11 Chapter 1

Chapter I
INTRODUCTION
1.1. GENERAL INTRODUCTION
Breast cancer
Cancer of the breast existed in ancient times and reference to this
disease can be found dating back as 3000 BC, in an Egyptian papyrus
(Breasted, 1930). Breast cancer refers to cancer originating from breast
tissue, most commonly from the inner lining of milk ducts or the lobules
that supply the ducts with milk. It is a clonal disease; a single transformed
cell- the end results a series of somatic (acquired) or germ line mutationsis able to express full malignant potential. Thus breast cancer may exist
for a long period as either a non-invasive disease or an invasive but nonmetastatic disease (Braunwald et al., 2001). The breast is made up of
lobes and ducts . Each breast has 15 to 20 sections called lobes, which
have many smaller sections called lobules and Lobules end in dozens of
tiny bulbs that can produce milk. The lobes, lobules, and bulbs are linked
by thin tubes called ducts. Each breast also has blood vessels and lymph
vessels which carry an almost colourless fluid called lymph . Lymph
vessels lead to organs called lymph nodes which are small bean-shaped
structures that are found throughout the body which filter substances in a
fluid called lymph and help to fight infection and disease. Clusters of
lymph nodes are found near the breast in the axilla (under the arm), above
the collarbone, and in the chest.
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Types of breast cancer
Ductal carcinoma in situ (DCIS) is a noninvasive , precancerous

condition in which abnormal cells are found in the lining of a
breast duct . The incidence increased in all ages but more in women
older than 50 years (Virnig et al., 2010). The abnormal cells have
not spread outside the duct to other tissues in the breast. In some
cases, DCIS may become invasive cancer and spread to other
tissues, although it is not known at this time how to predict which
lesions will become invasive.
Invasive (infiltrating) ductal carcinoma is the most common cell

type, comprising 70% to 80% of all cases. The tumors occur
throughout the age range of breast carcinoma, being most common
in women in their middle to late 50s. It is characterized by its solid
core, which is usually hard and firm on palpation. An associated
ductal carcinoma in-situ is frequently present and comedo necrosis
may occur in both invasive areas and areas of intraductal
carcinoma. Invasive ductal carcinoma commonly spreads to the
regional lymph nodes and carries the poorest prognosis among
various ductal types.
Lobular carcinoma in situ (LCIS) is a condition in which abnormal

cells are found in the lobules of the breast. This condition seldom
becomes invasive cancer; however, having lobular carcinoma in
situ in one breast increases the risk of developing breast cancer in
either breast.
Invasive lobular carcinoma is the 2nd most common type of

invasive breast cancer accounting for 8-14% of all breast cancers
(Singletary et al., 2005). It is characterized by greater proportion of
multicentricity in the same or the opposite breast. The lesions tend
to have ill-defined margins, and occasionally the only evidence is
subtle thickening or induration. Patients with infiltrating lobular
carcinoma are especially prone to have bilateral carcinoma. Stage
by stage, invasive lobular carcinoma has a similar prognosis to
infiltrating ductal carcinoma.
In inflammatory breast cancer is a rare and aggressive form of

breast cancer with unknown etiology and generally poor outcome
(Anderson, 2005). The breast looks red and swollen and feels
warm. The redness and warmth occur because the cancer cells
block the lymph vessels in the skin. The skin of the breast may also
show the pitted appearance called peau dorange (like the skin of
an orange).
Tubular carcinoma is also known as a well-differentiated

carcinoma. The frequency of axillary lymph node metastases is
approximately 10%, lower than that of ductal carcinoma.
Medullary carcinoma is characterized by a prominent lymphocyte

