**2. Risk factors of breast cancer**

Every woman is at risk for developing breast cancer. Several relatively strong risk factors for breast cancer that affect large proportion of the general population have been known for some time. However, the vast majority of breast cancer cases occur in women who have no identifiable risk factors other than their gender and age (Kelsey & Gammon, 1990). The other established risk factors are previous family history, age at first full-term pregnancy, early menarche, late menopause, genetic and breast tissue density. These factors are not easily modifiable and classified under unmodified factors. However, other factors associated with

Breast Cancer: Classification Based on Molecular Etiology Influencing Prognosis and Prediction 71

can begin in the connective tissue that's made up of muscles, fat and blood vessels. Cancer that begins in the connective tissue is called sarcoma. It accounts for less than 5% of all soft tissue sarcomas and less than 1% of breast cancer (Moore and Kinne, 1996). Phyllodes tumor and angiosarcoma are two common forms of sarcoma. Cancers are also classified as non invasive (in situ) and invasive (infiltrating). The term in situ means "in its original place" and refers to cancer that has not spread past the area where it initially developed. Invasive breast cancer has a tendency to spread (invade) to other tissues of the breast and/or other regions of the body. A less common type of breast cancer is inflammatory breast cancer characterized by general inflammation (red and swollen) of the breast (Fig. 3). The different types of invasive cancers, their frequency and percentage survival is shown in Table 1.2.

Age (65+ vs. <65 years, although risk increases across all ages until

Certain inherited genetic mutations for breast cancer (BRCA1

Two or more first-degree relatives with breast cancer diagnosed at

**Relative Risk Factor** 

Female

age 80)

and/or BRCA2)

Personal history of breast cancer

High-dose radiation to chest

Early menarche (<12 years) Late menopause (>55 years) No full-term pregnancies

Recent oral contraceptive use Recent and long-term use of HRT Obesity (postmenopausal)

No breast feeding

Alcohol consumption

Table 1. Factors that increase the Relative Risk for Breast Cancer.

High socioeconomic status

Height (tall)

Hulka BS, and Moorman PG 2001. Maturitas 2008; 38:103-113

High breast tissue density or 75% dense

Biopsy-confirmed atypical hyperplasia One first-degree relative with breast cancer

High bone density (postmenopausal)

Late age at first full-term pregnancy (>30 years)

Personal history of endometrial or ovarian cancer

Invasive ductal carcinoma is the most common breast cancer and it accounts more than 75% of breast cancer cases. Most are invasive ductal carcinoma (IDC) not otherwise specified (IDC NOS), and remaining IDC includes Inflammatory breast cancer, medullary carcinoma, metaplastic, apocrine and tubular carcinoma. Medullary carcinoma accounts <5% of breast cancers diagnosed, and takes its name from its color, which is close to the color of brain

an early age

**>4.0**

**2.1-4.0**

**1.1-2.0** Factors that affect circulating hormones

> 1.1 -2.0 Other factors

© 2001 Elsevier Science Ireland Ltd.

increased breast cancer risk are postmenopausal obesity, hormone replacement therapy (HRT), alcohol consumption, and physical inactivity, no breast feeding are modifiable and classified under modified factors. The relative risk of various factors responsible for breast cancer are shown in Table 1 (Hulka & Moorman, 2001).

Fig. 1. Demographic profiles of cancer cases in Indian females. Based on 2004-2005 data for Bangalore, Barshi, Bhopal, Chennai, Delhi, Mumbai, Ahmedabad and 2005 data for Kolkata.

#### **3. Classification of breast cancer**

#### **3.1.1 Histopathological classification**

Each breast has 15 to 25 sections called lobes, formed by groups of lobules, the milk glands. Each lobule is composed of grape-like clusters of acini (also called alveoli), the hollow sacs that make and hold breast milk. The lobes and lobules are connected by thin tubes, called ducts that deliver milk to nipple (Fig. 2). The pink or the brown pigmented region surrounding the nipple is called areola. Connective and fatty tissue fills the remaining space in between the lobes and ducts. The most common type of breast cancer is ductal cancer. It is found in the cells of the ducts. Cancer that starts in lobes or lobules is called lobular cancer. It is more often found in both breasts than other types of breast cancer. Rarely breast cancer

Fig. 2. Anatomy of female breast.

increased breast cancer risk are postmenopausal obesity, hormone replacement therapy (HRT), alcohol consumption, and physical inactivity, no breast feeding are modifiable and classified under modified factors. The relative risk of various factors responsible for breast

Fig. 1. Demographic profiles of cancer cases in Indian females. Based on 2004-2005 data for Bangalore, Barshi, Bhopal, Chennai, Delhi, Mumbai, Ahmedabad and 2005 data for Kolkata.

Each breast has 15 to 25 sections called lobes, formed by groups of lobules, the milk glands. Each lobule is composed of grape-like clusters of acini (also called alveoli), the hollow sacs that make and hold breast milk. The lobes and lobules are connected by thin tubes, called ducts that deliver milk to nipple (Fig. 2). The pink or the brown pigmented region surrounding the nipple is called areola. Connective and fatty tissue fills the remaining space in between the lobes and ducts. The most common type of breast cancer is ductal cancer. It is found in the cells of the ducts. Cancer that starts in lobes or lobules is called lobular cancer. It is more often found in both breasts than other types of breast cancer. Rarely breast cancer

cancer are shown in Table 1 (Hulka & Moorman, 2001).

