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Principles and Practice of

Cancer Prevention and Control
Edited by
Redhwan Ahmed Al-Naggar
Ibrahim Hashim
OMICD Group eBooks
001
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Principles and Practice of Cancer Prevention

and Control
Chapter: Breast Cancer
Edited by: Redhwan Ahmed Al-Naggar
Published Date: June 2014
Published by OMICS Group eBooks
731 Gull Ave, Foster City. CA 94404, USA
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Breast Cancer
Ahmed M ElSharkawy*
*Biochemistry department, Faculty of Science, Alexandria University, Alexandria,
Egypt
*Corresponding author: Ahmed M ElSharkawy, Biochemistry department,
Faculty of Science, Alexandria University, Alexandria, Egypt, Tel: +201000512872;
E-mail: [email protected]
Introduction
Cancer is a group of diseases causing cells in the body to change and proliferate beyond
of control. Most types of cancer cells eventually form a lump or mass called a tumor, and are
named after the part of the body where the tumor originates. Breast cancer begins in the breast
tissue, which contains glands for milk production, called lobules, and the ducts that connect
the lobules to the nipple. The remainder of the breast is made up of fatty, connective, and
lymphatic tissues. Breast cancer typically is detected either during a screening examination,
before symptoms have developed, or after symptoms have developed, when a woman feels
a lump. Most masses seen on a mammogram and most breast lumps turn out to be benign
which are non-cancerous lumps that do not grow uncontrollably, do not spread, and are
not life-threatening. If cancer is suspected after a clinical breast exam or breast imaging, a
microscopic analysis of breast tissue is necessary. This will provide a definitive diagnosis, help
determine the spread (in situ or invasive) and to characterize the pattern of the disease. The
tissue for microscopic analysis can be obtained via a needle or surgical biopsy. Selection of the
type of biopsy is based on individual patient clinical factors, availability of particular biopsy
devices, and resources.
Breast Structure
The breast lies between the second and sixth ribs, from the sternal edge to the edge of the
axilla, and against the pectoralis muscle on the chest wall. Breast tissue also projects into the
axilla as the tail of Spence. For clinical purposes, the breast is divided into four quadrants:
upper inner, upper outer, lower inner and lower outer quadrants. Cancer occurs most often in
the upper outer quadrant.
The breast is composed of 15-20 lobes that radiate from the nipple. Each lobe is surrounded
by fat and fibrous connective tissue and is divided into many lobules. The lobule (sometimes
called the ductal-lobular unit) is the basic structural unit of the breast and is lined by epithelial
cells. Each lobule is subdivided into 10 to 100 alveoli, the milk producing units of the breast.
Milk flows from the alveoli of the lobules into the ducts. The ducts gradually coalesce into 10
to 15 major ducts; each lobe containing one major duct terminating in the nipple.
The most common type of breast cancer is a carcinoma that originates in epithelial cells.
About 85% of breast carcinomas originate within the cells of the ducts (ductal carcinoma); the
Principles and Practice of Cancer Prevention and Control 1

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remaining 15% begin in the cells that line the lobules (lobular carcinoma). Non-carcinomatous
breast cancers are rare and originate in the connective tissues of the breast (Figure 1).
Breasts also contain blood and lymphatic vessels. Most lymphatic vessels within the
breast lead to axillary lymph nodes. Some also connect to supra- or infraclavicular nodes,
and internal mammary nodes. Cancer cells may enter lymphatic vessels and spread to lymph
nodes. Cancer cells may also enter blood vessels and spread to other parts of the body.
Beneath the tissues of the breast lie the muscles of the chest wall and between the two is the
fascia (a layer of connective tissue). Two layers of suspensory ligaments (Cooper’s ligaments)
link the breast to the fascia, providing support. As these ligaments stretch with age or weight
gain, the breast loses some of its firmness.
Figure 1: The Breast: cross-section scheme of the mammary gland.
1. Chest wall 2. Pectoralis muscles 3. Lobules 4. Nipple 5. Areola 6. Milk duct 7. Fatty
tissue 8. Skin
Breast development
Breast tissue begins to develop around the sixth week in utero with the formation of the
mammary ridge. Also called the mammary fold or milk line, this thickening of the skin extends
from just below the axilla to the inguinal region (groin area). It then recedes before birth,
leaving two primary breast buds on the upper half of the chest. In newborns, the nipples and
beginnings of the milk duct system are present. This rudimentary system remains essentially
at rest until puberty. For females, usually around the ages of 10 or 11, the release of ovary
producing hormones (estrogen and progesterone) stimulates further development of the ducts
and lobules. At the same time, increases in adipose tissue (fatty tissue) and fibrous connective
tissue cause the breasts to enlarge. By adulthood, all glandular elements are fully formed
and breast development is complete. At menopause, the lobules recede, leaving mostly ducts,
adipose and fibrous tissue. Histologically, postmenopausal and prepubertal breasts are very
similar.
Throughout a woman’s life, breast tissue remains sensitive to hormonal changes.

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Throughout a woman’s life, breast tissue remains sensitive to hormonal changes, including
those that occur during menstruation, pregnancy and lactation. During each menstrual
cycle, levels of estrogen and progesterone rise, causing ducts and milk glands to enlarge. In
pregnancy, rising hormonal levels cause further branching and differentiation of the ducts and
lobules, accompanied by an increase in adipose tissue and richer blood flow. With lactation,
lobules become dilated and engorged with colostrum and milk. Lactation also increases the
possibility of abnormal nipple discharge, infection and inflammation, although non lactating
women may also experience these types of benign breast changes.
General Types of Breast Cancer

Ductal Carcinoma In Situ (DCIS)
DCIS is a spectrum of abnormal breast changes that start in the cells lining the breast
ducts. DCIS is considered a noninvasive form of breast cancer because the abnormal cells
have not grown beyond the layer of cells where they originated. It is the most common type
of in situ breast cancer, accounting for about 83% of in situ cases diagnosed during 2006-
2010. DCIS may or may not progress to invasive cancer; in fact, some of these tumors grow so
slowly that even without treatment they would not affect a woman’s health. Studies suggest
that about one-third, and possibly more, of DCIS cases will progress to invasive cancer if left
untreated [1]. Identifying subtypes of DCIS that are most likely to recur or progress to invasive
cancer is an active area of research [2].
Lobular Carcinoma In Situ (LCIS, also known as lobular neoplasia)
LCIS is not a true cancer or precancer, but an indicator of increased risk for developing
invasive cancer. LCIS is much less common than DCIS, accounting for about 12% of female in
situ breast cancers diagnosed during 2006-2010.
Other in situ breast cancers have characteristics of both ductal and lobular carcinomas or
have unknown origins.
Most breast cancers are invasive, or infiltrating. These cancers have broken through the
ductal or glandular walls where they originated and grown into surrounding breast tissue. The
prognosis of invasive breast cancer is strongly influenced by the stage of the disease – that is,
the extent or spread of the cancer when it is first diagnosed.
TNM Classification of Breast Cancer

There are two main staging systems for cancer. The TNM classification of tumors uses
information on tumor size and how far it has spread within the breast (T), the extent of spread
to the nearby lymph nodes (N), and the presence or absence of distant metastases (spread
to distant organs) (M)[3]. Once the T, N, and M are determined, a stage of 0, I, II, III, or IV
is assigned, with stage 0 being in situ, stage I being early stage invasive cancer, and stage
IV being the most advanced disease. The TNM staging system is commonly used in clinical
settings. The Surveillance, Epidemiology, and End Results (SEER) Summary Stage system is
more simplified and is commonly used in reporting cancer registry data and for public health
research and planning [4].
According to this system:

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1- Local stage refers to cancers that are confined to the breast (corresponding to stage I and
some stage II cancers in the TNM staging system).
2- Regional stage refers to tumors that have spread to surrounding tissue or nearby lymph
nodes (generally corresponding to stage II or III cancers, depending on size and lymph node
involvement).
3- Distant stage refers to cancers that have metastasized (spread) to distant organs or
lymph nodes above the collar bone (corresponding to stages IIIc and IV).
Molecular Subtypes of Breast Cancer

Breast cancer is increasingly considered to be not one disease, but a group of diseases
distinguished by different molecular subtypes, risk factors, clinical behaviors, and responses
to treatment. Distinct molecular subtypes of breast cancer have been identified using
gene expression profiles, a process that is both complex and costly [5]. More convenient
approximations of molecular subtypes have been identified using biological markers, including
the presence or absence of Estrogen Receptors (ER+/ER-), Progesterone Receptors (PR+/PR-
), and Human Epidermal growth factor Receptor 2 (HER2+/HER2-). 6 Molecular subtypes
are increasingly being used for research purposes; however, questions remain about their
usefulness to further tailor breast cancer treatments and predict breast cancer prognosis [6,7].
a. Luminal A: About 40% of breast cancers are luminal A, making it the most common
breast cancer subtype [8]. These tumors tend to be ER+ and/or PR+ and HER2-, slow-growing,
and less aggressive than other subtypes. Luminal A tumors are associated with the most
favorable short-term prognosis, in part because expression of hormone receptors is predictive
of a favorable response to hormonal; however, long-term survival is similar to or even lower
than some other subtypes [9].
b. Luminal B: About 10% to 20% of breast cancers are luminal B [8,10]. Like luminal
A tumors, most luminal B tumors are ER+ and/or PR+, but they are distinguished by either
expression of HER2 or high proliferation rates (high numbers of cancer cells actively dividing)
[11].
c. Basal-like: About 10% to 20% of breast cancers are basal-like, and the majority of
basal-like breast cancers are referred to as “triple negative” because they are ER-, PR-, and
HER2-[10,12]. Basal-like tumors are more common in African American women, premenopausal
women, and those with a BRCA1 gene mutation [8]. Women diagnosed with basal-like breast
cancer have a poorer short-term prognosis than those diagnosed with other breast cancer
types because there are no targeted therapies for these tumors.
d. HER2 enriched: About 10% of breast cancers produce excess HER2 (a growth-
promoting protein) and do not express hormone receptors (ER- and PR-). 8 Similar to the
basal-like subtype, these cancers tend to grow and spread more aggressively than other breast
cancers and are associated with poorer short-term prognosis compared to ER+ breast cancers
[9]. However, the use of targeted therapies for HER2+ cancers has reversed much of the adverse
prognostic impact of HER2 overexpression.
Signs and Symptoms