infiltrate. Patients with medullary carcinoma tend to be younger
than those with other types of breast cancer (Braunwald et al.,
2001).
Epidemiology
Among women breast cancer is the most frequently diagnosed
cancer and the leading cause of cancer death worldwide. About 1.3
million new cases and 465,000 deaths from breast cancer are projected to
occur in 2007 and he 5 year survival rates vary widely across countries
from about 30% in sub-saharan countries to 45% in parts of south east
Asia to more than 80% in the North America depending on the availability
of screening and treatment services (Parkin and Bray, 2006). The breast
cancer incidence rates are highest in the economically developed countries
in North America, western and northern Europe, Australia, NewZealand
and Israel. Low rates are found in Africa and Asia. Inherited genetic
mutations with high penetrance such as BRCA 1 and BRCA 2, that are
more common in women of Ashkenazi Jewish descent, increase risk of
breast cancer (Ford et al., 1994) in affected individuals but have little
impact on global geographic differences or temporal trends (Struwing
et al., 1997). Although historical data is limited, the incidence of breast
cancer is thought to have increased during most of the 20 th century in
developed countries, first because of changes in the reproductive pattern
and more recently because of increased screening (Colditz et al., 2006)
Staging
A complete history and physical examination, complete blood
count, chemistry profile and chest radiography/ mammography constitute
an appropriate preoperative workup for symptomatic women with breast
cancer. Bilateral mammograms are performed in all women with biopsy-
proven breast cancer to look for other lesions in the involved breast as
well as the opposite breast. Metastasis from the invasive breast cancer
probably develop early during growth of the primary lesion, proliferate in
distant metastatic site as occult micro metastases and becomes clinically
detectable (~ 1 cm3 ) after approximately 30 tumour cell doublings. The
axillary lymph nodes are not barriers to metastasis; the number of axillary
nodes involved by tumour is directly correlated with the risk of both
regional and distant metastasis (Goldman and Ausiello, 2008).
Correct staging of breast cancer patients is of extraordinary

importance. Not only does it permit an accurate prognosis but in many
cases therapeutic decision making is based largely on TNM classification
(Table 1). It is based on the tumour size, the extent of breast involvement,
axillary lymph node involvement and distant metastasis. Determination of
tumour size is made by the pathologist on review of biopsy lumpectomy
or mastectomy specimens. Currently approximately 50-60% 0f women
with newly diagnosed breast cancer are node negative and 25-40 % are
node positive; of those who are node positive, approximately 60% have
involvement of only one to three nodes. Fewer than 10% of patients are
seen with distant metastasis.
Table 1 Staging of breast cancer: TNM (Tumour Node Metastasis) system

Tumour size: T (Largest Diameter)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Tis
carcinoma in situ (ductal or globular or Pagets disease with no tumour)
T1
tumour # 2cm in greatest dimension
T2
tumour >2cm but not > 5 cm in greatest dimension
T3
tumour > 5 cm in greatest dimension
T4
tumour of any size with direct extension to chest wall or skin
Nodal involvement: N (nodal status)

NX
Regional lymph node cannot be assessed
N0
No regional lymph node metastasis histologically
N1
Metastasis to one to three ipsilateral axillary node
N2
Metastasis to one to three ipsilateral axillary node or internal mammary

lymph nodes in the absence of axillary lymph node metastasis
N3
Metastasis to one to three ipsilateral axillary node or internal mammary

lymph nodes in the absence of axillary lymph nodes, to ispilateral
supraclavicular lymphnodes or to ispilateral infraclavicular lymphnodes
Metastasis: M
M0
No evidence of distant metastasis
M1
Distant metastasis
Source: Singletary et al. (2002)
Staging provides useful information about the current status of

cancer detection and management and the success of implementing new
strategies (Singletary and Connolly, 2006).
The following types and stages are recognised in breast cancer:

