Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients: A retrospective study

Abstract

Background: We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival.

Methods: From our original retrospectively collected tumor samples we selected a group of 525 pre-menopausal lymph node-positive patients (adjuvant treatment: CMF, 324 patients; anthracycline-based, 99 patients; no adjuvant chemotherapy, 102 patients). TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. TIMP-1 was analyzed as a continuous variable and as a dichotomized one using the median TIMP-1 concentration as a cut point between high and low TIMP-1 groups. We analyzed the benefit of adjuvant CMF and anthracyclines in univariate and multivariable survival models; endpoints were disease-free (DFS) and overall survival (OS).

Results: In this selected cohort of high-risk patients, and in the subgroup of patients receiving no adjuvant therapy, TIMP-1 was not associated with prognosis. In the subgroup of patients treated with anthracyclines, when analyzed as a continuous variable we observed a tendency for increasing TIMP-1 levels to be associated with shorter DFS (multivariable analysis, HR 1.75, 95% CI 1.00-3.07, P = 0.05) and a significant association between increasing TIMP-1 and shorter OS in both univariate (HR 3.52, 95% CI 1.54-8.06, P = 0.003) and multivariable analyses (HR 4.19, 95% CI 1.67-10.51, P = 0.002). No statistically significant association between TIMP-1 and DFS was observed in the CMF-treated patients although high TIMP-1 was associated with shorter OS when analyzed as a dichotomized variable (HR 1.64, 95% CI 1.02-2.65, P = 0.04).

Conclusion: In the subgroup of patients receiving adjuvant chemotherapy we found an association between shorter survival after treatment in TIMP-1 high patients compared with TIMP-1 low patients, especially in patients receiving anthracycline-based therapy. This suggests that high tumor tissue levels of TIMP-1 might be associated with reduced benefit from classical adjuvant chemotherapy. Our findings should be validated in larger prospective studies.

Figure 1

Kaplan-Meier plot showing the DFS (A) and OS (B) of untreated TIMP-1 low and high patients. The median TIMP-1 concentration of the total patient group (12.5 ng/mg of total protein) was used as cut point (TIMP-1 low patients N = 57, TIMP-1 high patients N = 45). Cox univariate regression analysis; DFS: HR 0.93, 95% CI 0.58-1.49, P = 0.76; OS: HR 0.72, 95% CI 0.39-1.33, P = 0.30.

Figure 2

Kaplan-Meier plot showing the DFS (A) and OS (B) of TIMP-1 low and high anthracycline-treated patients. The median TIMP-1 concentration of the total patient group (12.5 ng/mg of total protein) was used as cut point (TIMP-1 low patients N = 46, TIMP-1 high patients N = 53). Cox univariate regression analysis; DFS: HR 1.52, 95% CI 0.88-2.63, P = 0.13; OS: HR 2.53, 95% CI 1.19-5.39, P = 0.02.

Figure 3

Kaplan-Meier plot showing the DFS (A) and OS (B) of TIMP-1 low and high CMF-treated patients. The median TIMP-1 concentration of the total patient group (12.5 ng/mg of total protein) was used as cut point (TIMP-1 low patients N = 172, TIMP-1 high patients N = 152). Cox univariate regression analysis; DFS: HR 1.15, 95% CI 0.82-0.1.61, P = 0.42; OS: HR, 1.44 (0.91-2.29), P = 0.12.