The first noticeable symptom of breast cancer is typically a lump that feels different from
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the rest of the breast tissue. More than 80% of breast cancer cases are discovered when the
woman feels a lump [13]. The earliest breast cancers can be detected by a mammogram [14].
Lumps found in lymph nodes located in the armpits [13] can also indicate breast cancer.
Other signs of breast cancer other than a lump may include thickening of breast tissue, one
breast becoming larger or lower, a nipple changing position or shape or becoming inverted,
skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant
pain in part of the breast or armpit, and swelling beneath the armpit or around the collarbone
[15]. Pain (“mastodynia”) is an unreliable tool in determining the presence or absence of
breast cancer, but may be indicative of other breast health issues [13,14]. Inflammatory
breast cancer is a particular type of breast cancer which can pose a substantial diagnostic
challenge. Symptoms may resemble a breast inflammation and may include itching, pain,
swelling, nipple inversion, warmth and redness throughout the breast, as well as an orange-
peel texture to the skin referred to as peau d’orange [13] as inflammatory breast cancer
doesn’t show as a lump there is sometimes a delay in diagnosis. Another reported symptom
complication of breast cancer is Paget’s disease of the breast. This syndrome presents as skin
changes resembling eczema, such as redness, discoloration, or mild flaking of the nipple skin.
As Paget’s disease of the breast advances, symptoms may include tingling, itching, increased
sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately
half of women diagnosed with Paget’s disease of the breast also have a lump in the breast.
In rare cases, what initially appears as a fibroadenoma (hard, movable non-cancerous lump)
could in fact be a phyllodes tumor. Phyllodes tumors are formed within the stroma (connective
tissue) of the breast and contain glandular as well as stromal tissue. Phyllodes tumors are
not staged in the usual sense; they are classified on the basis of their appearance under
the microscope as benign, borderline, or malignant. Occasionally, breast cancer presents as
metastatic disease - that is, cancer that has spread beyond the original organ. The symptoms
caused by metastatic breast cancer will depend on the location of metastasis. Common sites of
metastasis include bone, liver, lung and brain [16]. Unexplained weight loss can occasionally
herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can
sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological
symptoms. These symptoms are called non-specific, meaning they could be manifestations
of many other illnesses. Most symptoms of breast disorders, including most lumps, do not
turn out to represent underlying breast cancer. Fewer than 20% of lumps, for example, are
cancerous, [17] and benign breast diseases such as mastitis and fibroadenoma of the breast
are more common causes of breast disorder symptoms. Nevertheless, the appearance of a
new symptom should be taken seriously by both patients and their doctors, because of the
possibility of an underlying breast cancer at almost any age [13].
Risk Factors
Many of the known breast cancer risk factors such as sex, age, family history, early
menarche, and late menopause, are not modifiable, that is they cannot be changed. However,
other factors associated with increased breast cancer risk, including postmenopausal obesity,
use of combined estrogen and progestin menopausal hormones, cigarette smoking, and
alcohol consumption are modifiable. Many risk factors affect lifetime exposure of breast tissue
to hormones (early menarche, late menopause, obesity, and hormone use). Reproductive
hormones are thought to influence breast cancer risk by increasing cell proliferation, thereby
increasing the likelihood of DNA damage, as well as promotion of cancer growth. Many of
the known risk factors for breast cancer are specifically associated with the ER+/luminal
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A subtype; less is known about risk factors for ER- and triple negative (basal-like) breast
cancers. Strategies that may help reduce the risk of breast cancer include avoiding weight gain
and obesity, engaging in regular physical activity, and minimizing alcohol intake [18]. Women
who choose to breastfeed for an extended period of time (studies suggest a year or more) may
also reduce their breast cancer risk. Women should consider the increased risk of breast
cancer associated with the use of estrogen and progestin when evaluating treatment options
for menopausal symptoms. Treatment with tamoxifen or raloxifene can also reduce the risk of
breast cancer among women at high risk. Breast cancer risk factors, along with factors that
may decrease the risk of breast cancer, are discussed below.
Personal and family history
Family history of breast cancer: Women (as well as men) with a family history of breast
cancer, especially in a first-degree relative (mother, sister, daughter, father, or brother), are
at increased risk of developing breast cancer; this risk is higher if more than one first-degree
relative developed breast cancer. Compared to women without a family history, risk of breast
cancer is 1.8 times higher for women with one first-degree female relative who has been
diagnosed, nearly 3 times higher for women with two relatives, and nearly 4 times higher for
women with three or more relatives [19]. Risk is further increased when the affected relative
was diagnosed at a young age. It is important to note that the majority of women with one
or more affected first-degree relatives will never develop breast cancer and that most women
who develop breast cancer do not have a family history of the disease. A family history of
ovarian cancer is also associated with increased breast cancer risk in both men and women.
Women with a history of breast or ovarian cancer in their immediate family or in either parent’s
extended family should discuss this with their physicians because it may signal the presence
of a genetic predisposition to cancer.
Genetic predisposition: It is estimated that 5% to 10% of breast cancer cases result from
inherited mutations, including those in the breast cancer susceptibility genes BRCA1 and
BRCA2 [20]. These mutations are present in less than 1% of the general population, but occur
more often in certain ethnic groups such as those of Ashkenazi (Eastern European) Jewish
descent [20]. The estimates of the risk of breast cancer in women with these mutations vary;
by age 70, between 44% and 78% of women with BRCA1 mutations and between 31% and 56%
of women with BRCA2 mutations will develop breast cancer [21,22].
Only about 15%-20% of familial breast cancers are attributed to BRCA1 or BRCA2 gene
mutations [23]. Other inherited conditions associated with smaller increased breast cancer
risk include Li-Fraumeni and Cowden syndromes and a number of more common genetic
mutations [23]. These mutations can be inherited from either parent and by sons as well
as daughters. In addition, low-risk variations in the genetic code may affect breast cancer
risk. Scientists believe that much of the occurrence of breast cancer in families results from
the interaction between lifestyle factors and these low-risk variations that may be shared
within a family [24]. Molecular tests are commercially available to identify some of the BRCA
mutations, as well as many of the family cancer syndromes responsible for inherited forms
of breast cancer; however, the interpretation of these tests and treatment decisions remains
complicated [25]. It is not yet possible to predict if or when women who carry a particular
genetic abnormality will develop breast cancer. Furthermore, tests are not available for all of
the genes that affect breast cancer risk.
Personal history of breast cancer: Women with a history of breast cancer are at increased