Stage 0 (carcinoma in situ)
There are 2 types of breast carcinoma in situ :
Ductal carcinoma in situ (DCIS)
Lobular carcinoma in situ (LCIS)
Pea, peanut, walnut, and lime show tumour sizes.
Stage I
In stage I, the tumour is 2 centimeters or smaller and has not spread
outside the breast.
Stage IIA
In stage IIA, no tumour is found in the breast, but cancer is found
in the axillary lymph nodes (the lymph nodes under the arm) or the
tumour is 2 centimeters or smaller and has spread to the axillary lymph
nodes or the tumour is larger than 2 centimeters but not larger than 5
centimeters and has not spread to the axillary lymph nodes.
Stage IIB
In stage IIB, the tumour is either larger than 2 centimeters, but not
larger than 5 centimeters and has spread to the axillary lymph nodes or
larger than 5 centimeters but has not spread to the axillary lymph nodes.
Stage IIIA
In stage IIIA, no tumour is found in the breast, but cancer is found
in axillary lymph nodes that are attached to each other or to other
structures or the tumour is 5 centimeters or smaller and has spread to
axillary lymph nodes that are attached to each other or to other structures
or the tumour is larger than 5 centimeters and has spread to axillary lymph
nodes that may be attached to each other or to other structures.
Stage IIIB
In stage IIIB, the cancer may be any size and has spread to tissues
near the breast (the skin or chest wall , including the ribs and muscles in
the chest); and may have spread to lymph nodes within the breast or under
the arm.
Stage IIIC
In stage IIIC, the cancer has spread to lymph nodes beneath the
collarbone and near the neck and may have spread to lymph nodes within
the breast or under the arm and to tissues near the breast. Stage IIIC breast
cancer is divided into operable and inoperable stage IIIC. In operable
stage IIIC, the cancer is found in 10 or more of the lymph nodes under the
arm or is found in the lymph nodes beneath the collarbone and near the
neck on the same side of the body as the breast with cancer or is found in
lymph nodes within the breast itself and in lymph nodes under the arm. In
inoperable stage IIIC breast cancer, the cancer has spread to the lymph
nodes above the collarbone and near the neck on the same side of the body
as the breast with cancer.
Stage IV
In stage IV, the cancer has spread to other organs of the body, most
often the bones, lungs, liver or brain.
Pathobiology
The causes of breast cancer remain elusive. Numerous risk factors
have been defined in Table 2 (Goldman and Ausiello, 2008).
The incidence of breast cancer increases dramatically with age

(Benz, 2008). More than 50% of women with breast cancer in US are
older than 60 years; and more than all of breast cancer deaths are in
women 65 years old and older. Increasing the number of menstrual cycles
could predispose women to greater DNA damage in the proliferating
breast ductal tissue and thus could increase the risk of mutations that
directly leads to breast cancer. Experimental data strongly suggests that
estrogens have a role in the development and growth of breast cancer
(Clemons and Goss, 2001). Oral contraceptive use increases risk if at all.
The use of estrogen- progestin in Hormone Replacement Therapy (HRT)
in postmenopausal women increases the risk approximately 1.5 times.
Exposure to environmental pollutants (DDT, PCB and others) may
increase the risk but such a relationship has not been confirmed. Women
whose Hodgkins disease has been treated with chest irradiation have a
10
risk that is at least 2 to 3 fold higher than the average, with a cumulative
lifetime risk of 30-40% (Goldman and Ausiello, 2008).
Table 2 Risk factors for breast cancer

Risk factors
Relative risk
Any benign breast disease
1.5
Post menopausal hormone replacement

(estrogen with or without progestin)
1.5
Menarche < 12 yr
1.1-1.9
Moderate alcohol intake (2or 3 drinks/ day)
1.1-1.9
Menopause at >55 yrs
1.1-1.9
Increased bone density
1.1-1.9
Sedentary lifestyle and lack of exercise
1.1-1.9
Proliferative breast disease without atypia
Age at first birth > 30 yrs or nulliparous
2-4
First- degree relative with breast cancer
2-4
Postmenopausal obesity
2-4
Upper socio-economic class
2-4
Personal history of endometrial or ovarian cancer
2-4
Significant radiation to chest
2-4
Increased breast density on mammogram
2-4
Older age
>4
Personal history of breast cancer (in situ or invasive)
>4
Proliferative breast disease with atypia
>4
Two first- degree relative with breast cancer
Atypical hyperplasia and first- degree relative with breast cancer
10
Source: Goldman and Ausiello (2008).
11
The risk of breast cancer is not affected by dietary saturated fat

intake during adulthood or by vitamin A, C and E consumption. Alcohol
intake is also related to breast cancer, in that women who have several
drinks daily have a moderately high risk than those who abstain. A small
proportion of breast cancers are due to a heritable predisposition. Two
predisposition genes for breast cancer, BRCA1 and BRCA2, have been
identified and cloned (Lakhani, 1999).
Clinical manifestations
Breast cancer typically produces no symptoms when the tumour is
small and most treatable. It is therefore important for women to follow the
recommended screening guidelines for detection of breast cancer at an
early stage before the symptoms develop. When it has grown to a size that
can be felt, the most common physical sign is a painless mass. It is usually
first detected as a palpable mass or a mammographic abnormality, but it
can also be manifested as nipple discharge, changes in skin over the
breast, or breast pain. Palpable masses, including discrete masses and
areas of asymmetrical thickening of breast glandular tissue, remains the
most common manifestations of breast cancer and are often first detected
by the patient. Spontaneous bloody or watery discharge from the nipple is
commonly associated with underlying breast malignancy.
Milky
discharge almost always has a benign cause. Patients with a clear or

