Abstract
BackgroundWe 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.MethodsFrom 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).ResultsIn 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).ConclusionIn 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.
Highlights
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
We hypothesized that high levels of TIMP-1 are associated with decreased benefit from adjuvant chemotherapy and we investigated this hypothesis in a cohort of 525 premenopausal lymph node-positive breast cancer patients, who constitute a subgroup of a large cohort previously described in several studies [14,18,19]
When comparing the TIMP-1 low and high CMF-treated groups with the untreated patients group, we found that both TIMP-1 low and high groups had a significantly better Disease-free survival (DFS) than untreated patients (TIMP-1 low patients: hazard ratio (HR) 0.51, 95% Confidence interval (CI) 0.36-0.73, P < 0.001; TIMP-1 high patients: HR 0.58, 95% CI 0.41-0.81, P = 0.002)
Summary
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. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and that high tumor tissue levels are associated with shorter survival. Many patients are offered adjuvant chemotherapy after surgery for primary breast cancer. Several options exist (reviewed in [1]) but currently, adjuvant chemotherapy only reduces breast cancer mortality by up to 50% [2] and further improvement is needed. Choosing the most effective adjuvant chemotherapy regimen up front should lead to a further reduction in disease recurrences and, to increased survival of the patients. Avoiding ineffective treatments would reduce unneeded toxicity and burden for the patients and the substantial costs associated with administration of adjuvant chemotherapy
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