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risk for developing breast cancer more than once in their lifetime. The risk is higher if the
diagnosis was at a younger age. Women diagnosed with early onset breast cancer (age <40)
have almost a 4.5-fold increased risk of subsequent breast cancer [26]. Genetic predisposition,
such as mutations in BRCA1 and BRCA2 genes, probably contribute to some of the excess
risk of subsequent breast cancers, particularly among women diagnosed at a young age [27].
Lobular carcinoma in situ: This uncommon condition is the result of abnormal cells
forming in the lobules or milk producing glands of the breast. Although LCIS seldom becomes
invasive cancer, women with LCIS are 7 to 12 times more likely to develop invasive cancer in
either breast than women without LCIS [28]. LCIS is not usually apparent on a mammogram
and is typically discovered during a biopsy performed for another reason, such as an abnormal
mammogram. Pure LCIS should be distinguished from DCIS and pleomorphic LCIS, as both
of these conditions are considered precursor lesions for breast cancer and require cancer-
directed therapy.
Benign breast disease: Some types of benign breast conditions are linked to breast cancer
risk. Doctors often categorize these conditions into 3 general groups, reflecting the degree of
risk: non-proliferative lesions, proliferative lesions without atypia (abnormal cells or patterns
of cells), and proliferative lesions with atypia. Non-proliferative lesions are not associated with
overgrowth of breast tissue and have little to no effect on breast cancer risk. Examples of non-
proliferative lesions include fibrosis (also known as fibrocystic changes), simple cysts, and
mild hyperplasia. Proliferative lesions without atypia are associated with a small increase in
the risk of breast cancer (1.5 to 2 times the risk of those who do not have one of these lesions)
and include non-atypical (or usual) ductal hyperplasia and fibroadenoma [29-32]. Proliferative
lesions with atypia are associated with the greatest breast cancer risk four to five times higher
than average risk [29,30,32]. These include Atypical Ductal Hyperplasia (ADH) and Atypical
Lobular Hyperplasia (ALH). Women should keep detailed records of any benign breast biopsy
results, as this information is valuable for risk assessment, screening, and counseling for
chemoprevention and risk-reduction strategies.
Breast density: High breast tissue density (a mammographic indicator of the amount
of breast and connective tissue relative to fatty tissue in the breast) has been shown to be a
strong, independent risk factor for the development of breast cancer [33]. A number of factors
can affect breast density, such as age, menopausal status, the use of certain drugs (such
as menopausal hormone therapy), pregnancy, and genetics. Breast density is influenced by
inherited genetic factors, but decreases with age and is further reduced by pregnancy and
menopause [34,35]. Percent breast density is generally lower among women with higher body
weight because of the higher proportion of fatty tissue [36]. Some drugs affect breast density,
including tamoxifen (decreases density) and combined menopausal hormone therapy (increases
density) [37]. The risk of breast cancer increases with increasing breast density; women with
very high breast density have a four to six fold increased risk of breast cancer compared to
women with the less dense breasts [33,38,39] In addition, mammographic detection of breast
cancer is impaired for dense breast tissue [38]. Some states have laws requiring that women be
informed if they have higher than average breast tissue density, along with the other findings
on their mammogram. In addition, some states also require that women with dense breasts
be told that they may benefit from additional screening [40]. However, at this time there is no
expert consensus about what other tests, if any, should be done in addition to mammograms
to screen for breast cancer in women with dense breasts.
Endogenous hormone levels: Postmenopausal women with high levels of endogenous
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hormones (estrogen or testosterone produced naturally in the body) have about twice the risk
of developing breast cancer compared to women with the lowest levels [41-43]. High circulating
hormone levels are associated with and may reflect the effects of other breast cancer risk factors,
such as postmenopausal obesity and alcohol use [44]. The relationship in premenopausal
women is less clear, which likely reflects the complexity of measuring hormone levels that
vary during the menstrual cycle. Nevertheless, there is growing evidence linking high levels of
testosterone to breast cancer risk in premenopausal women [45-47]. A recent study reported
that premenopausal women in the highest quintiles of total and free testosterone had an 80%
greater breast cancer risk compared to women in the lowest quintiles [45]. Two recent reviews
concluded that high estrogen levels are also associated with a slight increase in breast cancer
risk in premenopausal women [42,48].
Menstrual cycles: Women who have had more menstrual cycles because they started
menstruating before the age of 12 and/or went through menopause after age 55 have a slightly
higher risk of developing breast cancer [49,50]. The increased risk may be due to longer lifetime
exposure to reproductive hormones.
Pregnancy and breast feeding: Younger age at first full-term pregnancy (<30 years) and a
greater number of pregnancies decrease the risk of breast cancer over the long term; however,
there appears to be a transient increase in breast cancer risk following a full-term pregnancy,
particularly among women who are older at first birth [49,51]. Pregnancy-related risk factors
seem to be more strongly related to hormone receptor- positive than hormone receptor-negative
breast cancers [52,53]. Most studies suggest that breastfeeding for a year or more slightly
reduces a woman’s overall risk of breast cancer [54]. The protective effect may be greater for
basal-like breast cancers [54]. Longer duration is associated with greater risk reduction. In a
review of 47 studies conducted in 30 countries, the risk of breast cancer was reduced by 4.3%
for every 12 months of breastfeeding [55]. One possible explanation for this effect may be that
breastfeeding inhibits menstruation, thus reducing the lifetime number of menstrual cycles.
Another possible explanation relates to structural changes that occur in the breast following
lactation and weaning.
Bone mineral density: High bone mineral density in postmenopausal women has been
associated with increased risk for breast cancer in many, but not all, studies; risk appears
to be most strongly related to ER+ disease [56-60]. Bone density is not an independent risk
factor for breast cancer, but a marker for cumulative estrogen exposure [60]. Bone density is
routinely measured to identify women at increased risk for osteoporosis (high bone density
indicates absence of osteoporosis) and may help determine a woman’s risk for developing
breast cancer.
Lifestyle-related factors
Postmenopausal hormone use: Recent use of menopausal hormones (also referred to as
hormone therapy or HT) with combined estrogen and progestin increases the risk of developing
and dying from breast cancer, with higher risk associated with longer use [61,62]. Risk is also
greater for women who start hormone therapy soon after the onset of menopause compared
to those who begin use later [63-65]. The increased risk appears to diminish within 5 years
of discontinuation of hormone use [62,63,66]. Estrogen alone can be prescribed for women
without a uterus, and it is less clear if this therapy increases risk of breast cancer. Updated
results from the Women’s Health Initiative randomized trial found that use of estrogen-only
therapy for an average of 6 years is associated with decreased risk of breast cancer [67];

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however, several other observational studies have found a slight increase in risk, particularly
among lean women and for women who began therapy soon after menopause [63,66,68].
Obesity and weight gain: Obesity increases the risk of postmenopausal breast cancer [69].
The risk of postmenopausal breast cancer is about 1.5 times higher in overweight women and
about 2 times higher in obese women than in lean women [70]. Breast cancer risk associated
with excess weight is likely due to high estrogen levels because fat tissue is the largest source
of estrogen in postmenopausal women. Obesity is also a risk factor for type II diabetes, which
some studies have linked to modestly increased risk for postmenopausal breast cancer [71].
The inconsistencies likely reflect the complex relationship between obesity and diabetes,
as well as the fact that diabetic treatments may further affect the risk of developing breast
cancer [72]. In contrast, some studies have found that obesity protects against developing
breast cancer before menopause. A large meta-analysis found that among women ages 40-49,
the risk for developing breast cancer was about 14% lower in overweight women and about
26% lower in obese women compared to women who are normal weight [73]. The underlying
mechanisms for this inverse relationship are not well understood, but the protective effect may
be limited to ER+ breast cancers [52,74,75]. Many studies have looked at whether the timing of
weight gain influences breast cancer risk. Results from a study of more than 80,000 registered
nurses found that women who gained 55 pounds or more after age 18 had almost 50% greater
risk of breast cancer and gaining 22 pounds or more after menopause was associated with an
increased risk of 18%. 102 Although some studies have found weight loss to be associated with
reduced risk, results are not consistent [76-78].
It is more difficult to examine the effect of weight loss on breast cancer because weight loss
is often not sustained.
Physical activity: Growing evidence suggests that women who get regular physical activity
have a 10%-20% lower risk of breast cancer compared to women who are inactive, with stronger
evidence for postmenopausal than premenopausal women [69,79-81]. A recent report from the
Nurses’ Health Study of more than 95,000 women found that increases in physical activity
after menopause lowered breast cancer risk by 10%. 105 The benefit may be due to the effects
of physical activity on body mass, hormones, and energy balance [82].
Diet: Although numerous studies have examined the relationship between food consumption
(including fat, soy, dairy, meat, and fruits and vegetables) and breast cancer, there is no
conclusive evidence that diet influences breast cancer risk [83,84]. A recent meta-analysis of
animal fat intake and breast cancer, which included more than 20,000 breast cancer cases,
concluded there was no association [85]. Similarly, reducing dietary fat in postmenopausal
women did not affect risk of breast cancer in the Women’s Health Initiative dietary intervention.
However, the timing of the exposure may be important, as findings from the Nurses’ Health
Study showed that a high-fat diet during adolescence was associated with a moderate increase
in premenopausal breast cancer risk [86]. It has been suggested that soy consumption may
reduce breast cancer risk, in part because of historically low breast cancer rates among Asian
women. A meta-analysis showed that soy intake was inversely associated with breast cancer
risk in Asian but not Western populations [87]. There is growing evidence that high levels of
fruit and vegetable consumption may be associated with reduced risk of hormone receptor
negative breast cancer [88-90]. The effect of diet on breast cancer risk remains an active
area of research, with studies particularly focusing on timing of exposure, specific dietary
components, and whether risks may differ by tumor hormone receptor status.

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Alcohol: Numerous studies have confirmed that alcohol consumption increases the risk
of breast cancer in women by about 7% to 12% for each 10g (roughly one drink) of alcohol
consumed per day [91-93]. The increased risk is dose-dependent and exists regardless of the
type of alcoholic beverage consumed [93]. One of the mechanisms by which alcohol increases
risk of breast cancer is by increasing estrogen and androgen levels [94]. Alcohol use has been
more strongly related with increased risk for ER+ than ER- breast cancers [95,96].
Tobacco: In 2009, the International Agency for Research on Cancer concluded that
there was limited evidence that tobacco smoking causes breast cancer in women based on
a review of 150 studies [97]. A recent meta-analysis by American Cancer Society researchers
found that current smokers had a 12% higher risk of breast cancer than women who never
smoked [98]. Research also suggests that risk may be greater for women who begin smoking
before first childbirth [99,100]. In 2006, the US Surgeon General characterized the evidence
linking secondhand smoke and breast cancer as “suggestive but not sufficient” to infer a
causal relationship [101]. However, a subsequent meta-analysis concluded that there was no
association between secondhand smoke and breast cancer, regardless of the time of onset of
exposure [102]. The results of more recent studies have also failed to show a clear relationship
between passive smoking and breast cancer risk [98,103,104]. Nevertheless, it is clear that
avoiding exposure to secondhand smoke has multiple health benefits.
Oral contraceptive use: Recent use of oral contraceptives may increase the risk of breast
cancer by about 10% to 30%; however, since most studies have looked at older, high-dose
estrogen forms of oral contraceptives, the risk with current, low-dose formulations is not clear
[105]. Women who have stopped using oral contraceptives for 10 years or more have the same
risk as women who never used the pill [105].
Other risk factors
Radiation: The link between radiation exposure and breast cancer has been demonstrated
in studies of atomic bomb survivors and women who have received high-dose radiation therapy
to the chest, particularly for those who were first exposed at younger ages [106,107]. This may
be because breast tissue is most susceptible to carcinogens before it is fully differentiated,
which occurs with first childbirth [108]. Breast cancer is one of the most common types of
second cancers to occur among childhood cancer survivors. Secondary breast cancer is most
strongly associated with high-dose radiation therapy to the chest for women treated between
10 and 30 years of age, such as for Hodgkin lymphoma [109]. Breast cancer risk among
women with such exposure start to rise about 8 years after radiation treatment and continue
to be elevated for more than 25 years [107].
Diethylstilbestrol exposure: From the 1940s through the 1960s, some pregnant women
were given the Drug Diethylstilbestrol (DES) because it was thought to lower the risk of
miscarriage. These women have increased risk (about 30% higher) of developing breast cancer
compared to women who have not taken DES [110]. Some studies have found that women
whose mothers took DES during pregnancy also have a slightly higher risk of breast cancer
[111].
Environmental pollutants: Concerns have been raised among some advocacy groups and
survivors that rising breast cancer incidence in the latter half of the 20th century may have
been caused by environmental pollutants such as organochlorine pesticides. However, studies
to date have found no association between increased concentrations of organochlorines in blood

