الفهرس 
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Abstract
Breast cancer remains an important public health problem for women all over the world. Breast cancer is considered as systemic disease because micrometastases may be present even in patients with small tumors at early stages. Despite considerable advances in the diagnosis and treatment of solid tumors, distant metastases remain the principal cause of death. Breast carcinoma is a heterogeneous disease with a varying prognosis. New promising biological prognostic factors for breast cancer are continuously being introduced, but it is unclear which of them should be adapted to the clinical use.
Two new parameters that have been extensively studied as a possible new biomarkers in breast cancer are Tissue Inhibitor Metalloproteinase -1 (TIMP-1) and Vascular Endothelial Growth Factor (VEGF).
TIMP-1 is able to suppress extracellular matrix (ECM) break down by MMPS therefore, it should be expected to be a good prognostic marker but instead, TIMP-1 turned out to be tumor promoting factor. While VEGF mediated angiogenesis is considered to play an essential role in cancer progression and in metastatic process.
Detection of circulating TIMP-1 and VEGF in the serum of breast cancer patients can provide prognostic as well as therapeutic information and help in identifying patients at high risk for developing metastases. CA15.3 was also studied as it is widely used biomarker in detecting breast carcinoma.
The aim of this study is to investigate the role of serum TIMP-1 as possible inducing factor of VEGF and their role as prognostic markers of the disease as regards disease free survival.
This study included 40 females divided into 2 groups: the first group included 10 healthy females and the second group included 30 females with breast cancer of clinical stages II and III.
Patients were followed up from the start of the research to 24 months. Three blood samples were drawn: before surgery, after two weeks of surgery and after six cycles of chemotherapy. In all serum samples, TIMP-1 and VEGF levels were analyzed by ELISA and level of CA15-3 was evaluated by RIA technique.
This study showed that serum TIMP-1 and VEGF levels were significantly elevated in breast cancer patients either before surgery, 2 weeks after surgery and after 6 cycles of chemotherapy than their corresponding control values. Our results also revealed that the levels of CA.15.3 either before or after 2 weeks of surgery as well as after 6 cycles of chemotherapy were higher than the control group and the significant difference was observed only after 6 cycles of FAC treatment. On following patients up to 24 months, 18 of 30 patients developed metastasis.
The Receiver Operator Characteristic (ROC) curve showed that both TIMP-1and VEGF-A were convenient diagnostic markers (Area Under Curve (AUC) = 91.4% and 97.8% respectively), but not CA15.3 (AUC = 60.6%). The optimum cut-off point for TIMP.1 was 665 ng/ml, with a corresponding sensitivity 86.7% and specificity 83.3%, while the optimum cut-off point for VEGF was 50 pg/ml with a corresponding sensitivity 94% and specificity of 100%. For serum CA15.3, the optimum cut-off point was 34.2 ng/ml with a corresponding sensitivity(40%). Thus, there may be place to add serum TIMP-1 and VEGF to the preoperative diagnostic armamentarium, especially in cases of difficult decision between benign and DCIs on mammography.
Also, in this study, we analyzed the relation between TIMP-1, VEGF and prognosis by evaluating disease free survival (DSF) in total group of 30 patients. The analysis of DSF showed that higher levels of these two parameters are significantly associated with poor prognosis in patients with primary breast cancer. The log rank of serum TIMP-1 and VEGF were 4 and 3.9 respectively. These log rank values indicate that the possibility of relapse or recurrence in breast cancer patients with TIMP-1 VEGF levels above their cut-off values were 4 and 3.9 time fold than in breast cancer females with TIMP-1 and VEGF below their cut-off values during 24 month of follow up.
This study supports the finding that serum TIMP-1 and VEGF may add prognostic information to that obtained from classical prognostic factors.
The preoperative serum levels of CA15.3 failed to predict survival or relapse in primary breast cancer patients. Therefore, we can predict that serum CA15.3 levels can not be used for monitoring the response to chemotherapy and survieillance.