bloody discharge require breast examination and mammography
(Goldman and Ausiello, 2008)
12
Oxidative stress
The oxidative stress can be defined as an imbalance between the
production of reactive oxygen species (ROS) and a biological systems
ability to readily detoxify the reactive intermediates or easily repair the
resulting damage. These ROS can be generated within the cell not only by
external sources of radiation such as x-ray or atomic bombing, but also
within the body as a consequence of normal metabolic processes, which
include drugs, electron transport chain and chemicals including toxins and
dyes. ROS are responsible for DNA, lipid and protein damage and play an
important role in the development and progression of many human
diseases including cancer (Fig. 1). Thus, there is a need for biomarkers to
quantify as the intensity of oxidative stress. Direct measurements of ROS
are not reliable due to the very short half-life of ROS and none of the
techniques is sensitive for quantification of ROS. The indirect methods for
estimation of ROS and oxidative stress include estimation of oxidised
products of lipids, proteins and status of endogenous antioxidants (DalleDonne et al., 2006).
13
DNA damage
DNA is arguably the most biologically significant target of cellular
and oxidative stress. DNA damage and genome maintenance are highly
relevant to all aspects of oncology. Continuous oxidative DNA damage
has been implicated in age-related development of a variety of cancers
including colon, breast and prostate. The inhibition of replicative DNA
synthesis after DNA damage may be a critical step in avoiding the
progressive increase in genomic changes that characterizes neoplastic
transformation. Furthermore, cells that are inefficient at this inhibitory
process may be prone to neoplastic development. Hence it is essential to
characterize some of the mechanisms in mammalian cells that control the
cell cycle changes in response to DNA damage. Most mutations and large
genomic alterations (deletions, translocations, loss of heterozygosity and
amplifications) that are relevant to cancer originate from DNA injury or
aberrant genome maintenance. In addition, the epigenetic code is not
indefinitely stable. In addition to the spontaneous reaction that occurs,
affecting chromatin and DNA methylation, genome maintenance itself
involves extensive alterations in the components of chromatin (Huen and
Chen, 2008; Beneke and Burkle, 2007).
Prognostic variables
Tumour staging
The most important prognostic variables are provided by tumour
staging. The size of the tumour and the status of the axillary lymph nodes
provide reasonably accurate information on the likelihood of tumour
14
relapse. For most women the need for adjuvant therapy can be readily
defined on this basis (Braunwald et al., 2001).
Histological classification
Histopathologic evaluation of a breast cancer by biopsy studies is
necessary to provide the diagnosis of the tumour, to help determine a
patient's prognosis, and to help understand the nature of breast cancer
overall and to classify the breast cancer types as ductal carcinoma and
lobular carcinoma or other types (Li et al., 2005).
Tumour growth rate

Proliferation rate in breast cancer is directly related to poor clinical
outcome. S-phase as assessed by by flow-cytometry is by far the most
comprehensively validated method assessing proliferation. There are
however, several other methods for estimating the growth fractions in
tumours including mitotic index, thymidine-labelling index and IHC
against cell cycle related antigens (Clark, 1996). The last group includes
Ki-67, PCNA, Ki-S1 topoisomerase II, histone H3 and mitosin. Several
studies suggest that tumour with a with a high proportion of cells in the Sphase pose a greater risk of relapse and that chemotherapy offers the
greatest survival benefit for these tumours. Assessment of DNA content in
the form of ploidy is of modest value, with non-diploid tumours having a
somewhat poor prognosis (Braunwald et al., 2001).
15
Serum tumour markers