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and fat tissue and breast cancer risk [112-115]. Although animal studies have demonstrated
that prolonged, high-dose exposure to many industrial chemicals can increase mammary
tumor development, it is difficult to determine whether exposure to much lower concentrations
of these chemicals in the general environment - which occur alone or in combination, in air,
drinking water, and consumer products - increases the risk of human breast cancer [116]. In
general, epidemiological studies have not found clear relationships between environmental
pollutants and breast cancer, though these studies have had limited capability to study effects
on population subgroups or to quantify exposures at potentially critical periods of life, such
as adolescence. An association between environmental exposures and breast cancer may be
difficult to quantify because it may reflect an indirect pathway (e.g., an effect of these exposures
on early onset puberty). This continues to be an active area of research.
Occupational exposures: A few occupations have been linked to breast cancer risk.
One study found an increased risk of breast cancer among women employed in commercial
sterilization facilities who were exposed to high levels of ethylene oxide [117]. This chemical
has been shown to cause breast cancer in experimental animals. Night shift work may also
be associated with increased breast cancer risk. Most studies of nurses who work night shifts
and flight attendants who experience circadian rhythm disruption caused by crossing multiple
time zones have found increased risks of breast cancer associated with long-term employment
[118,119]. Animal studies suggest that exposure to light at night causes circadian rhythm
disruption and increases cancer incidence. 146 Some researchers suggest that the increased
risk of breast cancer may be due to decreases in melatonin levels that occur as a result of
exposure to light at night; melatonin may affect estrogen levels, as well as act as a tumor
suppressor [120]. Based on the results of studies in humans and experimental animals, the
International Agency for Research on Cancer concluded in 2007 that shift work, particularly
at night, was probably carcinogenic to humans [121]. Additional studies are needed to confirm
this relationship because shift work at night is a common exposure, involving about 15% to
20% of workers in the US and Europe, and because much of the population in industrialized
countries is exposed to artificial light at night.
Pathophysiology and Molecular Pathways of Breast Carcinogenesis

Breast cancer, like other cancers, occurs because of an interaction between an environmental
(external) factor and a genetically susceptible host. Normal cells divide as many times as needed
and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when
they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and
to die at the proper time.
Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until
then, they are protected from cell suicide by several protein clusters and pathways (Figure
2). One of the protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK
pathway. Sometimes the genes along these protective pathways are mutated in a way that
turns them permanently “on”, rendering the cell incapable of committing suicide when it
is no longer needed. This is one of the steps that causes cancer in combination with other
mutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready
for cell suicide. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/
AKT pathway is stuck in the “on” position, and the cancer cell does not commit suicide [122].
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure
[123]. Failure of immune surveillance, the removal of malignant cells throughout one’s life by

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the immune system [124]. Abnormal growth factor signaling in the interaction between stromal
cells and epithelial cells can facilitate malignant cell growth [125,126]. In breast adipose tissue,
overexpression of leptin leads to increased cell proliferation and cancer [127]. In the United
States, 10 to 20 percent of patients with breast cancer and patients with ovarian cancer have
a first - or second-degree relative with one of these diseases. The familial tendency to develop
these cancers is called hereditary breast–ovarian cancer syndrome. The best known of these,
the BRCA mutations, confer a lifetime risk of breast cancer of between 60 and 85 percent and
a lifetime risk of ovarian cancer of between 15 and 40 percent. Some mutations associated
with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA.
These mutations are either inherited or acquired after birth. Presumably, they allow further
mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant
organs [128]. However there is strong evidence of residual risk variation that goes well beyond
hereditary BRCA gene mutations between carrier families. This is caused by unobserved risk
factors [129]. This implicates environmental and other causes as triggers for breast cancers.
The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links
and DNA double strand breaks (known functions of the encoded protein) [130,131]. These
carcinogens cause DNA damage such as DNA cross links and double strand breaks that often
require repairs by pathways containing BRCA1 and BRCA2 [132,133]. However, mutations
in BRCA genes account for only 2 to 3 percent of all breast cancers [134]. Levin et al., states
that cancer may not be inevitable for all carriers of BRCA1 and BRCA2 mutations [135]. About
half of hereditary breast-ovarian cancer syndromes involve unknown genes. GATA-3 directly
controls the expression of Estrogen Receptor (ER) and other genes associated with epithelial
differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due
to cancer cell invasion and metastasis [136].

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Figure 2: Overview of signal transduction pathways involved in apoptosis. Mutations leading to loss of
apoptosis can lead to tumorigenesis.
Breast Cancer Treatment

Treatment decisions are made by the patient and the physician after consideration of the
optimal treatment available for the stage and biological characteristics of the cancer, the
patient’s age and preferences, and the risks and benefits associated with each treatment
protocol. Most women with breast cancer will have some type of surgery. Surgery is often
combined with other treatments such as radiation therapy, chemotherapy, hormone therapy,
and/or targeted therapy.
Surgery
The primary goals of breast cancer surgery are to remove the cancer from the breast and to
determine the stage of disease. Surgical treatment for breast cancer involves Breast-Conserving
Surgery (BCS) or mastectomy. With BCS (also known as partial mastectomy, quadrantectomy,
and lumpectomy), only cancerous tissue plus a rim of normal tissue are removed. Simple or
total mastectomy includes removal of the entire breast. Modified radical mastectomy includes
removal of the entire breast and lymph nodes under the arm, but does not include removal
of the underlying chest wall muscle, as with a radical mastectomy. Radical mastectomy is
rarely used because in most cases removal of the underlying chest muscles is not needed
to remove all of the cancer. Fifty-seven percent of women diagnosed with early stage (I or
II) breast cancer have BCS, 36% have mastectomy, 6% have no surgery, and about 1% do
not receive any treatment [13] In contrast, among women with late-stage (III or IV) breast
cancer, 13% undergo BCS, 60% have mastectomy, 18% have no surgical treatment, and 7%
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do not receive any treatment [13] Depending on age at diagnosis, 20%-40% of women who
undergo mastectomy elect to have breast reconstruction, either with an implant, tissue from
another part of the body, or a combination of the two [137-142]. A woman considering breast
reconstruction should discuss this option with her breast surgeon prior to her mastectomy. The
plastic surgeon and the surgeon performing the mastectomy will work together to coordinate
treatment plans. Some types of reconstruction can begin during the mastectomy itself, so
reconstruction may influence the surgical facility (inpatient versus outpatient) and other
aspects of the mastectomy. Since 1999, the Women’s Health and Cancer Rights Act (WHCRA)
has required group health plans, insurance companies, and health maintenance organizations
that offer mastectomy coverage to also pay for reconstructive surgery after mastectomy.
Breast reconstruction is also covered by Medicare and Medicaid, though Medicaid benefits
vary by state.
Both BCS and mastectomy are usually accompanied by removal of regional lymph nodes
from the armpit to determine if the disease has spread beyond the breast. The presence of any
cancer cells in the lymph nodes will help determine the need for subsequent therapy and the
course it should take. Sentinel Lymph Node Biopsy (SLNB), in which selected lymph nodes are
removed and tested before any others are excised, reduces the need for full axillary lymph node
dissections among most women with no evidence of sentinel lymph node involvement [143].
Furthermore, findings from a recent clinical trial suggest that for some breast cancer patients
treated by lumpectomy and radiation, the axillary lymph node dissection can be avoided even
if cancer cells are found in one or two sentinel lymph nodes [144]. Prior to surgery, patients
should talk with their doctors to determine whether they intend to perform SLNB. If a woman
is eligible for SLNB and wishes to have this procedure, her breast cancer surgery should be
performed at a facility with a medical care team experienced with the technique. SLNB is
widely available in the US Surgery and radiation therapy involving the axillary lymph nodes
can lead to lymphedema, a serious swelling of the arm caused by retention of lymph fluid.
Breast cancer patients who undergo axillary lymph node dissection are about 3 times more
likely to develop lymphedema compared to those who have SLNB [145]. It has been estimated
that about 5% of patients with SLNB and 16%-18% of patients undergoing axillary lymph node
dissection following SLNB will develop clinically measurable lymphedema [146,147]. Some
evidence suggests that upper body exercises may reduce the risk and lessen the severity of
this condition [148].
Radiation therapy
Radiation therapy is the use of high-energy beams or particles to kill cancer cells. Radiation
may be used after potentially curative surgery to destroy cancer cells remaining in the breast,
chest wall, or underarm area. BCS is almost always followed by radiation therapy because it
has been shown to reduce the risk of cancer recurrence by about 50% and the risk of breast
cancer death by about 20%. 214 Although there is a higher risk of local recurrence (cancer
returning to the breast) with BCS, clinical trials with more than 20 years of follow-up data have
confirmed that a woman who chooses BCS and radiation will have the same expected long-
term survival as if she had chosen mastectomy [149-152]. Some mastectomy patients also
require radiation if their tumor is larger than 5 cm or when cancer is found in the lymph nodes.
Radiation can also be used to treat the symptoms of advanced breast cancer, especially when
it has spread to the central nervous system or bones. Radiation therapy may be administered
internally or externally. Some patients are treated with both types of radiation in combination.

