الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer (BC) remains the most common malignancy in women worldwide and is the leading cause of female cancer-related mortality. This warrants early diagnosis and the improvement of specific subtype treatments, thus leading to significant improvements of the 5-year survival rates. However metastatic breast cancer (MBC) still remains incurable and accounts for the majority of BC mortality globally.
BC is a very complex heterogenous disease from the biological and clinical stand points. Its behavior differs from one woman to the other (inter-tumor heterogeneity) and even within each individual tumor in the same woman (intra-tumor heterogeneity). Solving the mystery of heterogeneity is the key to manage BC successfully with totally different outcome and longer progression free survival.
About 70% of breast cancer patients express ER alpha (ERα) and are considered estrogen dependent. Thus, endocrinal therapy which specifically targets the ER pathway to suppress the tumor growth, is the cornerstone treatment in the management of BC patients even in the metastatic setting. selective estrogen receptor modulators (SERMs) and Aromatase Inhibitors (AIs) are the most effectively used endocrine treatment for ER positive patients worldwide. They block the estrogen receptor (ER) either by competitively displacing the estrogen off the ER in the nucleus and binding itself to the receptor instead or by divesting the tumor of estrogen.
Unfortunately, the efficacy of endocrine therapy is limited by the development of endocrine resistance which is inevitable in the majority of patients and considered to be a major challenge in BC management in both the adjuvant and metastatic settings. Nearly half of ER+ BC patients develop acquired endocrinal resistance and relapse while on adjuvant hormonal therapy, and in metastatic setting it is a universal feature. This warrants the need for investigating markers that reflect hormonal resistance mechanisms, such as epigenetic aberrations, to help predict the outcome of the disease.
Recent studies now elicit the crucial role of epigenetic alterations, most commonly in the DNA methylation, in carcinogenesis as tumor suppressor genes (TSGs) can be silenced through aberrant DNA methylation of their promoter regions, mainly at CpG islands, leading loss of function and initiation and progression of cancer.
An epigenetic marker like the ESR1 promoter methylation which may potentially affect the response to endocrine treatment, might eventually be a one promising tool that help clinicians make the right treatment decisions allowing a tailored personalized regimen matching each tumor behavior.
Our present study aimed at evaluating the methylation status of ESR1 gene promotor in ER+ primary breast cancer and its corresponding metastases, in order to correlate the methylation status with the development of resistance to endocrine therapy and clinical outcome in ER+ BC.
To achieve this aim, 50 subjects were enrolled in this study recruited from the Clinical Oncology and Nuclear Medicine Department at Alexandria Main University Hospital and Medical Research Institute. They were 50 patients with recurrent and/or metastatic breast cancer, who were also known to have primary ER positive tumors, treated with hormonal therapy after primary resection surgery and their tissue specimens (primary and secondary) were available at the time of collection at the pathology department