الفهرس 
BREAST CANCEROnly 14 pages are availabe for public view
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Abstract
Worldwide, breast cancer is the most common malignancy in women. It is the second leading cause of cancer death in females, exceeded only by lung cancer, but it is the first in women under the age of 55 (Kinsey et al., 2008). In Egypt, it accounts for 31% of all female cancers, and is responsible for 15% of cancer deaths in women (El Gezeery et al., 2008).
Breast cancer is commonly diagnosed using clinical breast examination, mammography, and fine needle aspiration cytology referred to as “triple test”. The triple test is accurate and can replace open surgical biopsy for diagnosis when all 3 components are concordant; that is, all benign or all malignant (Morris et al., 2001). However, early-stage breast cancer typically produces no symptoms when the tumor is small and most treatable. It is therefore very important to detect breast cancer at an early stage, as this offers the best chance for its successful treatment (American Cancer Society, 2008).
American Cancer Society guidelines for the early detection of breast cancer include mammography and clinical breast examination, as well as magnetic resonance imaging (MRI). However, tumors that are too small will be missed by physical examination and mammography. Clearly, the available screening methods are inadequate for early detection and follow up of breast cancer patients (American Cancer Society, 2008).
The need for additional dignostic indicators to improve the identification of breast cancer patients has led to the use of a plethora of potential markers in the last ten years such as carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, tissue polypeptide antigen and HER- 2 (Omar et al., 2003 and Duffy, 2006).
Unfortunately, the currently available markers for breast cancer lack sensitivity for early stage disease, precluding their use in both screening and diagnosing early breast cancer. Moreover, these markers show a low specificity, which is essential to protect patients with false positive results from unwarranted diagnostic evaluations. In addition, most available prognostic markers require tumor tissue. Consequently, it would be desirable to have a circulating marker for breast cancer which improves the identification of breast cancer patients and provides prognostic information (Perkins et al., 2003 and Duffy, 2006).
Urinary polyamines (putrescine, spermine and spermidine) are candidate markers for both diagnosis and prognosis of breast cancer. They have generated much interest in the last few years because elevated levels of these compounds in human tissue and biological fluids have been found in various types of cancer. This elevation has been attributed to stimulation of ornithine decarboxylase (ODC). Moreover, ODC is known to be activated by E2 in breast cells. Several studies have also established that the urinary polyamine levels in cancer reflect the severity and clinical course of the disease (Criss, 2003, Enjoji et al., 2004 and Inoue et al., 2005).
In this regard, our study aimed to evaluate the role of urinary polyamines in the diagnosis of breast cancer, to consider their potential as novel prognostic markers and to investigate their relation with estrogen levels in Egyptian breast cancer patients.
The study was conducted on 50 Egyptian female patients attending the Surgery Department at Ain Shams University Hospitals. Patients were classified into two groups according to their diagnosis. group I included 30 newly diagnosed breast cancer patients who were further classified according to the stage of the disease, previously determined by TNM classification system and also classified according to the menopausal status of the patient (pre-menopause and post-menopause). group II included 20 patients with benign breast conditions. In addition, 20 apparently healthy females served as control subjects.
All patients in this study were subjected to full history taking, thorough clinical examination, mammography and / or ultrasonography for the breast. Furthermore, serum estradiol (E2) assay was performed for breast cancer patients. In both patients and control subjects, a random urine sample was obtained under standardized conditions for the assay of urinary creatinine level and urinary polyamines (putrescine, spermine and spermidine) assay by high performance liquid chromatography (HPLC) technique. In addition, serum CA 15-3 assay was performed for all participants in the study.
Urinary polyamines were significantly higher in patients diagnosed with breast cancer when compared to either patients with benign breast diseases or healthy controls (p<0.01, respectively). Our results have also shown significant elevation of urinary polyamine levels in breast cancer patients with TNM stage III and IV than those with earlier stages 0, I and II (p<0.01, respectively). Moreover, results of the current study showed that urinary putrescine and spermine levels were significantly higher in premenopausal compared to postmenopausal breast cancer patients (p<0.05, respectively). In addition, urinary putrescine was also found to be significantly elevated in premenopausal than in postmenopausal healthy subjects (p<0.01).
Furthermore, our results showed that serum CA 15-3 was significantly higher in breast cancer patients than in patients with benign breast diseases and healthy control subjects (p<0.01). Assessment of the diagnostic performance of CA 15-3 as a marker for distinguishing malignant from benign breast conditions revealed that at a cutoff of 30 ng/mL the diagnostic sensitivity was 33.3% and the specificity was 85%.
Correlation study revealed the presence of a significant positive correlation between the three polyamines (putrescine, spermine and spermidine) in breast cancer patients. Moreover, both putresine and spermine showed a significant positive correlation with E2.
Assessment of the diagnostic performance of urinary polyamines, measured by high performance liquid chromatography (HPLC) assay technique performed in our study, revealed that the best cutoff for putrescine to discriminate malignant from benign breast conditions was 150 µg/mg creatinine. This cutoff provides both a high sensitivity and a negative predictive value (NPV) of 100%.
Moreover, our study demonstrated the diagnostic utility of urinary polyamines in discriminating early breast cancer with TNM stages 0, I and II from those with more advanced TNM stages III and IV. Our results revealed that the best cutoff for spermine was 98 mg/ mg creatinine with a 100% specificity and positive predictive value (PPV).
In conclusion, patients with breast cancer have higher levels of urinary polyamines than those with benign breast diseases and healthy subjects. Moreover, patients with advanced stages of breast cancer have higher urinary polyamine levels than those with earlier stages. Nevertheless, this elevation is affected by menopausal status owing to the stimulatory effect of E2 on polyamine production. Thus, urinary polyamines are sensitive diagnostic markers for breast cancer superior to the commonly used CA 15-3. Moreover, they are novel prognostic markers of breast cancer efficiently discriminating early from late stages of the disease.