Study the Effect of Anastrozole on Estradiol and Cytochrome P450 (Aromatase Enzyme) in Postmenopausal Breast Cancer Patients

In this study sixty patients were selected according to a positive estrogen receptor. All of 60 naturally or surgically postmenopausal women that had a diagnosis of breast cancer verified by histology breast cancer. Subdivided to with hormone treatment or without any treatment, Forty patients (group P1) with the ages range from 46 to 75 years, and were being treated with an aromatase inhibitor, Arimidex (1 mg) once daily, and another twenty (group P2) as newly diagnosed of breast cancer with ages ranging from 47 to 75 years. While the age of control ranging from (48-75) years old, used as a reference. Recent investigations have challenged the hypothesis that aromatization of androgens into estrogen is the sole production pathway for estrogens in postmenopausal women. The finding that estradiol persists in the plasma of patients receiving anastrozole treatment despite a near total inhibition of the aromatase enzyme suggests that alternative pathways for estrogen synthesis exist, which appeared in our results, aromatase and estradiol with treatment (452.34pg/ml) and (13.09pg/ml) respectively. An although evidence a positive and strong correlation between aromatase enzyme and estradiol (r=0.573, P=0.00). Keyword: Breast cancer, Aromatase, Anastrozole, Estrogen receptor. Introduction Hormonal therapy for breast cancer is the first targeted therapy used in any type of cancer. It was used successfully without a known target for more than 50 years before Jensen described the estrogen receptor (ER) in the 1960s [1]. Subsequently, it was found that hormone therapy was effective only in those patients whose tumors expressed the ER, Currently, all breast cancers are tested for expression of Estrogen Receptor (ER), Progesterone Receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu) proteins. ER and PR tests are usually done by immunohistochemistry whereas HER2/neu is accessed by FISH. This protein profiling of tumors helps to predict the eventual prognosis and can assist in the determination of the most appropriate treatment for the individual [2]. ERs are over-expressed in around 70% of breast cancer cases, and are referred to as "ERpositive" tumors. Binding of estrogen to ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication and increases mutation rate. This causes disruption of the cell cycle, apoptosis and DNA repair processes eventually leading to tumor formation [3]. About 65% of ER-positive breast cancers are also PR-positive and about 5% of breast cancers are ER-negative and PR-positive. If cells have receptors for both hormones or receptors for one of the two hormones, the cancer is considered hormone-receptor positive [4]. In postmenopausal women, estrogens are synthesized in most of the body compartments, including the liver, muscle, connective tissue, and skin [5]. While one single aromatase gene exists, the gene contains at least ten different promoters [6], with different promoters and ligands regulating estrogen synthesis across different tissue types [7] . However, proteins coded for by the different promoters are similar. The aromatase (CYP19 gene), an enzyme catalyzing the conversion of testosterone into estradiol (E2) and androstenedione into estrone (E1) [8]. This process called aromatization is inhibited by aromatase inhibitors (AIs), is first-line systemic treatment for the majority of postmenopausal breast cancer patients with estrogen receptor (ER)-positive primary tumor [9]. Androgen ----------------> Estrogen Aromatase Mays Waad Abd-Allateef 44 its work by blocking the enzyme aromatase, a cytochrome p450, decreasing in this way the level of circulating estrogen which stimulates the growth of estrogen-receptor positive breast cancer cells, aromatase enzyme are available in different tissues such as adipose tissue, liver, muscle, brain, skin, bone, endometrium, and breast tissue [10]. Estrogens are the end-products of a sequence of steroid transformations [11]. Blockade of any conversion in the pathway potentially leads to decreased estrogen production, but more specific suppression will result from inhibition of the final step that is unique to estrogen biosynthesis. This reaction that changes androgens into estrogens is complex [12]. Three generations of AIs have been developed [13]. Each successive generation has been associated with higher specificity for the aromatase enzyme, fewer adverse events, and greater suppression of aromatase activity. The utility of first and second-generation AIs was limited by adverse events, such as rash, fatigue, dizziness, ataxia, nausea and vomiting, as well as by a lack of enzyme selectivity, whereas third-generation AIs are superior to earlier versions because they are associated with fewer adverse events and greater suppression of aromatase activity [14]. Third-generation aromatase inhibitors are currently recommended for adjuvant endocrine treatment as primary, sequential or extended therapy with tamoxifen, for postmenopausal women diagnosed with estrogen receptor positive breast cancer [15-17]. Arimidex (anastrozole), chemically known as 2,2’-(5-((1H-1, 2,4-triazol-1-yl)methyl)-1,3phenylene)bis(2-methylpropanenitrile), is the first-line endocrine therapy for postmenopausal HR-positive breast cancer patients. Anastrozole has been shown to significantly reduce the rates of breast cancer recurrences. This trial led to the approval of anastrozole by the US Food and Drug Administration for adjuvant treatment of HRpositive early stage breast cancer [18].