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The way the radiation therapy is given depends on the type, stage, and location of the tumor,
as well as doctor and patient preference. External beam radiation is the standard type of
radiation for women with breast cancer. Radiation is focused from a machine outside the
body on the area affected by cancer. This usually includes the whole breast and, depending
on the size and extent of the cancer, may include the chest wall and underarm area as well.
External beam radiation therapy is typically administered daily over a period of five to six
weeks; however, in recent studies, shortening the treatment to three weeks (referred to as
Accelerated Breast Irradiation or ABI) appears to be just as effective [153].
Internal radiation therapy, known as brachytherapy, is a form of Accelerated Partial Breast
Irradiation (APBI) which uses a radioactive substance sealed in needles, seeds, wires, or
catheters that are placed directly into or near the cancer. The ability to target radiation therapy
accurately has increased dramatically in recent decades, which has greatly diminished side
effects and can also reduce treatment time [154]. For example, the most common form of
brachytherapy used for breast cancer, intra-cavitary brachytherapy, is given for only five
days [155,156]. However, a recent retrospective study reported that women who were treated
with brachytherapy were more likely to have certain complications and receive a subsequent
mastectomy than those treated with whole breast radiation therapy [157]. Additional follow-
up data are needed to determine the long-term efficacy and risks associated with APBI and
to identify which patients are the best candidates. Clinical trials are also investigating other
forms of APBI that are designed to give radiation to a smaller segment of the breast, also over
a period of five days [158].
Systemic therapy
Systemic therapy is treatment that travels through the bloodstream and affects all parts of
the body, not just the cancer. These cancer drugs are given intravenously or orally. Systemic
therapy includes chemotherapy, hormone therapy, and targeted therapy, all of which work
through different mechanisms. For example, chemotherapy drugs work by attacking cells
that grow quickly, such as cancer cells. Hormone therapy works by either blocking the body’s
natural hormones or lowering the levels of those hormones, which sometimes act to promote
cancer growth. Newer targeted drugs work by attacking specific parts of cancer cells. Systemic
therapy is treatment that travels through the bloodstream and affects all parts of the body,
not just the cancer.
These cancer drugs are injected into a vein or given by mouth. Systemic therapy includes
chemotherapy, hormone therapy, and targeted therapy, all of which work through different
mechanisms. For example, chemo-therapy drugs work by attacking cells that grow quickly,
such as cancer cells. Hormone therapy works by either blocking the body’s natural hormones
or lowering the levels of those hormones, which sometimes act to promote cancer growth.
Newer targeted drugs work by attacking specific parts of cancer cells.
When systemic treatment is given to patients before surgery, it is called neoadjuvant
therapy. It is often used to shrink the tumor enough to make surgical removal possible or
allow for less extensive surgery (such as BCS in women who would otherwise have required
mastectomy). Neoadjuvant systemic therapy has been found to be as effective as therapy given
after surgery to improve survival, disease progression, and limit recurrence [159]. Systemic
treatment given to patients after surgery is called adjuvant therapy. It is used to kill any
undetected tumor cells that were left behind during surgery or had migrated to other parts of
the body. The use of adjuvant systemic therapy is primarily determined by the tumor stage and

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histopathological characteristics (hormone receptor and HER2 status).

Systemic therapy is the main treatment option for women with metastatic breast cancer
who may not benefit from surgery due to the extensive spread of the disease.
Chemotherapy: The benefit of chemotherapy is dependent on multiple factors, including
the size of the cancer, the number of lymph nodes involved, the presence of estrogen or
progesterone receptors, and the amount of HER2 protein made by the cancer cells. Basal-like
and HER2-enriched breast cancers tend to be more sensitive to chemotherapy, while luminal
A tumors are generally less responsive [160]. Research has established that in most cases,
combinations of drugs are more effective than one drug alone for breast cancer treatment.
Many combinations are being used, and it is not clear that any single combination is the best.
Depending on the combination of drugs used, chemotherapy is usually given for three to six
months. Chemotherapy is most effective when the full dose and cycle of drugs are completed
in a timely manner.
Hormonal therapy: Estrogen, a hormone produced by the ovaries, promotes the growth of
many breast cancers. Women whose breast cancers test positive for estrogen or progesterone
receptors can be given hormone therapy to lower estrogen levels or to block the effects of
estrogen on the growth of breast cancer cells. Tamoxifen and toremifene (Fareston) are drugs
that prevent estrogen from binding to breast cancer cells and are effective in both post -
menopausal and premenopausal women. Treatment of ER+ breast cancer with tamoxifen for
five years has been shown to reduce the rate of recurrence by 39% throughout the first decade,
and reduces breast cancer mortality by about one-third throughout the first 15 years [161].
Recently released results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) study
showed that extended use of tamoxifen (10 years versus 5 years) may further reduce the risk of
breast cancer recurrence and mortality [162]. Fulvestrant (Faslodex) is a newer drug (given by
injection once a month) that blocks estrogen binding and then reduces the number of estrogen
receptors on breast tumors. It is often effective in postmenopausal women even if the breast
cancer is no longer responding to tamoxifen. Premenopausal women with hormone-sensitive
tumors may also benefit from the removal or suppression of the ovaries (ovarian ablation),
which are the main source of estrogen prior to menopause. Ovarian ablation may also allow
some other hormone therapies to work better [163]. Permanent ovarian ablation can be done
by surgically removing the ovaries (oophorectomy). More often, potentially reversible ovarian
ablation is achieved with a class of drugs called Luteinizing Hormone-Releasing Hormone
(LHRH) analogs (e.g., goserelin [Zoladex] or leuprolide [Lupron]). Studies have shown that the
addition of these drugs to tamoxifen and/or chemotherapy reduces the risk of breast cancer
recurrence and death among premenopausal women with early stage, hormone-sensitive
breast cancer [164].
Aromatase Inhibitors (AIs), such as letrozole, anastrozole, and exemestane, are another
class of drugs that are used to treat both early and advanced hormone receptor positive
breast cancer in postmenopausal women. They work by interfering with the body’s ability to
produce estrogen. AIs are not usually an effective treatment in women with functioning ovaries
(including premenopausal women). Clinical trials have demonstrated a clear advantage to
using either an AI instead of tamoxifen for a total of five years or switching to an AI after at
least two to three years of tamoxifen, compared to tamoxifen alone for five years [165].
In 2010, clinical guidelines were issued recommending that AIs be included in the treatment
of postmenopausal women with hormone receptor positive breast cancer [166]. Clinical trials

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continue to assess the optimal timing and duration of treatment.

Although AIs have fewer serious side effects than tamoxifen, they can cause osteoporosis
(with resulting bone fractures), joint pain, and other musculoskeletal symptoms because they
completely deplete postmenopausal women of estrogen.
Targeted therapy:
Therapy aimed at HER2: Approximately 15% to 20% of breast cancers overproduce
the growth-promoting protein HER2 [12]. Tumors overproducing HER2 are more likely to
recur compared to those that do not overproduce the protein. Trastuzumab (Herceptin), a
monoclonal antibody that directly targets the HER2 protein and has been considered a gene-
based approach to minimizing the effects of HER2. The combined results of two large trials
indicate that adding trastuzumab to standard chemotherapy for early stage HER2-positive
breast cancer reduces the risk of recurrence and death by 52% and 33%, respectively,
compared to chemotherapy alone [167]. Currently, this drug is also a standard part of the
treatment for advanced (metastatic) HER2-positive breast cancer. In 2006, the US Food and
Drug Administration (FDA) approved trastuzumab for all HER2- positive breast cancers. In
addition, it is recommended that all invasive breast cancers should be tested for the HER2 gene
amplification or protein overexpression in order to identify women who would benefit from this
therapy. Guidelines were released in 2007 aimed at improving the accuracy of HER2 testing
[168]. Like trastuzumab, pertuzumab is a monoclonal antibody that attaches to the HER2
protein however, it attaches in a different location. This drug is used to treat HER2-positive,
metastatic, breast cancer. When given along with docetaxel (Taxotere) and trastuzumab to
patients who have not yet received chemotherapy, it has been shown to cause tumor shrinkage
and stop growth for approximately six months longer than giving docetaxel and trastuzumab
alone [169]. In addition, the drug ado-trastuzumab emtansine (Kadcyla, formerly called TDM-
1), was recently approved by the FDA to treat HER2-positive metastatic breast cancer, and
has been shown to shrink tumors and extend patient survival. It is made up of the same
monoclonal antibody found in trastuzumab, which is attached to a chemotherapy drug known
as DM-1. The antibody acts as a homing device, taking the chemotherapy drug directly to the
cancer cells [170]. Lapatinib (Tykerb) is another drug that has been found to be effective in
delaying disease progression in women with HER2- positive advanced breast cancers that have
become resistant to trastuzumab [171].
Other targeted therapies: Everolimus (Afinitor) is a type of targeted therapy that blocks
mTOR, a protein that promotes cell growth and division. By blocking this protein, everolimus
can help stop cancer cells from growing. Everolimus may also stop tumors from developing
new blood vessels, which can also limit growth. This drug seems to improve the effectiveness
of hormone therapy drugs in treating breast cancer. Everolimus was recently approved to
treat advanced, hormone receptor-positive, HER2-negative breast cancer in postmenopausal
women. It is meant to be used with exemestane in those women whose cancers have grown
while they were being treated with either letrozole or anastrozole. Everolimus is also being
studied in combination with other hormone therapy drugs [172,173].
Bevacizumab (Avastin) is a drug that targets the Vascular Endothelial Growth Factor (VEGF)
protein, which helps tumors form new blood vessels. After granting accelerated approval of
bevacizumab (Avastin) for the treatment of HER2-negative, metastatic breast cancer in 2008,
the FDA revoked approval of the drug in November 2011 based on subsequent studies that
demonstrated minimal benefit combined with some potentially dangerous side effects.

