Clinical implications of proteolytic activity imbalance in breast cancer diagnosis.

BACKGROUND: Matrix metalloproteinase-9 and its tissue inhibitor TIMP-1 have been documented as putative tumor markers because of their involvement in cancer invasion and metastasis. OBJECTIVE: The aim of our study was to elucidate the diagnostic efficacy of proteolytic activity markers among traditional tumor markers (CEA and CA15.3) and clinicopathological variables. METHODS: Serum samples were withdrawn from 160 individuals (80 patients with primary breast cancer, 40 patients with benign breast lesions and 40 individuals serve as healthy controls). MMP-9 and TIMP-1 were measured by ELISA and gelatin zymography. RESULTS: The best cutoff points for MMP-9 and TIMP-1 were depicted by receiver operating characteristic (ROC) curve. The positivity rates and the median levels for MMP-9 and TIMP-1 showed significant difference among the three investigated groups (P< 0.0001). MMP-9 and MMP-9/TIMP-1 were inversely related to clinical stage and lymph node involvement (P< 0.0001). TIMP-1 was significantly correlated with hormonal receptor status (ER, and PgR). MMP zymography results were comparable to those from ELISA. The sensitivity and the specificity of MMP-9, TIMP-1 and MMP-9/TIMP-1 were superior to traditional tumor markers (CEA and CA15.3) especially for early stages (T1) and low grade breast cancer patients. CONCLUSION: These findings indicate that investigated biomarkers are constructive for early diagnosis of breast cancer and MMP-9/TIMP-1 ratio might be a new significant marker in predicting breast cancer development.

Metronomic chemotherapy in metastatic breast cancer: impact on VEGF.

BACKGROUND: Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents; including cyclophosphamide (CTX) and capecitabine (Cap) when given at lower doses for prolonged period (metronomic chemotherapy) postulating an antiangiogenic activity as well. AIM OF WORK: To evaluate the action and tolerability of metronomic chemotherapy (MC) and its impact on serum vascular endothelial growth factor (VEGF) levels in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: In this study we evaluated the clinical efficacy and tolerability of low dose, capecitabine (500mg twice daily) together with oral cyclophosphamide (CTX) (a dose of 50mg once daily) in patients with metastatic breast cancer. Vascular endothelial growth factor (VEGF), an angiogenic marker, was measured in the serum samples; at base line, and after 2 and 6months of therapy. RESULTS: Sixty patients were evaluable. One achieved complete response (CR), 12 partial responses (PR), and 21 stable diseases (SD), while 26 were with progressive disease (PD). The overall response rate was 21.7% with overall disease control (CR, PR, and SD) 56.7%. The median time to progression was 7±2.59months and overall survival 16±8.02months. Toxicity was mild, Palmar-plantar erythrodythesia was the most common side effect and was observed in 22 patients (37%), leucopenia (G1+2) was the most common hematological toxicity, and it was reported in 27% of the cases. The median VEGF level was significantly declined after 2 and 6months of therapy compared to the base line among the patients with disease control (CR, PR, and SD). In multivariate logistic regression analysis, patients with post-menopausal, positive hormonal receptors, negative HER-2/Neu, and one metastatic site, were statistically significant and have a better disease control rate. CONCLUSIONS: MC induced drop in VEGF, and was effective, minimally toxic regimen for the treatment of metastatic breast cancer patients.

Prognostic value of cell-cycle regulators and cellular biomarkers in laryngeal squamous cell carcinoma.

OBJECTIVE: Combining information derived from cellular biomarkers as telomerase and genes encoding cyclin dependent kinase inhibitors (p16(INK4a) and p15(INK4b)) is needed to facilitate the stratification of individual patients within the conventional clinicopathologic parameters. DESIGN AND METHODS: One hundred forty laryngeal squamous cell carcinoma (LSCC) tissue specimens were investigated for telomerase activity and the deletions of p16(INK4a) and p15(INK4b) genes. RESULTS: Of the 140 tissues assayed, 71% demonstrated high telomerase activity, 68.6% and 80% showed deletions in p16(INK4a) and p15(INK4b) genes, respectively. Significant difference was observed between telomerase activity, p16(INK4a) and p15(INK4b) deletions among each other and with advanced stage, poorly differentiated grades, high proliferation and DNA aneuploidy. The markers and the aforementioned clinicopathological factors were correlated with progression in univariate analysis; and associated with survival in multivariate analysis. CONCLUSION: Progression of LSCC is accompanied by a parallel increase in telomerase activity and deletions in cell-cycle regulators (p16(INK4a), p15(INK4b)) which may assist in prognostication and better classification of patients for treatment.