Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer.
BACKGROUND
Tissue inhibitors of metalloproteinase (TIMPs) have at least 2 different functions. They inhibit the catalytic activity of matrix metalloproteinases, and they act as growth factors.


METHODS
Pretreatment ethylenediamine tetracetic acid plasma TIMP-1 was assayed from 251 patients who were enrolled in a Phase III, second-line, hormone therapy trial, and from a control group of 50 healthy, postmenopausal women by using the TIMP-1 enzyme-linked immunosorbent assay.


RESULTS
The plasma TIMP-1 levels from the postmenopausal control group (n = 50 women) were 201 +/- 86 ng/mL mean +/- standard deviation (range, 49-455 ng/mL). The upper limit of normal was defined as the mean +/- 2 standard deviations of the control group (373 ng/mL). Patient pretreatment plasma TIMP-1 levels ranged from 70 ng/mL to 982 ng/mL. Plasma TIMP-1 was elevated above the mean + 2 standard deviations of the control group (373 ng/mL) in 19 patients (7.6%). In univariate analysis, patients who had elevated versus normal plasma TIMP-1 levels had a reduced clinical benefit rate (CBR) (16% vs 42%; P = .03). The time to progression (TTP) (84 days vs 174 days; P < .0001) and overall survival (141 days vs 860 days; P = .0001) also were significantly shorter in patients who had elevated TIMP-1 levels. TTP and overall survival also were significantly shorter in patients who had higher TIMP-1 plasma levels when it was analyzed as a continuous variable. In multivariate analysis, elevated plasma TIMP-1 level remained a prognostic factor for reduced overall survival (P < .0001) along with elevated serum HER-2/neu (P < .0001) and the presence of visceral metastases (P = .008).


CONCLUSIONS
Elevated pretreatment plasma levels of TIMP-1 predicted a decreased response to second-line hormone therapy and reduced survival in women with metastatic breast cancer.
Lipton
Allan
A
Department of Hematology-Oncology, Penn State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
Ali
Suhail M
SM
Leitzel
Kim
K
Demers
Laurence
L
Evans
Dean B
DB
Hamer
Peter
P
Brown-Shimer
Sheryl
S
Pierce
Karen
K
Carney
Walter
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D017316:Fadrozole / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019290:Megestrol Acetate / Q000627:therapeutic use; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood; D015996:Survival Rate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017316:Fadrozole; D019290:Megestrol Acetate; D018719:Erb-b2 Receptor Tyrosine Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1