**3. Challenges in breast cancer diagnosis and treatment**

In the Middle East, 25% of all reported cases of female cancer in 2012, were breast cancers. It has been projected that by 2020 about 2 million women will be diagnosed with breast cancer worldwide, a disturb increase of approximately 18.4% [3, 10]. Moreover, about 30% of Middle Eastern patients with newly diagnosed early stage breast cancer will go on to develop metastasis despite extensive therapy [6].

To prevent an advanced stage breast cancer diagnosis, women undergo periodic screening including self-breast examination and yearly mammograms beginning at the age of 40. More frequent monitoring is recommended for women at a high risk of contracting the disease, including those with a family history of it or genetic predisposition [11]. An epidemiological survey concluded in January 2017 reported that female breast cancer is the most frequently diagnosed cancer worldwide [12]. Though the gold standard for detecting breast cancer is mammography, it can cause significant discomfort, and it is not consistently reliable for the detection of smaller tumors at an early stage [3, 13].

#### **3.1. Classification of breast cancer-**

Breast cancer has been traditionally classified in the clinic as either non-invasive or invasive, according to grade and stage. The classification system is based on the histological features of breast samples as well as the location of abnormal tissues. The two main forms of non-invasive breast cancer are ductal carcinoma *in situ* (DCIS) and lobular carcinoma *in situ* (LCIS). Noninvasive forms remain localized to the breast and do not migrate to nearby tissues and organs. However, most breast cancer are invasive and have been classified as infiltrating ductal carcinoma, tubular carcinoma, invasive lobular carcinoma, medullary carcinoma, inflammatory carcinoma and colloid carcinoma. Breast cancer is considered metastatic if it spreads to the other regions of the body through the blood or lymphatic systems.

Breast cancers are currently classified according to four molecular subtypes: luminal A, luminal B, HER-2 enriched and basal-like cancer. This classificationis based on the expression level of the progesterone receptor (PR), estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2). Seventy percent of breast cancers are responsive to hormone receptors and present an overexpression (abundance) of either PR or ER receptors or a combination of the two. Luminal A type cancers are known to overexpress the hormonal receptor (ER+ve and/or PR+ve and HER2−ve), while luminal B type cancers overexpress all 3 receptors (ER+ve/and/or PR+ve and HER+ve). Luminal A and B cancers are characterized by significant gene expression in the luminal epithelial layers of the mammary glands. However, breast cancers that have been shown to have an abundance exclusively of HER2 are referred to as HER2 enriched and account for about 20% of all cases. Basal-like breast cancers have distinct gene signatures. They are mainly triple negative breast cancer (TNBC), which means that the tumors do not express any hormone receptors. TNBCs are held to account for approximately 10% of all cancers of the breast that are known to have a high mortality rate. mRNA profiling has revealed that to date there are ≥6 identified molecular subtypes of triple negative breast cancer. Variable MiR expression levels are observed in each type. These breast cancer classifications include the immunomodulatory (IM) subtype, luminal androgen receptor (LAR), basal-like (BL1 and BL2), mesenchymal stem cell-like (MSL) and mesenchymal (M) [14].
