<strong>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)</strong>
Predictive markers are needed to guide planning of adjuvant therapy for patients with breast cancer. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer patients (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-containing 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 by use of 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 below for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the group treated with CMF, 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 appear to benefit more from the adjuvant therapy than TIMP-1 high patients although these results did not reach significance in the present analyses. CMF-treated (HR, 95% CI) Anthracycline-treated (HR, 95% CI TIMP-1 low 0,47 (0,31-0,72) 0,65 (0,39-1,07) TIMP-1 high 0,58 (0,39-0,87) 0,90 (0,56-1,44) Conclusion: This study suggests that high tumor tissue TIMP-1 concentrations 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. The anthracycline-treated 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 from the therapy than TIMP-1 low patients.