Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Metalloproteinase 7 (MMP-7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP-7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP-7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP-7 expression was determined by enzyme-linked immunoabsorbent assay. We assessed serum MMP-7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP-7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p /= 0.10. Advanced CRC patients have a significant higher mean serum MMP-7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP-7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002-1.031). Serum MMP-7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP-7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP-7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation.     

Serum soluble interleukin 2 receptor levels in patients with breast cancer

Preoperative levels of serum soluble interleukin-2 receptor (1L-2R) were examined in 37 patients with breast cancer. We investigated the correlations of serum soluble IL-2R levels with various factors such as stage grouping, lymph node metastasis, distant metastasis, tumor size, histophthological type, estrogen receptor (ER), progesterone receptor (PgR) and CA 15-3. Serum soluble 1L-2R levels were measured with an enzyme-linked immunosorbent assay. Levels of serum soluble 1L-2R in the patients with stage III and IV breast cancer were significantly higher than those in the normal controls, and patients with stage I and II breast cancer. Preoperative levels of serum soluble IL-2R in patients with T3 and T4 were also significantly higher than those in patients with T1 and T2. Serum levels of IL-2R in patients with distant metastasis were also significantly higher than those in patients without distant metastasis. Moreover, serum levels of soluble IL-2R in patients with higher CA 15-3 were significantly higher than those in patients with normal CA 15-3 levels. We conclude that preoperative serum soluble IL-2R levels in patients with breast cancer may be a valuable parameter, especially in evaluating whether they have distant metastasis or not.     

Serum neopterin levels in patients with breast cancer

The aim of this study was to determine the importance of serum neopterin level in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology. The patients were classified into three representative groups and a control group: group A (n = 26), patients with newly diagnosed primary breast cancer and without metastasis; group B (n = 33), patients with metastatic breast cancer who had undergone treatment for their diseases and on whom metastasis was detected during their follow-up; group C (n = 16), off-therapy patient whose cancer had been in remission for at least 5 years; group D (n = 20) healthy controls. The median serum neopterin levels of the 75 patients with breast cancer 11.0 (range, 0–23.6) nmol/L were significantly higher than those of controls (8.3 (range, 1.2–12.0) nmol/L). In group B patients, neopterin levels (12.6 (range, 0–23.6) nmol/L) were statistically significantly higher than those of controls, primary breast cancer patients, and off-therapy patients (P < .05). In group B, patients with visceral metastases had higher neopterin levels than did those with bone or local metastases; however, that difference was not statistically significant. The median serum neopterin levels of the primary breast cancer patients in group A (8.8 (range, 0–20) nmol/l) were not statistically significantly different from those in controls and off-therapy patients. Serum neopterin levels were significantly elevated in patients with metastatic breast cancer. Neopterin seems to be an indicator of metastatic cancer rather than a marker for local cancer. In patients with metastatic breast cancer, determining the serum neopterin levels may be useful in estimating survival; however, additional long-term follow-up will be needed.     

Serum immunoglobulin levels in patients with breast cancer.

Serum immunoglobulin levels IgA, IgG, and IgM have been estimated in 92 patients with breast cancer and 50 control patients, 40 of whom had benign disease of the breast. In patients with breast cancer, IgA was significantly raised at all stages and IgG was significantly reduced, but the two abnormalities were not necessarily concomitant. These findings may suggest a disturbance in the secretory immune system, and immunologic defect even when the cancer is localized to the breast.     

Serum c-erB-2 levels in monitoring of operable breast cancer patients.

