Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer.
OBJECTIVE
Only about 50% of metastatic breast cancer patients benefit from cytotoxic chemotherapy. Today, no validated markers exist for prediction of chemotherapy sensitivity/resistance in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis, and the purpose of the present study was to test the hypothesis that tumors expressing high levels of TIMP-1 are protected against apoptosis-inducing agents and thus less sensitive to apoptosis-inducing chemotherapeutic drugs.


METHODS
We investigated the association between primary tumor expression levels of TIMP-1 protein and objective response to first-line chemotherapy in 173 patients with metastatic breast cancer.


RESULTS
When analyzed as a continuous log-transformed variable, increasing TIMP-1 levels were significantly associated with lack of response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy (P = 0.01; odds ratio, 2.0; 95% confidence interval, 1.1-3.3). In a multivariate model, including lymph node status, steroid hormone receptor status, menopausal status, dominant metastases site, type of chemotherapy, and disease-free interval, TIMP-1 was significantly associated with resistance to treatment (P = 0.03; odds ratio, 1.7; 95% confidence interval, 1.1-3.3).


CONCLUSIONS
In the present exploratory study, we showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to chemotherapy. By using TIMP-1, we identified a group of patients with metastatic breast cancer, which hardly respond to the most frequently used chemotherapy regimes (i.e., cyclophosphamide/methotrexate/5-fluorouracil and anthracyclines).
Schrohl
Anne-Sofie
AS
Department of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, Frederiksberg C, Denmark.
Meijer-van Gelder
Marion E
ME
Holten-Andersen
Mads N
MN
Christensen
Ib Jarle
IJ
Look
Maxime P
MP
Mouridsen
Henning T
HT
Brünner
Nils
N
Foekens
John A
JA
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000556:secondary*; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D016896:Treatment Outcome
D018943:Anthracyclines; D019715:Tissue Inhibitor of Metalloproteinase-1; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate