The role of interleukin 8 and matrix metalloproteinases 2 and 9 in breast cancer treated with tamoxifen

PURPOSE: To evaluate the role of interleukin 8 (IL8) and matrix metalloproteinase (MMP) 2 and 9 as potential parameters of response to adjuvant tamoxifen and to examine possible associations between biomarkers that might imply possible biological dependence. METHODS: The study included 59 postmenopausal breast cancer patients who received adjuvant tamoxifen. Biomarker levels were determined by ELISA in cytosol tumor extracts. RESULTS: Estrogen receptor (ER) proved as a reliable parameter of response to tamoxifen; patients with ER+ status had significantly longer median relapse-free survival (RFS) compared to those with ER- status (p=0.04). Patients with IL8-status had longer median RFS compared to those with IL8+ status (77 and 53 months, respectively) but without significant difference. Patients with MMP9+ status had longer median RFS compared to those with MMP9-status (92 and 66 months, respectively) but without significant difference. There was no significant difference in RFS between the subgroups formed according to MMP2 median value. A significant positive correlation was found between IL8 and MMP9 levels (p<0.001). Expression of MMP9 was significantly higher in patients with IL8 levels higher than the median (p=0.001). CONCLUSIONS: IL8 showed a tendency to act as an unfavorable parameter while MMP9 showed a tendency to act as a favorable parameter of response to tamoxifen, whereas the role of MMP2 as a potential predictive parameter is more complex. The results indicate that possible existence of positive feedback between IL8 and MMP9 might contribute to progression of breast cancer.

Breast cancer in postmenopausal patients: Impact of age.

PURPOSE: We analyzed the significance of age together with other classic prognostic parameters on the course of breast cancer in postmenopausal patients. METHODS: Our study included 151 postmenopausal patients with primary breast cancer, of which 55% received adjuvant tamoxifen therapy and 45% did not receive any kind of therapy. Probabilities of disease-free interval (DFI) were estimated using the Kaplan-Meier method and were compared by the log-rank test. A p value<0.05 was considered as statistically significant. RESULTS: In the tamoxifen-treated subgroup, patients with estrogen receptor (ER) or progesterone receptor (PR) concentration≥5 fmol/mg had favorable course of disease (p<0.01, p<0.04), respectively. Patients≥66 years of age had a worse disease course compared to those<66 years. Also, patients≥66 years with pT1 tumors had a worse disease course compared to those<66 years and pT1 tumors. This result was repeated in other groups as well. In pT2 (≥2 cm), ER-positive, PR-positive and invasive ductal carcinoma (IDC) subgroups, patients≥66 years always had a worse disease course compared to patients<66 years. In the untreated subgroup, patients with ER≥52 fmol/mg (p<0.01), tumors≥2 cm (p<0.01), IDC (p<0.01) type or ≥56 years (p<0.04) had statistically more recurrences. Among patients≥56 years, those with ER-positive or pT2 tumors had shorter DFI compared to ER-negative or pT1. Positive correlation between ER, PR and age of patients was also shown in this subgroup (p<0.03, p<0.02). CONCLUSION: Age of patients, ER and PR are significant prognostic factors in the tamoxifen-treated subgroup. In the untreated subgroup relevant prognostic parameters are age, tumor size, histological type and ER. The above prognostic factors retained their value in the long-term follow up in both the investigated subgroups of patients.

Metformin effects on malignant cells and healthy PBMC; the influence of metformin on the phenotype of breast cancer cells.

The aim of research was to determine the effects of maximally therapeutically achievable concentrations of metformin on malignant cells and healthy peripheral blood mononuclear cells (PBMC). Eight patients with T2D or hyperglycemia and nine healthy volunteers were included in the study. For determination of the influence of metformin on the phenotype of breast carcinoma, 1,410 patients with surgically removed tumors were included. From this group 37 breast cancer patients had DM type 2 or hyperglycemia and were pretreated with metformin alone or sometimes in combination with other antidiabetic drugs. Our results proved that metformin at low concentrations induced mild decrease in survival of malignant cells and PBMC stimulated for proliferation, but it didn't affect survival of resting PBMC. The effects of plasma of hyperglycemic patients who were under metformin therapy on autologous PBMC-induced decrease in survival of MDA-MB-361 cells, was noticeable in some patients. Metformin pretreatment for 24 h of HER2+ MDA-MB-361 cells, which were subsequently treated for 48 h with Herceptin, induced additional decline in cell survival. The analysis of influence of metformin on phenotype of breast cancer cells revealed significantly lower number of diabetic cancer patients treated with metformin with overexpressed HER2+ tumors (p < 0.013), while the number of patients with ER+PR+ tumors was not significantly changed (p < 0.832). In conclusion, therapeutically used concentrations of metformin exhibit mild cytotoxic action on malignant and dividing normal cells pointing to its preferred role in malignant and autoimmune diseases. The use of metformin was associated with pronounced decrease in HER2 overexpressing tumors.

Treatment response to preoperative anthracycline-based chemotherapy in locally advanced breast cancer: the relevance of proliferation and apoptosis rates.

Objectives were to evaluate the relevance of proliferating fraction (Ki-67) along with apoptotic index (AI) which denoted growth index (Ki-67/AI ratio, GI) to predict pathological response to preoperative chemotherapy, and the pattern of their modifications following chemotherapy in women with locally advanced breast cancer. Archival material of diagnostic biopsies and surgical specimens from 106 patients were examined. Response rate to chemotherapy in this group was 95 %, eight (8 %) patients achieved a pathological complete remission (pCR) and five (5 %) had a progressive/stable disease (PD/SD). The expression of Ki-67 and AI were assessed using immunohistochemistry and in situ DNA nick labeling assay respectively. Higher baseline level of Ki-67 and GI were associated with an improved pathological response (p = 0.0001 and p = 0.008), but the degree of correlation with GI was no greater than that with Ki-67 alone. Ki-67 below 1 % highly indicated a lack of tumor response. High AI which characterized the opposite chemo-sensitive tumors, pCR vs. PD/SD (p = 0.72) implied that treatment response was not influenced by the "presence" or "absence" of apoptosis. A significant decrease in Ki-67 (p < 0.001), AI (p = 0.035) and GI (p = 0.008) was found following chemotherapy, but percentage change in biomarker values revealed an increase in a number of cases. Higher initial Ki-67 and AI was associated with profound reduction of GI and raising value of GI after treatment, respectively. Such a variance of a given parameter elicited by chemotherapy may have various impact on disease outcome.

Selection of clinically useful angiogenesis-related biomarkers: an update.

Angiogenesis is a complex phenomenon that involves interaction between growth factors/cytokines and their receptors, and proteolytic enzymes and their inhibitors, which, in addition to and in accordance with their main roles, act together during this multistep process. Cancer angiogenesis is specific, because the same factors that enable angiogenesis are involved in the process of carcinogenesis. The aim of this review was to analyze the current knowledge regarding the significance of selected biomarkers in cancer angiogenesis, with emphasis on their prognostic value in the circulation.