUSIONS
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.
Lipton
Allan
A
Penn State University, Hershey Medical Center, Hematology/Oncology, 500 University Dr, Hershey, PA 17033, USA. alipton@psu.edu
Leitzel
Kim
K
Chaudri-Ross
Hilary A
HA
Evans
Dean B
DB
Ali
Suhail M
SM
Demers
Laurence
L
Hamer
Peter
P
Brown-Shimer
Sheryl
S
Pierce
Karen
K
Gaur
Victor
V
Carney
Walter
W
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D017698:Postmenopause / Q000097:blood; D013629:Tamoxifen / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D014230:Triazoles / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D019715:Tissue Inhibitor of Metalloproteinase-1; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole