الفهرس 
I. Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
As the main reason for cancer-related death and the top-ranking malignancy among women worldwide, breast cancer has been established to be complicated disease of many biological subtypes with various clinical, pathological and molecular characteristics. Breast cancer early detection, to ameliorate its survival and outcome, remains the backbone of the disease monitoring. Currently, breast cancer diagnosis depends mainly on mammography and imaging methods. But, tumor screening using these techniques limited by radiation exposure, breast tumor is required to be at least a few millimeters in size for detection and thus low sensitivity and low specificity. Otherwise, blood tumor marker is more acceptable and could also overcome imaging limitations. So that, there is an urgent need to develop a biomarker for breast cancer early detection.
In the detection and management of breast cancer patients, biomarkers play an important role. Human epididymal protein 4 (HE4) is a secretory protein initially identified in human epididymis epithelial cells. Its expression has been demonstrated in several types of normal human tissues, particularly in the epithelium of the respiratory and genitourinary tracts of men and women, and increased HE4 expression has been demonstrated in a range of malignant neoplasms, particularly those of gynecological, pulmonary and gastrointestinal origin. Findings of some studies indicated that HE4 is significant in association with breast cancer. However, limited studies were found that concerning withHE4 serum levels in breast cancer patients, and their diagnostic and prognostic potential.
from another hand, trefoil factors are stable and small peptides that secreted by gastrointestinal tract epithelial mucus secreting cells. They constitute 3 peptides family (TFF1, 2, and 3) that are broadly expressed in tissue
specific manner. In normal breast tissue, TFF3 expression was reported to be in lower amounts. In contrast, elevated expression was reported in BC tissues. TFF3 was positive in >90% of invasive ductal carcinoma.
The joint detection of several tumor markers in early BC diagnosis can make up for deficiency of one tumor marker alone. Thus, the aim of this study is to evaluate a multimarker index (BC-DETECT) combining HE4 and TFF3 in breast cancer screeningto improve diagnosis. We also evaluate the clinical value of this index compared to established tumor markers (CEA and CA-15.3) and evaluate the association between the it and some tumor severity features including, number of lesions, tumor, stage, grade, size and lymph node invasion.
In present study:
1. Serum samples from 200 Egyptian women were included. They were 160 female patients (120 with breast cancer and40 with benign breast diseases) and 40 age-matched (P>0.05) healthy females as a control group. Tumor features such as invasion, depth, histological grade, lymph node invasion and tumor size were collected from patient’s records.
2. Both HE4 and TFF3 serum levels were detected in all samples of patients and controls using high sensitive ELISA assay.
3. In contrast to CEA and CA-15.3, serum levels of HE4 (5 (2-11.9)) and TFF3 (5.3 (4.5-6.7)) significantly (P=0.02) increased in BC patients compared to benign (3.1 (1.8-5.4) and 4.7 (4-4.8), respectively) and healthy controls (1 (1-3.5) and 3.9 (3-4.4), respectively).
4. HE4 (AUC=0.783) and TFF3 (AUC=0.759) have good predictive power for breast cancer diagnosis which is superior to CEA (AUC=0.570) and CA-15.3 (AUC=0.619).
5. The best overall formula was then constructed by entering these tumor markers together into the stepwise linear regression analysis. As a result, HE4 and TFF3 retained significant when combined with each other and one index (BC-DETECT= HE4 + TFF3) was produced that includes the sum of these proteins.
6. BC-DETECT values were significantly (P=0.0132) elevated in BC (10.9 (8.4-17.2)) compared to benign (7.2 (5.4-10.1)) and healthy (5.1 (4-6.3)) controls. AUC values for identifying BC from all non-cancer (benign and healthy combined) (P<0.0001) and only healthy (P<0.0001) individuals were 0.850 and 0.926, respectively.
7. BC-DETECT improves the diagnostic performance of HE4 and TFF3 for BC detection. BC-DETECT sensitivity, specificity, and positive and negative predictive values and accuracy were 84.2%, 70%, 80.8%, 74.7%, and 78.5%, respectively. These diagnostic performances were increased to 84.2%, 82.5%, 87.8%, 77.6%, and 83.5%, respectively when discriminate BC patients from only healthy controls.
8. The odds ratio for breast cancer development increased with the increase in BC-DETECT values (OR=2.186, 95%CI (1.45-3.28)).
9. Compared to each protein alone, BC-DETECT have high correlation with tumor features. BC-DETECT high values were associated with BC severity and features associated with poor survival and prognosis including large tumors, late T-stage, high grade, positive lymph node invasion, multiple lesions, advanced clinical stages and non-luminal subtypes of BC (Non-luminal HER2+ and Triple negative tumors).
In conclusion, our experimental findings showed that expression levels of HE4 and TFF3 were increased in BC patients compared to patients with benign diseases and healthy controls. The joint detection of the two markers (BC-DETECT) could be a reliable index that significantly improve the sensitivity in BC diagnosis, as well as facilitate the screening of early BC so as to give timely treatments.