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Research
Applications of nanoparticles in breast cancer nanotechnology
Introduction: The use of nanoparticles in cancer therapy is attractive for several reasons:
they exhibit unique pharmacokinetics, including minimal renal filtration; they have high
surface-to-volume ratios enabling modification with various surface functional groups that
home, internalize, or stabilize; and they may be constructed from a wide range of materials
used to encapsulate or solubilize therapeutic agents for drug delivery or to provide unique
optical, magnetic, and electrical properties for imaging and remote actuation. The topology of
a nanoparticle-core, coating, and surface functional groups-makes it particularly amenable
to modular design, whereby features and functional moieties may be interchanged or
combined. Although many functionalities of nanoparticles have been demonstrated, including
some clinically approved drug formulations and imaging agents [174,175], the consolidation
of these into multifunctional nanoparticles capable of targeting, imaging, and delivering
therapeutics is an exciting area of research that holds great promise for cancer therapy in the
future. Figure 3 schematically depicts a hypothetical multifunctional particle that has been
engineered to include many features such as the ability to target tumors, evade uptake by the
Reticuloendothelial System (RES), protect therapeutics that can be released on demand, act
as sensors of tumor responsiveness, and provide image contrast to visualize sites of disease
and monitor disease progression. Some of these features, such as targeting, leverage biological
machinery. Others are derived synthetically and enable external probing or manipulation that
is otherwise not feasible in biological systems. In this chapter, we review both bio-inspired and
synthetic nanoparticle functionalities that have been used in cancer therapy and address both
current efforts and future opportunities to combine these into multifunctional devices.
Figure 3: Schematic depiction of a multifunctional nanoparticle. A hypothetical nanoparticle

targets the tumor, senses and reports molecular signatures, and delivers a therapeutic in
response to an external or biological trigger [176].
Chemotherapeutic Nanoparticles: Chemotherapeutic drugs are “cytotoxic” in nature,

which means cell-killing drugs. They play a vital role in the management and treatment of both
initial-stage breast cancer and advanced breast cancer. Cytotoxic chemotherapy is essential

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for palliation of women with hormone-insensitive or hormone-refractory breast cancer and

is administered into human body by taking therapeutic goals into consideration such as
relief from pain, disease progression, relief from symptoms, prolonged life of patient, and
improvement in mood disturbances of suffering women [177]. It is administered orally or by
intravenous injection. It works systemically by killing cancer cells the body along with normal
cells, which leads to various short-term and long-term side effects. Mostly chemotherapy is
used in advanced breast cancer, but may also be used to treat early-stage breast cancer.
By using nanoparticles as carrier, cytotoxic side effects may be reduced and targeting may
be achieved. Even the most advanced chemotherapeutic agents do not differentiate between
normal cells and cancerous cells efficiently, which leads to nonspecific distribution of drug in
the body and causes systemic toxicity and adverse effects [178]. The maximum allowable dose
of the drug gets limited; in order to achieve the desired therapeutic effect in the tumor tissue,
large quantity of drug has to be administered in order to achieve anticancer effect, but this
is not economical and undesirable toxicity may also appear [178,179]. Nanoparticles are the
promising carrier system for the targeted delivery of chemotherapeutic agents by using both
active and passive targetings, and systemic toxicity or normal cell toxicity can be avoided [179].
Active and Passive Drug Delivery: Mostly the nanoparticles accumulate in tumor cells
as expected because of pathophysiological characteristics of tumor blood supplying vessels.
There is an increased demand of oxygen and nutrients to the tumor cells or tissue as it is
increasing in size as well as in its shape.
In order to supply nutrients and oxygen, new blood capillary system is being developed
which is not developed properly and hence becomes permeable to some particles of specific
size [180]. Types of targeting are shown in Figure 4.
Figure 4: Types of targeting by nanodelivery system.
Passive Targeting by Nanoparticles: Passive targeting can differentiate between normal

and tumor tissues and has the advantage of direct permeation to tumor tissue (Figure 5).
Drug administered passively in the form of prodrug or inactive form, when exposed to tumor
tissue, becomes highly active. Nanoparticles that are expected to show localization on specific
tissues or at specific sites of disease follow the biological mechanisms such as ERS (Enhanced
Retention System) or EPS (Enhanced Permeation System) effect. To prolong the circulation and

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to achieve increased targeting efficiency, the size should be below 100 nanometers in diameter
and the surface of the nanoparticles should be hydrophilic in nature in order to circumvent
clearance by macrophages. The hydrophilic surface of the nanoparticles provides protection
against plasma protein adsorption to the surface, and this can be made possible by using
hydrophilic polymer coating, like Polyethylene Glycol (PEG), polysaccharides, poloxamines, or
poloxamers or by using block or branched amphiphilic copolymer [181,182]. Passive targeting
system is further classified into (a) leaky vasculature, (b) tumor microenvironment, and (c)
local drug application.
1. Leaky Vasculature: Maeda and Matsumura had first displayed the enhanced
permeation and retention effect by using polymer to form nanoparticles. Concept of enhanced
permeability and retention is based on two factors [183]. (a) The capillary endothelium system
in malignant tissue shows more permeation to macromolecules in comparison to normal tissue
endothelium; this makes circulating polymeric nanoparticles permeable into the tumor. (b)
Tumor lacks lymphatic drainage; hence, more drugs get accumulated in side tumor tissue. By
using a suitable biodegradable polymer, the concentration of drug gets 10 to 100 times higher
than that of free circulating drug.
2. Tumor Microenvironment: Tumor microenvironment provides the advantage of the
passive drug targeting. Active state of chemotherapeutic agent is conjugated with tumor
specific material and administered into the body. When this drug-polymer conjugate reaches
its desired destination, tumor environment converts into more active form. This phenomenon
is called tumor activated prodrug therapy. Mansour et al., had developed an albumin-bound
form of doxorubicin and showed in an in vitro study, that doxorubicin was efficiently cleaved
by matrix metalloproteniase-2 [184].
3. Local Drug Application: Direct application of the chemotherapeutic agent locally to
tumor site prevents systemic toxicity and increased concentration of drug at the tumor site.
Nomura et al., had synthesized intratumoral injection of mitomycin c-dextran conjugate; this
results in increased concentration of anticancer drug at tumor site and decreased systemic
toxicity [19]. Prabha and Labhasetwar had worked on nanoparticles-mediated wild-type p53
gene for breast cancer and observed the sustained and increased antiproliferative effect [185].

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Figure 5: Passive targeting.
Figure 5: Passive targeting.
Active Targeting: By conjugating the nanoparticles with a drug to desired target site, an
active targeting may be achieved (Figure 6). Active targeting allows the increased accumulation
of the drug in cancer tissue. Directing the nanoparticles to the cancer cell can be done by
the following ways. This approach is basically based on the specific interactions, like lectin
carbohydrate, ligand receptor, and antibody-antigen [186].

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Figure 6: Active targeting.
1. Carbohydrate-Directed Targeting: An excellent example of active drug targeting is lectin

carbohydrate. Carbohydrates present on the surface of tumor cell are different than those
in the normal cell. Lectin is a non-immunological protein, which is capable of binding
and recognizing the glycoproteins which are present on the surface of the cell. Certain
carbohydrates interact with lectins to form the cell-specific binding moieties. These
carbohydrates moieties can be used for target drug delivery systemfor lectins (lectin direct
targeting); similarly, lectins can also be used for the targeting of the surface carbohydrates
(reverse lectin targeting). Specific carbohydrate present on tumor can be targeted and
anticancer effect may be achieved.
2. Receptor Targeting: Endocytosis plays a major role in this type of active targeting. Ideally
drug is being conjugated to polymer carrier; this carrier gets incorporated into the cell
and localized at the cell surface. Once the drug-polymer conjugate reaches the tumor
intracellular environment, dissociation of drug takes place and anticancer effect is being
achieved.
Three essential molecules can be delivered by this targeting system:
(a) antigen or receptors,
(b) drug-polymer conjugates, and
(c) ligands or antibodies.
3. Antibody Targeting: Kirpotin et al., had described the evidence of monoclonal antibody
mechanism for targeting nanoparticles to solid tumor tissue in vivo. Prepared formulation was
targeted towards the HER-2 (Human Epidermal growth factor Receptor 2) cancer and was
prepared by conjugating the anti-HER-2 monoclonal antibody fragments with liposomal-grafted
polyethylene glycol chain. Increased cellular uptake of the drug was observed; hence, antibody
targeting provides the new opportunities for drug delivery system in breast cancer [187].