BACKGROUND: Various methods and criteria are used to determine protein overexpression of c-erbB-2 and the clinical utility of c-erbB-2 is under investigation. We have reported previously that the levels of cytosol c-erbB-2 in breast cancer were significantly different between the clinical stages. METHODS: The levels of c-erbB-2 protein were determined in sera from 210 breast cancer patients using a sandwich enzyme immunoassay between November 1996 and March 1998. The cut-off level was set at 5.4 ng/ml for healthy female blood donors. RESULTS: First, serum c-erbB-2 levels were analyzed in 73 preoperative breast cancer patients with stage I-IIIB disease. The range and median values were 2.3-32.3 and 4.8 ng/ml, respectively. The positive rate was 38%. Overexpression of serum c-erbB-2 was significantly associated with tumor size, clinical stage, histological grade, lymphatic invasion, nodal status and overexpression of cytosol c-erbB-2, but not with hormonal receptor status and other clinico-pathological factors. Second, c-erbB-2, CEA and CA15-3 in sera were examined in 157 postoperative breast cancer patients. In the 137 disease-free patients, specificities of c-erbB-2, CEA and CA15-3 were 72, 93 and 99%, respectively, but in the 20 first recurrent patients, these sensitivities were 80, 25 and 25%, respectively. CONCLUSIONS: These results suggest that serum c-erbB-2 protein is a useful marker for predicting aggressive behavior and first recurrence of breast cancer.     

Serum HER2 levels determined by two methods in patients with metastatic breast cancer

Background  

The role and the optimal measurement method of serum HER2 levels are not defined in patients with metastatic breast cancer (MBC). We prospectively assessed the prognostic value of serum HER2 levels in MBC using two methods, enzyme immunoassay (EIA) and chemiluminescence immunoassay (CLIA).     

Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients’ survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.     

Serum CD44 levels and overall survival in patients with HER2-positive breast cancer

CD44 is an adhesion molecule involved in tumor cell invasion and metastasis. The function of CD44 in breast cancer is not understood completely, or is its role as a predictive or prognostic factor. In this study, we tested for the hypothesis that the concentration of soluble CD44 (sCD44) in serum is correlated with clinicopathological factors, especially HER2, and survival in patients with breast cancer. We retrospectively identified 110 patients with breast cancer who had been treated at The University of Texas MD Anderson Cancer Center (MDACC) from September 2001 to May 2004. Sera were collected before definitive surgery in patients with stage I or II breast cancer, before initiation of neoadjuvant chemotherapy (if indicated) for patients with stage I–III breast cancer, and before initiation of systemic therapy in patients with stage IV breast cancer. sCD44 levels were determined using an enzyme-linked immunosorbent assay. The median age at diagnosis was 51 years (range, 28.6–87.1 years). sCD44 concentration was correlated with tumor stage (P = 0.0308). sCD44 serum concentration did not predict pathological response in patients treated with neoadjuvant chemotherapy. Among patients with distant metastases, sCD44 levels were significantly higher in patients with liver involvement than in patients with metastases at other sites. The overall survival rate did not differ between patients with high sCD44 concentration and patients with low sCD44 concentration. However, sCD44 concentration was a significant predictor of overall survival for patients with HER2-positive breast cancer, while no difference in overall survival rates was observed in patients with HER2-negative breast cancer. To the best of our knowledge, this is the first study to show an association between circulating sCD44 levels and survival in HER2-positive breast cancer patients. Our results suggest a role for sCD44 as a prognostic marker. Furthermore, sCD44 level may offer a new clinical therapeutic target in HER2-positive breast cancer.     

Serum levels of hepatocyte growth factor in patients with breast cancer.

OBJECTIVE: Hepatocyte growth factor (HGF) has been reported the cause of many biological events, including cell proliferation, movement, invasiveness, morphogenesis, and angiogenesis. Elevated hepatocyte growth factor content in tumor tissue was reported to predict a more aggressive biology in non-small cell lung cancer patients. However, there is still limited knowledge about the role of HGF in breast cancer. This study was designed with the aim to elucidate the possible relationship between the preoperative circulating soluble HGF and breast cancer. MATERIALS AND METHODS: One hundred twenty-four consecutive patients with invasive breast cancer undergoing surgery were prospectively included and evaluated. Venous blood samples were collected before the surgery. Sera were obtained by centrifugation and stored at -70 degrees C until assayed. The control group consisted of 35 patients with benign breast tumor (20 with fibrocystic disease and 15 with fibroadenoma). Serum concentrations of soluble HGF were measured by the quantitative sandwich enzyme immunoassay technique. The data on primary tumor staging, age, estrogen receptor status, lymph node status, distant metastases status, histologic grading, and tumor-node-metastasis (TNM) staging were reviewed and recorded. RESULTS: The mean value of serum soluble HGF in patients with invasive breast cancer was 529.05 +/- 123.33 pg/mL and that of control group was 343.00+/- 31.03 pg/mL and the difference was significant (P < 0.001). Furthermore, there were significantly higher serum levels of soluble HGF in patients with negative estrogen receptor (P = 0.035), in patients with poorer differentiated tumor (P < 0.001), in patients with more advanced primary tumor staging (P < 0.001), in patients with more advanced lymph node status (P < 0.001), in patients with distant metastases (P < 0.001), and in patients with more advanced TNM staging (P < 0.001). In multivariate analysis by the multiple linear regression method, TNM staging (P < 0.001) seemed an independent factor regarding the significant higher serum levels of soluble HGF. CONCLUSION: Patients with more advanced TNM staging were shown to have higher serum soluble HGF. Thus, preoperative serum soluble HGF levels might reflect the severity of invasive breast cancer and deserve further evaluation.     