Tumour markers are substances that can be found in the body when
cancer is present. They are most often found in the blood or urine, but
they can also be found in tumours and other tissue. They are products of
the cancer cells themselves, or by-products of metabolism of cells made
by the body in response to cancer or other conditions. Most tumour
markers are proteins. There are many different tumour markers. Some are
seen only in a single type of cancer, while others can be found in many
types of cancer. Conventional serum markers include CA19-9, CEA,
CA125, CA15-3, CA27.29, tissue polypeptide antigen (TPA), Tissue
polypeptide specific antigen (TSP) and the shed form of HER2 (Seregni
et al., 2004; Dirix et al., 2005). CA 15-3 is mainly used to watch patients
with breast cancer. Elevated Tumour markers level in blood are found in
less than 10% of patients with early disease and in about 70% of patients
with advanced disease. CA 27.29 is another marker that can be used to
follow patients with breast cancer during or after treatment. Although
these biomarkers are used routinely for monitoring the course of the
disease, their application to screening is limited to by the lack of adequate
sensitivity and specificity (Duffy, 2006).
Inflammatory markers
Chronic inflammation is thought to promote carcinogenesis and
may predispose an individual to cancer (Shacter and Weitzman, 2002).
Inflammatory markers such as IL-6, TNF- and CRP increase manifold in
response to tissue damage and active disease state. Both cancer risk and
16
the plasma level of inflammatory markers increases with age (Hutchinson

et al., 2000; Ershler, 1993). Cytokines, signaling molecules that mediate
and regulate immunity, inflammation, and hematopoiesis, are an
important component of the biological milieu associated with breast
cancer. They have been used as biomarkers in research for prognosis and
have been associated with symptoms and adverse outcomes in multiple
conditions, including breast cancer. However, the examination of cytokine
patterns has been limited by traditional laboratory methods at present.
Advances in proteomic technology now permit the characterization of a
broader array of cytokines in a single specimen. Because cytokines
operate in integrated networks, a more complete understanding will be
gained as multiple cytokines can be examined for patterns of response that
may be associated with symptoms and prognosis.
Molecular markers
Molecular changes in tumours are also useful. Molecular events
leading to breast epithelial carcinogenesis (Haber, 2000) involve
modifications of the structure and expression of both oncogenic and
suppressive genes. This leads to unbalanced growth that is characterised
by high rates of proliferation, migration and tendency to survive
environmental
stress
that
would
otherwise
lead
to
apoptosis
(Adriaenssens et al., 2002). Not more than 10% of human breast cancers
can be linked directly to germ line mutations. Several genes have been
implicated in familial cases.
17
Breast cancer
Molecular Biomarkers
Her2
Immunotherapy
ER
Hormonal therapy
BRCA
Chemotherapy
Fig.2 Schematic representation of current molecular biomarkers used in

clinical management of breast cancer (Braunwald et al., 2001).
Her2/ neu
Her2/ neu or c-erb B2 is an oncogene whose protein product may
function as growth factor and may also be involved in promoting cellular
differentiation, adhesion and mortality ( De Potter and Schelfhout, 1995).
Amplification of Her2/ neu is seen in almost all cases of intraductal
carcinoma and about 20-30% of invasive ductal carcinoma. This over
expression can transform human breast epithelium.
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Estrogen receptor (ER)

Estrogens have long been recognized as being important for
stimulating the growth of a large proportion of breast cancers (Ali and
Coombes, 2002). The discovery of the estrogen receptor (ER) provided us
not only with a powerful predictive and prognostic marker, but also an
efficient target for the treatment of hormone-dependent breast cancer with
anti-estrogens (Sommer and Fuqua, 2001). Estrogen by interacting with
estrogen receptor (ER) plays a central role in regulating the proliferation
and differentiation of normal breast epithelium and a subset of breast
carcinomas that express ER.
Progesterone receptor (PR)

