Tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525).

Abstract

Abstract Abstract #6054 Predictive markers are needed to guide planning of adjuvant therapy for breast cancer patients. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer (Schrohl et al, Clin Cancer Res, 2006) suggesting that TIMP-1 may be a predictive marker in breast cancer patients.
 Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-based regimen.
 Patients and Methods: 525 pre-menopausal lymph node-positive patients were included; 324 patients received adjuvant CMF, 99 received an adjuvant anthracycline-containing regimen and 102 had no adjuvant chemotherapy. Total TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. Using the untreated patient group as a reference group we analyzed the benefit of adjuvant CMF and anthracyclines in TIMP-1 high and low patients, respectively. The median TIMP-1 concentration was used to dichotomize patients into high and low TIMP-1 groups. End points were disease-free and overall survival (DFS, OS).
 Results: The median TIMP-1 level in the total patient group was 12,54 ng/mg of total protein (range, 0 – 112,9 ng/mg). TIMP-1 levels in subgroups according to adjuvant therapy were not significantly different (P=0,20). In a multivariate model including basic clinico-pathological parameters, TIMP-1 low and high patients benefited differentially from adjuvant CMF and anthracyclines when compared to untreated patients. In particular, patients with high tumor levels of TIMP-1 had little benefit from adjuvant anthracyclines. Hazard ratios (HR) and 95% confidence intervals (CI) are given in the table for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the CMF-treated group, both TIMP-1 low and high patients had significantly better survival than untreated patients (P<0,01). Among anthracycline-treated patients those with TIMP-1 low tumors appeared to benefit more from the adjuvant therapy than TIMP-1 high patients although these results did not reach significance in the present analyses.
 
 Conclusion: This study suggests that high tumor tissue TIMP-1 levels are associated with decreased benefit from adjuvant chemotherapy. Especially in the group treated with anthracycline-based therapy there is a strong tendency for TIMP-1 high tumors to be less sensitive to the treatment. This group, however, is small and should be enlarged to confirm our results. In the group treated with CMF all patients benefit from the therapy with TIMP-1 high patients having slightly less benefit than TIMP-1 low patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6054.