Prognostic role of matrix metalloproteinase 9 in early breast cancer

MMP9 is involved in extracellular matrix degradation during various physiological and pathological conditions, including tumorigenesis. The present study aimed to assess the prognostic role of intratumoral MMP9 and to determine its association with circulating tumor cells (CTCs) in patients with early breast cancer. A total of 318 patients with primary breast cancer (PBC) were enrolled into the present study. Specimens were subjected to immunohistochemistry analysis, using the MMP9 monoclonal antibody. MMP9 expression was scored using a weighted histoscore (WH). The results demonstrated that the mean WH ± SEM for MMP9 expression was significantly higher in breast tumor cells compared with tumor associated stromas (132.0±5.2 vs. 50.8±3.7; P<0.00001). Furthermore, a positive association was observed between MMP9 expression, the hormone positive status and proliferation index of analysed breast cancer tumour cells. Notably, the prognostic role of MMP9 was not observed in tumor cells [hazard ratio (HR) =0.96; 95% confidence interval (CI), 0.58–1.59; P=0.864] or tumor associated stroma (HR=1.29; 95% CI, 0.60–2.78; P=0.547). Subgroup analysis demonstrated that patients that were HR negative or triple negative, with low MMP9 expression in tumor cells and stroma had a significantly improved disease-free survival than patients with high MMP9 expression. Taken together, the results of the present study demonstrated that high MMP9 expression in PBC was associated with favorable tumor characteristics. However, the prognostic value of MMP9 was limited to only the HR negative and CTC epithelial-to-mesenchymal transition positive subgroups. Thus, analyzing MMP9 tumor expression may help identify patients with increased risk of disease recurrence in these subgroups.     

Serum adiponectin and leptin levels in Taiwanese breast cancer patients

The role of two adipocytokines, adiponectin and leptin, in Taiwanese breast cancer patients remains to be determined. In this study, we analyzed the correlations between the serum levels of adiponectin and leptin and the various clinicopathological parameters in 100 newly diagnosed, histologically confirmed breast cancer patients and 100 controls. We found serum levels were decreased significantly for adiponectin in the breast cancer patients, in comparison to controls (Student t-test, P=0.003), while serum levels were increased significantly for leptin in the breast cancer patients in comparison to controls (Student t-test, P=0.025). Leptin/adiponectin (L/A ratio) were increased significantly in the breast cancer patients, in comparison to controls (Student t-test, P=0.009). Among the clinicopathological parameters, estrogen receptor, progesterone receptor, HER2/neu, lymph node metastasis, tumor stage, and tumor grade all showed no effect on the serum levels of adiponectin and leptin. BMI was negatively and positively correlated to serum adiponectin and leptin levels, respectively (Spearman's correlation, r=-0.333 and 0.323, respectively; P<0.001 for both). Intriguingly, serum L/A ratio disclosed a positive correlation to tumor size (r=0.21, P=0.036). In summary, our results suggest that low serum adiponectin levels and high serum leptin levels are associated with an increased risk for breast cancer. Also, independent of the effect of BMI, the increased serum ratio of L/A may indicate the presence of aggressive breast cancers.     

