Alkaline Phosphatase as a Biomarker for Metastatic Breast Cancer View PDF

Breast cancer is the most common malignant disease in women worldwide [1]. It is considered the most common type of cancer in both developing and developed countries, and is the fifth cause of cancer mortality in the world [2]. In Iraq it is the leading type of cancer among Iraqi women, accounting for one-third of the total registered female cancer patients in Iraq [3], with a rapidly rising incidence among Iraqi population [4].

Breast cancer patients who are presented with locally advanced disease require management by a multidisciplinary team that utilizes diagnostic imaging, chemotherapy, surgical intervention, and pathological assessment. The outcome of treatment for each patient could depend on the level of integration of this multidisciplinary approach in addition to the experience of the team members. Coordination between those members is of particular importance in the management of those patients with locally advanced breast cancer, because those patients have a high risk of recurrence of the disease if no optimal treatment was provided. However, the outcome of patients with locally advanced disease has improved recently with the routine use of chemotherapy. Before the routine use of chemotherapy there was a high rate of distant metastases and death among patients treated with mastectomy or radiation [5].

Early detection of breast cancer is essential for its cure. Cancers that are detected early when the tumor is still small in size can potentially be cured by complete surgical removal [6]. However, most cancers produce symptoms only after the tumor is too large for surgical removal or after the spread of cancerous cells to other tissues by metastasis [7].

These facts necessitate the need for non-invasive and sensitive methods for early detection of malignant diseases. This can be achieved by measuring certain products and metabolites that are associated with the malignant tumor [7, 8]. These products are called tumor markers, and are useful for screening of populations, diagnosing, staging and prognosis. Tumor markers are also useful for detecting the presence of occult metastatic disease and to monitor the response to treatment [8].

Breast cancer has different types that exhibit variable histopathological and biological features, with difference in clinical response and outcome. The histopathological classification is adopted worldwide and is based on the diversity of the morphological features of the disease. It classifies the disease into either invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or not otherwise specified [9]. Different breast cancers have different prognoses and different treatment requirements; therefore, certain characteristics have been defined that allow reliable distinction between those that require aggressive treatment and follow-up from those that don't [10].

To investigate for the disease, a complete history is essential, followed by triple assessment which include physical examination, radiological investigation, and needle biopsy. It is preferred to use core biopsy rather than fine-needle aspiration since the core biopsy provides a histological diagnosis and can be used for differentiation between invasive and in situ carcinoma. Also, it is possible to test for estrogen receptor, progesterone receptor and human epidermal growth factor status using biopsy specimen. Other investigations include full blood count, liver function tests, and calcium level in serum [11]. Routine staging of asymptomatic patients with T1 or T2 primary breast cancer is not indicated. However, staging investigations are performed in patients with advanced disease since it may affect management, and these investigations include chest X-ray, liver ultrasonography, bone scan, computed tomography (CT) scan of thorax or abdomen, and magnetic resonance imaging (MRI) scanning [12]. Also, there is growing interest in the use of 18F-fluirodeoxyglucose positron emission tomography (PET)/CT in the staging of disease in patients with locally invasive breast cancer, especially in inflammatory disease. In a study conducted on 41 females with inflammatory breast cancer, it was found that PET/CT could detect distant metastases that could not be detected by other studies in 17% of the study participants [13].

Therefore, changes in serum ALP level may be useful in the diagnosis and follow up of breast cancer [14]. The level of ALP in serum normally varies with age, generally as a result of bone growth and development. It is found to be higher in childhood and puberty, followed by a decline after the age of 15, then rise again after the age of 50. It is also slightly higher in males than in females. As a serum protein, ALP has a half-life of 7 days, but the site of its degradation is not known [15].

Various methods exist for determining the level of serum ALP. The difference among those methods is generally in the used substrate, alkaline buffer pH value, and the resulting normal values. The main principle for these tests is based on the ability of ALP to hydrolyze phosphate esters. The most commonly used method worldwide uses p-nitrophenyl phosphate as a substrate, with amino-alcohol as the buffer. The activity of ALP is detected by measuring the rate of release of either phosphate or p- nitrophenol from the substrate, and the result is given in IU/L. Those various methods seem to have similar effectiveness in measuring abnormalities in ALP level [15].

When ALP is elevated alone or elevated out of proportion with other liver enzymes; evaluation of the patient should be directed towards the identification of the cause of this elevation and the source of abnormality. Highest elevations (up to 4-fold increase of the upper normal value) are usually seen in cases with cholestasis, whether intrahepatic or extrahepatic. Such high increases are also seen in other conditions including biliary obstruction resulting from malignancy. Certain infections such as cytomegalovirus or cryptosporidiosis especially in AIDS patients are also associated with high levels of ALP. Moderate elevations are usually considered non-specific and may be associated with various conditions including liver cirrhosis, viral hepatitis, congestive heart failure, and certain malignancies [15]. Malignancy may raise ALP level by several mechanisms: it may locally obstruct the bile duct, increasing the leakage of liver isoenzyme. It may produce its own ALP such as Hodgkin lymphoma. Or it may have certain paraneoplastic effect that causes the hepatic isoenzyme to leak into the circulation [15].

Management of early breast cancer in primary disease is done with surgery, specifically modified radical mastectomy, which involves the surgical removal of the entire breast, areola and nipple. It is commonly accompanied by axillary dissection of lymph nodes. While breast conservation therapy comprises wide local excision and postoperative radiotherapy. Similar outcomes were found for either approach [16, 17].

Patients with invasive breast cancer usually undergo axillary dissection, which was the preferred technique until recently, and required at least 10 lymph nodes for the pathologic evaluation in order to stage the axilla accurately [18]. Clearance of axillary node comprise clearing the contents of axilla contained within the following boundaries: anteriorly pectoralis muscles, posteriorly teres major, latissimus dorsi and subscapularis, medially chest wall, laterally the axillary skin, and superiorly the lower border of axillary vein. Certain complications are associated with axillary node clearance including pain and numbness in axilla, chronic lymphoedema, and limitation in the movement of the arm [11].

Bisphosphonates are given for patients with bone metastasis to relieve the pain and reduce the skeletal-related events frequency. Other localized problem may arise in patients with metastatic breast cancer, requiring certain treatment modalities including radiotherapy, surgery, or regional chemotherapy [11].

The aim of this study is to assess the relationship between increased serum ALP level and the occurrence of metastasis in breast cancer patients, and to assess the possibility to use this enzyme as a biomarker for the detection of metastasis in breast cancer.