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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 mutations-

is 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 non-

metastatic 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 50’s. 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.



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• 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 d’orange (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).



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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 20th 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-



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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.



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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 Paget’s 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).



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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.



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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



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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 Hodgkin’s disease has been treated with chest irradiation have a



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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 1.1-1.9Sedentary lifestyle and lack of exercise 1.1-1.9

Proliferative breast disease without atypia 2

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 >4Personal history of breast cancer (in situ or invasive) >4

Proliferative breast disease with atypia >4

Two first- degree relative with breast cancer 5

Atypical hyperplasia and first- degree relative with breast cancer 10

Source: Goldman and Ausiello (2008).



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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)



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Oxidative stress

The oxidative stress can be defined as an imbalance between the

production of reactive oxygen species (ROS) and a biological system’s

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 (Dalle-

Donne et al., 2006).



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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



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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 S-

phase 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).



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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- á and CRP increase manifold in

response to tissue damage and active disease state. Both cancer risk and



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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.



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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.

Breast cancer

Molecular Biomarkers

Her2 ER BRCA

Immunotherapy Hormonal therapy Chemotherapy



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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



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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



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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. Breast-

conserving 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 .



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(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



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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.

Ø Haematological studies

• To study the haematological changes in breast carcinoma

patients



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Ø 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

Ø 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

Ø Histopathological analyses

• To perform histopathological analysis of cancerous tissue of

breast by biopsy studies

Ø 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

Ø To monitor the correlation between the various parameters that

might prove vital for early diagnosis and prognosis of breast cancer

patients



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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 1990’s. 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.



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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 bio-

samples 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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