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PARP Inhibitors in Breast Cancer

PARP and the DNA Damage Response: The cellular response to DNA damage is highly
regulated and may result in survival of a normal cell, cell death, or mutagenesis depending
on the magnitude of the insult, efficiency of repair, and the cellular context [188] The human
genome is protected from various endogenous and exogenous DNA damaging insults by a
complex system of DNA repair machinery designed to respond to and repair a wide spectrum
of DNA damage. Double-strand DNA breaks are highly toxic lesions, and 2 major pathways-
nonhomologous end joining and homologous recombination contribute to the repair of these
lesions. The excision repair pathways, including Base Excision Repair (BER), Nucleotide
Excision Repair (NER), and mismatch repair, employ a “cut and patch” mechanism to excise
the damaged or incorrect DNA sequence and fill the resulting gap using the complementary
DNA strand as a template.1 As a member of a large family of poly (ADP-ribose) Polymerases
(PARP), PARP1 is an abundant nuclear enzyme that is activated by and recruited to sites of
DNA base damage [189]. The enzyme itself is composed of 3 functional domains, including a
DNA binding domain, an automodification domain, and a catalytic domain [190] Following
DNA damage, PARP1 is recruited and binds to the damaged DNA with a subsequent increase
in catalytic activity that results in the formation of poly (ADP-ribose) polymers using the
substrate NAD+ that are transferred to acceptor proteins and to PARP1 itself. Formations
of these poly (ADP-ribose) polymers are important for recruitment of the BER machinery to
the site of the DNA damage and relaxation of the chromatin structure to facilitate repair.
Early work that contributed to the elucidation of this mechanism implicated a potential role
of inhibitors of PARP in the treatment of cancer after it was observed that 3-Aminobenzamide
(3AB) could enhance the cytotoxicity of alkylating agents [189].
Strategies Employing PARP Inhibitors in the Treatment of Cancer: Two primary
therapeutic strategies employing PARP inhibitors in the treatment of cancer are currently
under investigation; the first is the use of PARP inhibitors as sensitizers to DNA damaging
chemotherapy or radiation, while the second approach exploits specific genetic characteristics
of certain cancers that leave them vulnerable to DNA damage via the mechanism of “chemical
synthetic lethality” [191] (Figure 7). Since many effective cytotoxic chemotherapies and
ionizing radiotherapy exert their antitumor effect through production of DNA damage,
it was hypothesized that interference with cellular DNA repair using PARP inhibitors may
mitigate repair of this injury, resulting in decreased treatment resistance. Indeed, following
the observation that inhibitors of PARP enhance the cytotoxicity of DNA methylating agents,
potentiation of ionizing radiation effect via inhibition of PARP was demonstrated [192]. In
the 1990s, more potent PARP inhibitors were developed and evaluated preclinically for their
potential as chemotherapy or radiation sensitizers. In 2005, however, a pair of pivotal papers
suggested a novel application of PARP inhibitors in the treatment of human cancers. These
studies demonstrated that the use of inhibitors of PARP in cells deficient in BRCA1 and BRCA2
function resulted in selective cytotoxicity, compared to cells that are wild-type or heterozygous
for BRCA1 or BRCA2 [193,194]. This concept of “chemical synthetic lethality” of PARP inhibitors
in the treatment of BRCA1 and BRCA2 mutation-associated cancer generated tremendous
enthusiasm and fueled the rapid development of clinical investigation in this area. Based on
these 2 principles, a number of PARP inhibitors are currently in clinical development for the
treatment of cancer (Table 1). In genetics, a synthetic lethal interaction describes the scenario
where mutation in either of 2 genes alone has no phenotypic effect, but the combination of
both mutations results in death of the cell [195]. Tumors arising in patients with a germline

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BRCA mutation are associated with reduced DNA repair capacity due to the loss of BRCA
function and are hypothesized to rely more heavily on alternate compensatory DNA repair
processes for survival. The BRCA1 and BRCA2 proteins are best known for their important role
in homologous recombination, though BRCA1 has been implicated as having additional roles
in NER and BER [196,197].
PARP plays a central role in BER. It is required for the repair of oxidative damage associated
with breaks in single-strand DNA. If PARP is inhibited, repair-associated breaks result in
replication fork–mediated double-strand break formation, which requires BRCA1- and BRCA2-
associated recombination to resolve [198]. Thus, in tumors lacking intact BRCA function
due to loss of a second allele, chemical inhibition of PARP with a small molecule inhibitor is
postulated to be the “second hit” that renders the cell incapable of survival and mimics genetic
absence of PARP. However, in the host’s somatic tissues that are heterozygous for a BRCA
mutation and that maintain normal BRCA protein function, PARP inhibitors are thought to
have little or no effect.

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Figure 7: Two distinct strategies for targeting poly (ADPribose) polymerase in the
treatment of cancer. HR=homologous recombination.
Figure 7: Two distinct strategies for targeting poly (ADPribose) polymerase in the treatment of cancer. HR=homologous recombination.
Drug Name Manufacture Route of Administration Tumors Targeted in Ongoing Clinical Trials Phase
Breast, ovarian, primary peritoneal, fallopian tube, colon,
Veliparib
Abbott Oral prostate, melanoma, HCC, hematologic malignancies/CLL, I,II
ABT-888
lymphoma, advanced solid tumors

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AG014699 Triple-negative breast, BRCA-associated breast, BRCA-

Pfizer Intravenous I,II
PF01367338 associated ovarian, advanced solid tumors
Triple-negative breast, BRCA-associated breast, BRCA-
Olaparib
AstraZeneca Oral associated ovarian, ovarian, gastric, colon, pancreas, I,II
AZD2281
melanoma, advanced solid tumors
Triple-negative breast*, BRCA-associated breast,
Iniparib BiPar BRCAassociated pancreas, BRCA-associated ovarian,
BSI-201 Sciences/ Intravenous ovarian, primary peritoneal fallopian tube, uterine I,II,III*
SAR240550 Sanofi-Aventis carcinosarcoma, glioblastoma multiforme, NSCLC,
squamous cell lung*
CEP8983 Cephalon Oral Advanced solid tumors I
Advanced solid tumors, prostate, ovarian, primary
MK-4827 Merck Oral I
peritoneal, fallopian tube
Table 1: PARP Inhibitors in Clinical Development for the Treatment of Cancer.
CLL=Chronic Lymphocytic Leukemia; HCC=Hepatocellular Carcinoma; NSCLC=Non–Small Cell Lung Cancer
BRCA1 and BRCA2 Mutation-associated Breast Cancer: The breast and ovarian cancer
syndromes caused by germline mutations in the BRCA1 and BRCA2 genes account for a
minority of breast cancer overall (approximately 5%), though it was this population that
provided clinical “proof of principle” of chemical synthetic lethality with PARP inhibitors. To
date, the majority of clinical investigation in BRCA mutation–associated cancer has been with
the oral PARP inhibitor olaparib (AstraZeneca), and few data exist for this drug outside of
this population. Fong and colleagues reported a phase I dose escalation study of olaparib in
patients with advanced refractory solid tumors [199]. A total of 60 patients were enrolled,
including 22 patients with known BRCA1 or BRCA2 mutations. Objective responses were
seen in this study, though only in patients with BRCA mutation–associated ovarian, breast, or
prostate cancer. Few patients had breast cancer, however, including 6 with no BRCA mutation
and 3 with documented BRCA2 mutations. No responses were observed in patients lacking
known BRCA mutations. At the 2009 American Society of Clinical Oncology (ASCO) Annual
Meeting, Tutt and colleagues presented the first phase II results of olaparib for the treatment
of women with BRCA1 and BRCA2 mutation–associated stage IIIB–IV breast cancer that had
progressed on at least 1 prior systemic chemotherapy regimen [200]. Two sequential cohorts
of 27 patients were enrolled at dose levels of 100 mg twice daily orally and 400 mg twice daily
orally every 28 days. Patients had received a median of 3 prior chemotherapy regimens for
advanced breast cancer, and 64% and 50% of patients had the triple-negative subtype of
breast cancer in the 100 mg and 400 mg cohorts, respectively. The objective response rate was
41% in the 400 mg cohort and 22% in the 100 mg cohort. One complete response was observed
with the higher dose. The responses seen in both triple-negative (Estrogen Receptor [ER]-
negative, Progesterone Receptor [PR]-negative and Human Epidermal Growth factor [HER] 2/
neu nonover-expressing) and nontriple-negative (but BRCA-mutation carrier) patients were
an important observation and suggest that the selection of patients based on shared DNA
repair defects due to BRCA mutations supersedes phenotypic subtype. To date, the activity
of olaparib in non-BRCA–mutant triple-negative breast cancer remains unclear. Gelmon and
colleagues recently reported results of a phase II study of single-agent olaparib 400 mg orally
twice daily [201]. In a cohort of fifteen BRCA-negatives, triple-negative breast cancer patients
with advanced disease, no objective responses were observed. Following these successes, many
companies are examining the efficacy of their PARP inhibitors in patients with BRCA mutation-
associated breast cancer. The majority of these studies are recruiting patients with advanced
BRCA mutation-associated breast cancer, though BSI-201 (BiPar Sciences/Sanofi-Aventis) is