Progesterone receptor (PR) is an ER regulated gene product with
many of the same prognostic implications as ER in breast cancer (Clark,
1996). PR is usually measured in addition to ER because it indicates
whether or not the central estrogen/ ER regulated pathways are in fact
providing enhanced predictive power when the two tests are combined
(McGuire, 1991).
BRCA-1
BRCA-1 a putative tumour suppressor gene has been identified at
the chromosomal locus 17q21; this gene encodes a zinc finger protein, and
the product therefore may function as a transcriptional factor. The gene
appears to be involved in gene repair. Women who inherit a mutant allele
of this gene from either parent have an approximately 50-80% chance of
19
developing breast cancer and about 33% chance of developing ovarian

cancer. Men who carry a mutant allele of this gene have an increases
incidence of prostrate cancer but usually not of breast cancer. Evidence
for BRCA-1 mutation in primary breast cancer has not been reported.
However, decreased expression of BRCA-1 mRNA and abnormal cellular
location of BRCA-1 have been found in some breast cancers. Loss of
heterozygosity of some genes suggests that tumour suppressor activity
may be inactivated in sporadic cases of breast cancer (Braunwald et al.,
2001).
BRCA-2
The BRCA2 gene is located on the long (q) arm of chromosome 13
at position 12.3 (13q12.3) from base pair 31,787,616 to base pair
31,871,804 (Wooster et al., 1994) which has been associated with an
increased incidence of breast cancer in men and women. In addition to
breast cancer in men and women, mutations in BRCA2 also lead to an
increased risk of ovarian, Fallopian tube, prostate, and pancreatic cancers,
as well as malignant melanoma.
Other genes
The other genes that are highly penetrant tumour suppressor genes
in breast cancer (and result in a very significant increase in risk when a
mutant copy is inherited) and are much less prevalent in the population
and therefore less clinically relevance. They include p53 (Li-Fraumeni
20
syndrome),
PTEN
(Cowden
syndrome)
and
LKB1/
STK
11
(Peutz-Jeghers syndrome) (Hearle et al., 2006).
Other variables
Other variables that have also been used to evaluate prognosis
include proteins associated with invasiveness, such as type IV
collagenase, cathepsin D, plasminogen activator, plasminogen activator
receptor, adiponectin and metastasis suppressor gene, nm23 (Braunwald
et al., 2001).
Treatment of breast cancer

Four types of standard treatment are used:
1. Surgery
Most patients with breast cancer have surgery to remove the cancer
from the breast. The main goal of surgical therapy is to remove the cancer
and accurately define the stage of disease. Surgical options broadly consist
of breast conservation therapy followed by radiation therapy. Breastconserving surgery, an operation to remove the cancer but not the breast
itself, includes the following:
(a) Lumpectomy: Surgery to remove a tumour (lump) and a small
amount of normal tissue around it.
(b) Partial mastectomy: Surgery to remove the part of the breast
that has cancer and some normal tissue around it. This procedure is also
called a segmental mastectomy .
21
(c) Total mastectomy: Surgery to remove the whole breast that has
cancer. This procedure is also called a simple mastectomy. Some of the
lymph nodes under the arm may be removed for biopsy at the same time
as the breast surgery or after. This is done through a separate incision.
(d) Modified radical mastectomy: Surgery to remove the whole
breast that has cancer, many of the lymph nodes under the arm, the lining
over the chest muscles, and sometimes, part of the chest wall muscles.
Modified radical mastectomy. Dotted line shows entire breast and some
lymph nodes are removed. Part of the chest wall muscle may also be
removed.
(e) Radical mastectomy: Surgery to remove the breast that has
cancer, chest wall muscles under the breast, and all of the lymph nodes
under the arm. This procedure is sometimes called a Halsted radical
mastectomy (Hammer et al., 2008).
2. Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy
X-rays or other types of radiation to kill cancer cells and suppress them
from growing. There are two types of radiation therapy. External radiation
therapy uses a machine outside the body to send radiation toward the
cancer. Internal radiation therapy uses a radioactive substance sealed in
needles, seeds, wires, or catheters that are placed directly into or near the
cancer. The way the radiation therapy is given depends on the type and
stage of the cancer being treated.
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3. Chemotherapy
Prior to the introduction of chemotherapy the mainstay of treatment
was based on surgery and radiotherapy (Mc Ardle et al., 2010).
Chemotherapy is a cancer treatment that uses drugs to stop the growth of
cancer cells, either by killing the cells or by stopping them from dividing.
When chemotherapy is taken by mouth or injected into a vein or muscle,
the drugs enter the bloodstream and can reach cancer cells throughout the
body (systemic chemotherapy). When chemotherapy is placed directly
into the spinal column, an organ , or a body cavity such as the abdomen ,
the drugs mainly affect cancer cells in those areas (regional
chemotherapy). The way the chemotherapy is given depends on the type
and stage of the cancer being treated.
4. Hormone therapy
Hormone therapy is a cancer treatment that removes hormones or
blocks their action and stops cancer cells from growing. Some hormones
can cause certain cancers to grow. If tests show that the cancer cells have
places where hormones can attach (receptors), drugs, surgery, or radiation
therapy are used to reduce the production of hormones or block them from
working.
Hormone therapy with tamoxifen is often given to patients with

