**3. Classification of breast cancer**

### **3.1. Histopathological classification**

Breast cancer can be broadly classified based on the location and aggressiveness of the disease. Two main classes of breast cancer are in situ carcinoma and invasive (infiltrating) carcinoma. Breast carcinoma in situ can be divided into two types. Ductal carcinoma in situ (DCIS) originates from the cells lining the ducts that transport milk to the nipple while lobular carcinoma in situ (LCIS) occurs in the cells of lobules, the milk-producing glands at the end of breast ducts [3, 7]. Both DCIS and LCIS are premalignant lesions that do not invade deeper or spread through the body. Women with these lesions have higher likelihood of getting cured but also have increased risk of developing invasive breast cancer in the future. DCIS is significantly more common accounting for 80–90%, while LCIS accounts for 10–20% of breast cancer cases [3]. DCIS has been traditionally sub-classified to five well-recognized subtypes as Solid, Papillary, Micropapillary, Cribriform and Comedo based on the architectural features of the tumor [8]. Invasive carcinomas, similar to in situ carcinomas are differentiated into histological subtypes. These subtypes include infiltrating ductal (IDC), invasive lobular (ILC), mucinous (colloid), medullary, tubular and papillary carcinomas (**Figure 1**) [7]. IDC is considered as the most common histological subtype of breast cancer, and it accounts for 70–80% of all invasive lesions [9], while ILC is the second most prevalent and accounts for roughly 10% of all breast cancers. These subtypes differ from each other based on clinicopathologic aspects, natural history, epidemiology and

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Breast cancer is a heterogeneous disease with diverse histological and molecular variations determining the biological behavior and therapeutic response. The occurrence as well as death due to breast cancer is on the rise globally despite advances in the development of diagnostic techniques and medications. There are many factors including age, family history, receptor status and others that have been investigated to assess patients' risk and treatment selection. It has been proven that receptor status is the most valuable in determining prognosis and responsiveness to therapy [11, 12]. Based on the receptor status, breast cancers are divided into three main groups. The first group includes estrogen receptor (ER) or progesterone receptor (PR) positive, while the second group comprises tumors that tested positive for human epidermal growth factor receptor 2 (HER2) with or without ER and PR positivity. Finally, triple-negative breast cancer (TNBC) is defined by the absence of ER/ PR expression and HER2 amplification [11]. Targeted therapy is available for breast cancer patients that express ER, PR or HER2 receptors; however, no standard treatment options are in practice for TNBC patients. Traditional chemotherapeutic regimens are utilized for this

A number of techniques including immunohistochemistry (IHC), DNA microarray technology, fluorescent in situ hybridization (FISH) are utilized to reveal molecular differences within the same or different histopathological specimens [14–16]. Using IHC and DNA microarrays lead to the identification of five discrete subtypes of breast cancer. These subtypes

), luminal B (ER<sup>+</sup>

/PR−

/HER2−

and/or PR <sup>+</sup>

and 17<sup>+</sup>

using IHC range between 0 and 1 or by

) and normal breast-like. These different breast cancer

/6<sup>+</sup>

, cytokeratin 5<sup>+</sup>

and HER2+

/6<sup>+</sup>

[17, 18].On the other

), HER2

and/or epi-

and HER2<sup>−</sup>

, PR−

receptors by specific inhibitors may lead to the inhibition of tumor growth [20].

), basal-like (ER−

subtypes are diverse in prognosis and therapeutic management [11]. Microarray classification of breast cancer is represented in **Table 2**. This classification is based on two types of epithelial cells including luminal and basal cells (and/or myoepithelial) in human mammary gland. These cells can be identified using IHC technique as luminal cells express ER and PR

, whereas basal cells are keratins 5<sup>+</sup>

and HER2<sup>−</sup>

Various receptors including estrogen receptor (ER) and other growth factor receptor signaling pathways play an important role in breast cancer initiation and progression. Targeting these

molecular alterations [10].

**3.2. Molecular classification**

type of patients [13].

include luminal A (ER<sup>+</sup>

receptors and keratins 8<sup>+</sup>

overexpressing (ER−

and/or PR<sup>+</sup>

, HER2<sup>+</sup>

and PR<sup>−</sup>

/18<sup>+</sup>

dermal growth factor receptor (EGFR)<sup>+</sup>

hand, TNBC can be identified by ER−

FISH negative if 2+ on IHC [15].

**Figure 1.** Histological classification of breast cancer subtypes. Modified from Malhotra et al., 2010 [7].

ductal (IDC), invasive lobular (ILC), mucinous (colloid), medullary, tubular and papillary carcinomas (**Figure 1**) [7]. IDC is considered as the most common histological subtype of breast cancer, and it accounts for 70–80% of all invasive lesions [9], while ILC is the second most prevalent and accounts for roughly 10% of all breast cancers. These subtypes differ from each other based on clinicopathologic aspects, natural history, epidemiology and molecular alterations [10].