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being investigated in the neoadjuvant setting in combination with gemcitabine Gemzar, Eli Lilly)
and carboplatin for patients with stage I–IIIA BRCA1 and BRCA2 mutation–associated breast
cancer, regardless of breast cancer subtype. Pfizer has also recently launched a randomized
phase II study of cisplatin, with or without PF-01367338, in early stage BRCA1- or BRCA2-
positive patients with residual disease after neoadjuvant chemotherapy. BRCA1 and BRCA2
carriers with triple-negative or ER and/or PR-positive, HER2-negative breast cancer subtypes
are eligible for this study.
Another exciting area of PARP inhibitor development relates to their potential use as
chemoprevention agents in patients with high breast cancer risk. Studies examining this
hypothesis in BRCA mutation carriers are currently in development.
Triple-negative Breast Cancer: Sporadic triple-negative breast cancers share many
pathologic and molecular features with breast cancers caused by hereditary BRCA1 mutations,
including basal-like gene expression, high histologic grade, frequent p53 mutations,
cytogenetic abnormalities, increased genomic instability, and EGFR overexpression [202-
204]. Based on these similarities and the role of BRCA1 in multiple DNA repair pathways,
the hypothesis emerged that sporadic triple-negative breast tumors may possess similar DNA
repair deficiencies and exhibit similar chemosensitivities as BRCA1 mutation-associated breast
tumors. Interestingly, basal-like breast cancer cell lines, like BRCA1-deficient cancer cell
lines, are more sensitive to oxidative DNA damage compared to luminal breast tumor cells or
normal breast epithelial cells, and are deficient in BER [197]. Similar to BRCA1-deficient cells,
basal-like tumor cells also demonstrate increased sensitivity to PARP inhibition, cisplatin, and
gemcitabine, [197,205] and PARP1 has been observed to be overexpressed in triple-negative
breast cancer [206]. These observations provided the rationale to investigate DNA damaging
chemotherapies and PARP inhibitors in triple-negative breast cancer patients. At ASCO 2009,
O’Shaughnessy and colleagues reported the first clinical results exploring the role of PARP
inhibition in the treatment of sporadic triple-negative advanced breast cancer [207]. In this
randomized phase II trial, women with advanced breast cancer were treated with intravenous
gemcitabine 1,000 mg/m2 and intravenous carboplatin area under the concentration of 2 on
days 1 and 8, with or without the PARP inhibitor BSI-201 dosed at 5.6 mg/kg intravenously
on days 1, 4, 8, and 11. A total of 123 women treated with up to 2 prior chemotherapy
regimens for metastatic disease were enrolled. This study demonstrated improvements in the
clinical benefit rate (21% vs 62%; P=0.0002), overall response rate (16% vs 48%; P=0.002),
median progression-free survival (3.3 vs 6.9 months; Hazard Ratio [HR], 0.342; P<0.0001)
and median overall survival (5.7 vs 9.2 months; HR, 0.348; P=0.0005) among patients who
received BSI-201. Prolongation of survival is rarely observed in clinical trials of women with
advanced breast cancer and, as such, these results were received with great enthusiasm in the
oncology community. The overall survival data were updated at the 2009 San Antonio Breast
Cancer Symposium, and they continued to show a significant survival advantage among
women treated with BSI-201 in an intention-to-treat analysis (7.7 vs 12.2 months; HR, 0.50;
P=0.005) [208]. Of particular note, approximately 40% of women treated on the control arm
crossed over to receive BSI-201 at the time of disease progression. In July 2009, a randomized
phase III registration study of gemcitabine and carboplatin, with or without BSI-201, was
launched to examine the safety and efficacy of this combination in a larger patient population
(n=420). Accrual was extremely rapid, with the study closing to accrual in February 2010. A
subsequent study examining this combination in advanced triple-negative breast cancer has
recently been launched in Europe and is testing gemcitabine and carboplatin with 2 different
doses and schedules of BSI-201: 11.2 mg/kg intravenously on days 1 and 8 versus 5.6 mg/kg
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intravenously on days 1, 4, 8, and 11. Other ongoing PARP inhibitor studies in triple-negative
breast cancer include a phase II study of neoadjuvant gemcitabine, carboplatin, and BSI-201
in women with stage I–IIIA triple-negative breast cancer and a phase I/II study of cisplatin,
with or without olaparib, as neoadjuvant therapy in women with early-stage, triple-negative
breast cancer. Pfizer has recently launched a randomized phase II study of cisplatin with
or without PF-01367338 in early-stage triple-negative breast cancer patients with residual
disease after neoadjuvant chemotherapy. ABT-888 (Veliparib, Abbott) is being investigated in
combination with weekly paclitaxel and every 3 weekly carboplatin followed by doxorubicin
and cyclophosphamide in the neoadjuvant treatment of early breast cancer as part of the
multicenter I-SPY2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response
With Imaging and Molecular Analysis). Data with single-agent BSI-201 in breast cancer, in
particular triple-negative breast cancer, are limited. Likewise, data with single-agent olaparib
in sporadic triple negative breast cancer are also limited. Though PARP inhibitors were
investigated in triple-negative disease based on the hypothesis that this breast cancer subtype
is “BRCA-like,” it is unknown at present whether the activity seen in the BSI-201 study was a
result of a synthetic lethal interaction between a genetic defect characteristic of this subtype
and the PARP inhibitor, a result of enhanced chemosensitivity of gemcitabine and carboplatin
in combination with BSI-201, or possibly a combination of both. It is quite possible that the
mechanism may vary by patient, and identification of a means to distinguish these patients
and their responses is a high priority of research.
Breast Cancer Prevention

Women may reduce their risk of breast cancer by maintaining a healthy weight, drinking
less alcohol, being physically active and breastfeeding their children [209]. These modifications
might prevent 38% of breast cancers in the US, 42% in the UK, 28% in Brazil and 20% in
China [209]. The benefits with moderate exercise such as brisk walking are seen at all age
groups including postmenopausal women [209,210]. Marine omega-3 polyunsaturated fatty
acids also appear to reduce breast cancer risk [211]. Removal of both breasts before any
cancer has been diagnosed or any suspicious lump or other lesion has appeared (a procedure
known as prophylactic bilateral mastectomy) may be considered in people with BRCA1
and BRCA2 mutations, which are associated with a substantially heightened of developing
breast cancer [212,213]. BRCA testing is recommended in those with a high family risk after
genetic counseling. It is not recommended routinely [214]. This is because there are many
different forms of changes in BRCA genes, ranging from harmless polymorphisms to obviously
dangerous frameshift mutations. The effect of most of identifiable changes in the genes is
uncertain. Testing in an average-risk person is particularly likely to return one of these
indeterminate, useless results. The selective estrogen receptor modulators (such as tamoxifen)
reduce the risk of breast cancer but increase the risk of thromboembolism and endometrial
cancer [216]. However, there is no overall change in the risk of death [215,216]. They are thus
not recommended for the prevention of breast cancer in women at average risk but may be
offered for those at high risk [217]. The benefit of breast cancer reduction continues for at least
five years after stopping a course of treatment with these medications [218].
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Principles and Practice of

Principles and Practice of Cancer Prevention

Published by OMICS Group eBooks

731 Gull Ave, Foster City. CA 94404, USA

Copyright © 2014 OMICS Group

A free online edition of this book is available at www.esciencecentral.org/ebooks

Principles and Practice of Cancer Prevention and Control 1

Figure 1: The Breast: cross-section scheme of the mammary gland.

Principles and Practice of Cancer Prevention and Control 2

General Types of Breast Cancer

TNM Classification of Breast Cancer

Principles and Practice of Cancer Prevention and Control 3

Molecular Subtypes of Breast Cancer

Signs and Symptoms

Principles and Practice of Cancer Prevention and Control 6

Principles and Practice of Cancer Prevention and Control 8

Principles and Practice of Cancer Prevention and Control 9

Principles and Practice of Cancer Prevention and Control 10

Pathophysiology and Molecular Pathways of Breast Carcinogenesis

Principles and Practice of Cancer Prevention and Control 11

Principles and Practice of Cancer Prevention and Control 12

Breast Cancer Treatment

Principles and Practice of Cancer Prevention and Control 14

Principles and Practice of Cancer Prevention and Control 15

histopathological characteristics (hormone receptor and HER2 status).

Principles and Practice of Cancer Prevention and Control 16

continue to assess the optimal timing and duration of treatment.

Principles and Practice of Cancer Prevention and Control 17

Figure 3: Schematic depiction of a multifunctional nanoparticle. A hypothetical nanoparticle

Chemotherapeutic Nanoparticles: Chemotherapeutic drugs are “cytotoxic” in nature,

Principles and Practice of Cancer Prevention and Control 18

for palliation of women with hormone-insensitive or hormone-refractory breast cancer and

Figure 4: Types of targeting by nanodelivery system.

Passive Targeting by Nanoparticles: Passive targeting can differentiate between normal

Principles and Practice of Cancer Prevention and Control 19

Principles and Practice of Cancer Prevention and Control 20

Figure 5: Passive targeting.

Figure 5: Passive targeting.

Principles and Practice of Cancer Prevention and Control 21

Figure 6: Active targeting.

1. Carbohydrate-Directed Targeting: An excellent example of active drug targeting is lectin

Principles and Practice of Cancer Prevention and Control 22

PARP Inhibitors in Breast Cancer

Principles and Practice of Cancer Prevention and Control 23

Principles and Practice of Cancer Prevention and Control 24

Principles and Practice of Cancer Prevention and Control 25

AG014699 Triple-negative breast, BRCA-associated breast, BRCA-

CLL=Chronic Lymphocytic Leukemia; HCC=Hepatocellular Carcinoma; NSCLC=Non–Small Cell Lung Cancer

Principles and Practice of Cancer Prevention and Control 26

Breast Cancer Prevention

Principles and Practice of Cancer Prevention and Control 28

15. Watson M (2008) Assessment of suspected cancer. InnovAiT 1: 94-107.

Principles and Practice of Cancer Prevention and Control 29

Principles and Practice of Cancer Prevention and Control 30

Principles and Practice of Cancer Prevention and Control 31

Principles and Practice of Cancer Prevention and Control 32