early stages of breast cancer and those with metastatic breast cancer
(cancer that has spread to other parts of the body). Hormone therapy with
tamoxifen or estrogens can act on cells all over the body and may increase
23
the chance of developing endometrial cancer. Women taking tamoxifen

should have a pelvic examination every year to look for any signs of
cancer. Any vaginal bleeding, other than menstrual bleeding, should be
reported to a doctor as soon as possible.
Hormone therapy with an aromatase inhibitor is given to some

postmenopausal women who have hormone-dependent breast cancer.
Hormone-dependent breast cancer needs the hormone estrogen to grow.
Aromatase inhibitors decrease the body's estrogen by blocking an enzyme
called aromatase from turning androgen into estrogen. Aromatase
inhibitors are also being tested in clinical trials to compare them to
hormone therapy with tamoxifen for the treatment of metastatic breast
cancer. This results in substantial improvements in disease free and
overall survival for women with operable breast cancer (Mauri et al.,
2006).
1.2. AIM AND OBJECTIVES OF THE PRESENT RESEARCH
WORK
The present research work comprises of the following aspects with
the respective standard procedures and protocols on bio-samples of breast
carcinoma patients.
Haematological studies
To study the haematological changes in breast carcinoma
patients
24
Biochemical analyses
To quantify the intensity of oxidative stress
To
determine
the
enzymatic
and
non-
enzymatic
antioxidants
To determine the diagnostic potential of serum tumour
markers
To assess the hormonal profile and its significance in
hormone therapy
Immunological investigations
To evaluate the immunoglobulin status namely IgG, IgA,
IgE and IgD
To analyse the prognostic role of inflammatory mediators
and cytokines
To appraise the role of Anti- Inflammatory mediator
Histopathological analyses
To perform histopathological analysis of cancerous tissue of
breast by biopsy studies
Molecular studies
To assess the DNA damage due to oxidative stress
To screen for the expression of Her2/ neu oncoprotein
To study the Estrogen receptor and progesterone receptor
status
To monitor the correlation between the various parameters that
might prove vital for early diagnosis and prognosis of breast cancer
patients
25
1.3. SCOPE OF THE PRESENT RESEARCH WORK

The incidence of breast cancer continues to increase although, the
mortality rates have decreased since the early 1990s. A single biomarker
that would enable the early detection and prognosis remains elusive in
spite of extensive research carried out in breast cancer and a combination
of biomarkers are proposed to be tested in the present work. Analysis of
the above aspects may pave the way in future to improve our knowledge
on the biochemical, immunological and molecular mechanisms underlying
the process of cell proliferation thereby enabling us to diagnose early and
to explore its prognostic and therapeutic benefits. Screening of oncogenes
and oncoproteins would help us to detect breast cancer and to assess the
risk at an early stage. Screening of hormone receptors might help to
improve the treatment regimes by being more precise and by minimising
the complications and side effects associated with chemotherapy and
radiotherapy. Assessment of DNA damage would help us to predict the
uncontrolled proliferation of tumour cells and also to know about the
defective repair system present in cancerous cells. The present study
would throw light on the Research findings which would be useful to the
medical physicians and therapist, oncologist and future researchers on
breast carcinoma.
1.4. PLAN OF THE RESEARCH THESIS
The chapterization of the thesis comprises the following:
The Chapter I INTRODUCTION comprises of the General
Introduction related to breast cancer. It also includes Aims and Objectives
of the Research work, scope of the study and plan of the thesis.
26
The Chapter II REVIEW OF LITERATURE relates to the