乳腺癌MMP9与C-erbB-2表达相关性研究

目的:研究乳腺癌基质金属蛋白酶9表达与C-erbB-2表达间的相关性.方法:采用免疫组织化学法检测120例乳腺癌组织MMP9和C-erbB-2的表达.结果:120例乳腺癌组织中MMP9阳性表达率为62.5%(75/120),C-erbB-2阳性率为69.2%(83/120),其中C-erbB-2过表达阳性率为36.7%(44/120).MMP9阳性表达与C-erbB-2过表达具有显著相关性.结论:MMP9阳性表达和C-erbB-2过表达与乳腺癌浸润转移相关,是乳腺癌预后指标.     

Serum EGFR levels and efficacy of trastuzumab-based therapy in patients with metastatic breast cancer

The antibody trastuzumab inhibits signal transduction in Her-2/neu overexpressing human breast cancer. However, the activation of co-expressed EGFR has also been show to additionally modulate the anti-tumoural effects of this drug. Similar to Her-2/neu, the extra cellular binding region of EGFR is believed to be proteolytically released from the cell surface upon receptor activation and can be detected in patients' serum (sEGFR). Considering the biological significance of an interaction between EGFR and Her-2/neu signalling in other human malignancies, we have investigated if trastuzumab treatment would affect sEGFR in 33 patients with Her-2/neu overexpressing metastatic breast cancer. We detected EGFR expression in 33% of Her-2/neu overexpressing breast tumours. In contrast to serum Her-2/neu (ECD) levels, which were correlated with the degree of Her-2/neu expression (P=0.048, Mann-Whitney test), we did not detect significant differences between sEGFR serum levels in EGFR expressing or non-expressing tumours. Furthermore, sEGFR serum levels were not correlated with clinical parameters such as response or clinical benefit rates, and no association was found between increased sEGFR levels and progression-free survival or overall survival. While we have previously observed a selective and significant decrease of ECD levels in patients who derived a clinical benefit from trastuzumab treatment during the first weeks of treatment, we were unable to find similar alterations in sEGFR concentrations. We therefore conclude that the measurement of systemic sEGFR levels in addition to ECD serum concentrations do not allow the prediction of clinical course of trastuzumab-treated patients more accurately.     

Serum long-chain alcohol levels in healthy individuals and in patients with breast cancer.

Total long-chain alcohols were analyzed in blood sera from normal individuals and patients with diagnosed breast cancer. Tetra-, hexa- and octadecan-1-ol were the major long-chain alcohols detected in both groups. While the qualitative composition of the serum alcohols was similar in the two groups the average alcohol content of the serum of the breast cancer patients was approximately six times greater than that of the normal group. This difference in serum alcohol levels between the two groups was significant at p less than 0.01.     

乳腺癌MMP9与C-erbB-2表达相关性研究

目的：研究乳腺癌基质金属蛋白酶9表达与C-erbB-2表达间的相关性.方法：采用免疫组织化学法检测120例乳腺癌组织MMP9和C-erbB-2的表达.结果：120例乳腺癌组织中MMP9阳性表达率为62.5%（75/120）,C-erbB-2阳性率为69.2%（83/120）,其中C-erbB-2过表达阳性率为36.7%（44/120）.MMP9阳性表达与C-erbB-2过表达具有显著相关性.结论：MMP9阳性表达和C-erbB-2过表达与乳腺癌浸润转移相关,是乳腺癌预后指标.     

Serum sialyl transferase levels in patients with metastatic breast cancer treated by chemotherapy.

Serum sialyl transferase (SST) was measured in 49 female patients with advanced breast cancer and 60 female controls. The mean SST level was significantly raised in patients with advanced breast cancer. There was no correlation between specific sites, or numbers of sites of metastatic disease and SST levels. The patients with advanced breast cancer were all treated with chemotherapy; in 13/21 responders there was a significant fall in SST and in 2 responders a significant rise in SST. The 6 patients who died after one course of chemotherapy had a significantly higher mean SST than those surviving longer. SST appears to lack sufficient specificity to be of practical value as a marker of response in patients with breast cancer treated by chemotherapy, though constant measurement of changes in SST may be of use in monitoring drug response. Raised SST at the commencement of chemotherapy may signify poor prognosis.