**3. Classification of breast cancer 3.1.1 Histopathological classification** 

Fig. 2. Anatomy of female breast.

can begin in the connective tissue that's made up of muscles, fat and blood vessels. Cancer that begins in the connective tissue is called sarcoma. It accounts for less than 5% of all soft tissue sarcomas and less than 1% of breast cancer (Moore and Kinne, 1996). Phyllodes tumor and angiosarcoma are two common forms of sarcoma. Cancers are also classified as non invasive (in situ) and invasive (infiltrating). The term in situ means "in its original place" and refers to cancer that has not spread past the area where it initially developed. Invasive breast cancer has a tendency to spread (invade) to other tissues of the breast and/or other regions of the body. A less common type of breast cancer is inflammatory breast cancer characterized by general inflammation (red and swollen) of the breast (Fig. 3). The different types of invasive cancers, their frequency and percentage survival is shown in Table 1.2.


Hulka BS, and Moorman PG 2001. Maturitas 2008; 38:103-113 © 2001 Elsevier Science Ireland Ltd.

Table 1. Factors that increase the Relative Risk for Breast Cancer.

Invasive ductal carcinoma is the most common breast cancer and it accounts more than 75% of breast cancer cases. Most are invasive ductal carcinoma (IDC) not otherwise specified (IDC NOS), and remaining IDC includes Inflammatory breast cancer, medullary carcinoma, metaplastic, apocrine and tubular carcinoma. Medullary carcinoma accounts <5% of breast cancers diagnosed, and takes its name from its color, which is close to the color of brain

Breast Cancer: Classification Based on Molecular Etiology Influencing Prognosis and Prediction 73

**breast carcinoma Frequency (%) 10-year OS (%)** 

Apocrine carcinoma 1–4 Like IDC NOS

Table 2. Frequency and outcome of histological types of invasive breast cancer.

Breast cancer is a clinically heterogeneous disease. Histologically similar tumors may have different prognosis and may respond to therapy differently. It is believed that these differences in clinical behavior are due to molecular differences between histologically similar tumors. DNA microarray technology, Immuno-histochemistry (IHC), Fluorescent in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR) are ideally suitable techniques to reveal molecular differences among the same or different groups of histopathological specimens. Each of these molecular techniques has the potential for proper prognosis and prediction of human cancers, including breast. IHC was developed more than 30 years back and it is used for classification of breast cancer into ER positive and ER negative tumors. FISH was developed 20 years back and is used to classify breast tumors into *HER-2* amplified or non amplified categories. Breast cancer cells generally overexpress estrogen receptor (ER)/ progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) receptor for breast tumor formation and progression. Thus, breast cancer can be classified into three sub-groups (i) ER/PR positive (ii) ER negative or HER-2 positive and triple negative (ER, PR and HER-2 negative) on the basis of receptor status. The classification of breast cancer on the basis of ER status improves the prognosis and clinical outcome of ER+ tumors as ER+ cancer cells depend on estrogen for their growth, and the treatment of patients with anti-estrogen agents (e.g. tamoxifen) will inhibit the effect of estrogen and thus improves the treatment outcome. Generally, HER-2+ had a worse prognosis, however HER-2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab, (in combination with conventional chemotherapy) and this has improved the prognosis and pathological complete response significantly (Chang et al., 2010). Triple-negative breast cancer is a high risk breast cancer that lacks the benefit of specific therapy that targets these proteins. It can be categorized in basal subtypes (Rakha et al., 2007). It is found in 10-20% of breast cancer cases and mostly diagnosed in younger women with BRCA1 and BRCA2 mutations (Dent et al., 2007; Dawood et al., 2009). The rate of recurrence is very high, and it reaches its peak within first 3 years and then declines after that. Patients with triple negative breast cancer are most likely to die within 5 years than

specified (IDC NOS) 50-60 35-50 Inflammatory carcinoma 1-6 30-40

Medullary carcinoma 5–7 50–90 Metaplastic carcinoma *<*5 Unknown Micropapillary carcinoma 1-2 Unknown Tubular carcinoma 1–2 90–100 Invasive lobular carcinoma 5–15 35–50 Adenoid cystic carcinoma 0.1 85–100 Mucinous carcinoma <3 85–95 Neuroendocrine carcinoma 2–5 Unknown Mammary Paget disease 1-4 40-50

**Histopathological type of invasive** 

**3.1.2 Molecular classification** 

Invasive ductal carcinoma not otherwise

tissue, or medulla. It is an invasive breast cancer that forms a distinct boundary between tumor tissue and normal tissue. Metaplastic breast cancer is a form of invasive ductal cancer, meaning that it forms in the milk ducts and then moves into other tissues of the breast. Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less than 1% of all invasive mammary carcinomas (Reis-Filho et al., 2005), such as squamous (skin) or osseous (bone) cells. The other groups of invasive breast cancers are invasive lobular carcinoma, adenoid cystic carcinoma, micropapillary carcinoma, mucinous carcinoma (formed by the mucus-producing cancer cells), etc as shown in Fig. 3.

Fig. 3. Histology of breast carcinoma. Breast carcinoma is classified into Ductal (A), Lobular carcinoma (B) and Inflammatory carcinoma. (C). It can be further classified into noninvasive (A-B) and invasive carcinoma (C-L). Invasive cancer includes Inflammatory (C), Invasive lobular (D), tubular (E) apocrine (F), medullary, (G) metaplastic (H), micropapillary, (I) adenoid cystic (J), mucunous carcinoma (K), and paget disease (L).


Table 2. Frequency and outcome of histological types of invasive breast cancer.