chronological order of the research papers of breast cancer in the broad
aspects of Haematological studies, Biochemical analyses, Immunological
investigations, Histopathological analyses
and Molecular
studies on
earlier work.
The Chapter III MATERIALS AND METHODS deals with the

choice of the bio-samples of breast carcinoma patients, collection of biosamples of study, Instrumentation related standard Methodology of
procedures and protocols dealing with investigations of Haematological,
Biochemical, Immunological, Histopathological, and Molecular studies
and also the plan design of the Research study.
The Chapter IV RESULTS deals with the findings of experiments

and investigations dealing with the bio-samples under Haematological
studies,
Biochemical
analyses,
Immunological
investigations,
Histopathological analyses and Molecular studies substantiated with

statistically analysed data in the form of, tables, graphs/ figures and
photos/ plates.
The Chapter V DISCUSSION deals with the comparison of the

present valid findings with the earlier works of other researchers and
discussions with suggestions, clinical guidelines and conclusions.
27
The Chapter VI SUMMARY and CONCLUSIONS summarizes the

actual findings of the present research work with suggestions and
conclusions.
The Summary is followed by REFERENCES and APPENDIX.

Appendix includes in addition to composition of reagents/ stains, List of
publications and copies of published papers in National and International
journals.

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Chapter I

Types of breast cancer

Ductal carcinoma in situ (DCIS) is a noninvasive , precancerous

Invasive (infiltrating) ductal carcinoma is the most common cell

Lobular carcinoma in situ (LCIS) is a condition in which abnormal

Invasive lobular carcinoma is the 2nd most common type of

In inflammatory breast cancer is a rare and aggressive form of

Tubular carcinoma is also known as a well-differentiated

Medullary carcinoma is characterized by a prominent lymphocyte

Correct staging of breast cancer patients is of extraordinary

Table 1 Staging of breast cancer: TNM (Tumour Node Metastasis) system

Primary tumour cannot be assessed

No evidence of primary tumour

carcinoma in situ (ductal or globular or Pagets disease with no tumour)

tumour # 2cm in greatest dimension

tumour >2cm but not > 5 cm in greatest dimension

tumour > 5 cm in greatest dimension

tumour of any size with direct extension to chest wall or skin

Nodal involvement: N (nodal status)

Regional lymph node cannot be assessed

No regional lymph node metastasis histologically

Metastasis to one to three ipsilateral axillary node

Metastasis to one to three ipsilateral axillary node or internal mammary

Metastasis to one to three ipsilateral axillary node or internal mammary

No evidence of distant metastasis

Source: Singletary et al. (2002)

Staging provides useful information about the current status of

The following types and stages are recognised in breast cancer:

The incidence of breast cancer increases dramatically with age

Table 2 Risk factors for breast cancer

Any benign breast disease

Post menopausal hormone replacement

Moderate alcohol intake (2or 3 drinks/ day)

Menopause at >55 yrs

Increased bone density

Sedentary lifestyle and lack of exercise

Proliferative breast disease without atypia

Age at first birth > 30 yrs or nulliparous

First- degree relative with breast cancer

Upper socio-economic class

Personal history of endometrial or ovarian cancer

Significant radiation to chest

Increased breast density on mammogram

Personal history of breast cancer (in situ or invasive)

Proliferative breast disease with atypia

Two first- degree relative with breast cancer

Atypical hyperplasia and first- degree relative with breast cancer

Source: Goldman and Ausiello (2008).

The risk of breast cancer is not affected by dietary saturated fat

discharge almost always has a benign cause. Patients with a clear or

Tumour growth rate

Serum tumour markers

the plasma level of inflammatory markers increases with age (Hutchinson

Fig.2 Schematic representation of current molecular biomarkers used in

Estrogen receptor (ER)

Progesterone receptor (PR)

developing breast cancer and about 33% chance of developing ovarian

(Peutz-Jeghers syndrome) (Hearle et al., 2006).

Treatment of breast cancer

Hormone therapy with tamoxifen is often given to patients with

the chance of developing endometrial cancer. Women taking tamoxifen

Hormone therapy with an aromatase inhibitor is given to some

1.3. SCOPE OF THE PRESENT RESEARCH WORK

The Chapter II REVIEW OF LITERATURE relates to the