PATHOPHYSIOLOGY AND IMMUNOLOGICAL ROLE IN MAMMARY

CARSINOMA

Member of the group:

No Name NPM
1. Cokorda Gede Ari Dananjaya 14700121
2. A.A. Gede Indra Pramana Putra 14700123
3. I Made Elga Aldela Paramerta 14700125
4. Adex Wahyu Artha Febryawan 14700127
5. Gabriel Renata Handoyo 14700129
6. Ifwandani Saleh Putra 14700131
7. Tiza Ridho Riskyah 14700133
8. Muhammad Dhadhang Setyawan 14700135
9. Ni Putu Intan Yustika Rini Dewi 14700137
10. Ni Luh Putu Dian Utami Putri 14700139

FAKULTAS KEDOKTERAN
UNIVERSITAS WIJAYA KUSUMA SURABAYA
TAHUN AKADEMIK 2017/2018

LIST OF CONTENT
CHAPTER I INTRODUCTION
A. Background ....................................................................... 1
B. Problem ............................................................................. 4
C. Aim .................................................................................... 4
D. Benefit ............................................................................... 4

CHAPTER II lLITERATURE REVIEW

A. Mammary carcinoma......................................................... 6
1. Anatomy of the female breast..................................... 6
2. The immune system in cancer..................................... 7
3. Epidemiology of breast cancer.................................... 7
4. Pathophysiology of breast cancer............................... 9
5. Clasification................................................................ 9
6. Etiology of breast cancer............................................ 9
7. Detection of breast cancer........................................... 12

CHAPTER III CONCLUSION

REFERENCE

CHAPTER I
 INTRODUCTION

A. Background
Breast cancer or mammary cancer is the most common female cancer, the second
most common cause of cancer death in women, and the main cause of death in women
ages 40 to 59. It has been reported that mortality rate from breast cancer has been
significantly greater in women whose cancer was first diagnosed during pregnancy
compared with those who had never been pregnant. Nowadays, many women all over
the world faced the challenge of living with breast cancer. The lifetime probability of
developing breast cancer is one in six overall. High prevalence of breast cancer and high
mortality rate of women who stricken by, appoint it among the most challenging
subjects in the area of experiments. (ostad, parsa. 2014)

The link between the immune system and cancer has been widely appreciated for
over a century and was first high- lighted by Rudolph Virchow over 150 years ago. The
underlying basis for this relationship between cancer and immunity involves three basic
principles of how the immune system acts to defend and protect an individual: it detects
“nonself” antigens from pathogens or infected/malignant cells; it encompasses effector
functions to specifically target and destroy the pathogen or infected/malignant cells
while protecting the host; and it develops immunological memory via the adaptive
immune responses for subsequent defense mechanisms following an injury or an attack
against the host. (Pandya, et al. 2016).

Breast cancer is cancer that develops from breast tissue. Signs of breast cancer
include a lump in the breast, a change in breast shape, dimpling of the skin, nipple
discharge or a red scaly patch of skin. Risk factors for breast cancer include female sex,
older age, genetics, lack of childbearing or lack of breastfeeding, higher levels of
estrogens, certain dietary patterns, exposure to radiation, positive family history of
breast cancer and obesity. Tobacco smoking appears to increase the risk of breast
cancer. In those who are long-term smokers, the risk is increased 35% to 50%. Oral
contraceptives might represent a predisposing factor for the development of
premenopausal breast cancer. There is a relationship between diet and breast cancer,
including an increased risk with a high fat diet, alcohol intake, obesity and high
cholesterolintake. Dietary iodine deficiency may also play a role. (Kabel, Baali. 2015)

B. Problem
1. How to diagnose mammary carsinoma?
2. How to treat mammary carcinoma?
3. What is included in the pathophysiology and immunological role of mammary
carcinoma?

C. Aim
1. General Purpose
a. To know about pathophysiology and immunological role in mammary
carcinoma.
2. Special Purpose
a. To know how to diagnose patients with mammary carsinoma
b. To know about therapheutic options for patients with mammary carsinoma

D. Benefit
1. Benefits for Practitioners
a. Benefits for the community
To provide a scientific overview for the medical officer or community about
pathophysiology and immunological role of breast cancer

b. Benefits for the institution

It is expected to be effective in the development of therapy for mammary
carcinoma through research.
2. Theoretical benefits
Expected to be used as research in the field of internal medicine and surger
CHAPTER II
 lLITERATURE REVIEW

A. Mammary Carcinoma
1. Anatomy of The Female Breast
The breast is a symmetrical organ located on the front of the chest on both
sides of the midline. It occupies an area that stretches from the third rib to the
seventh rib and from the edge of the sternum to the armpit (Balboni et al., 2000).
The volume, shape and degree of development are very variable in relation to
various factors such as age, gland development, amount of fat and relative in
uence of endocrine stimulation. Before puberty, the mammary region is at, but
upon full development it assumes in females a hemispherical pro le. Normal
breast glands may be conical shaped, pear shaped or discoid (Testut and Latarjet,
1972). At the center of the breast there are the nipple and areola. The areola is a
at hyperpigmented area of skin with a round or oval shape and of variable
diameter, usually, between 3.5 and 6 cm. The nipple stays at center of the areola
and has a variable size and shape (conical, cylindrical). At its apex there are
several small depressions that represent the outlets of the ducts.
The areolar surface is irregular due to the presence of the 8-12 tubercles of
Morgagni, representing sebaceous glands. The mammary gland is made of three
components: glandular, adipose and brous tissues. Functionally, it can be
considered a modi ed apocrine sweat gland, in relation to breast feeding. The
glandular structure is composed by 15-20 lobes arranged in clusters with an
irregular radial pattern around and behind the nipple (Testut and Latarjet, 1972).
Each lobe is an independent glandular entity made of numerous lobules,
constituted by alveoli, which are the secreting units. The alveolar ducts converge
into the lobular ducts which in turn converge into the milk ducts. The milk ducts,
then, converge to the nipple with an ampullary dilatation, the lactiferous sinus.
The stroma is composed of dense brous and adipose tissues that surround the
entire gland and penetrate between the lobes. It may be divided in three portions:
a subcutaneous part, that lies between the skin and the gland, an
intraparenchymal portion, located between lobes and lobules, and a
retromammary portion, located behind the gland.
The breast parenchyma is contained by a two-layer fold of the
subcutaneous super cial fascia, that may be divided in two parts: the super cial

layer that covers the gland and contains brous septa, called Cooper’s ligaments,
which penetrate the gland and form the support structure of the parenchyma, and
the deep layer, which covers the posterior portion of the gland and separates it
from the underlying supercial fascia of the pectoralis major muscle. Cooper’s
ligaments are the suspensory ligaments of the breast gland and divide the
parenchyma into lobes (Stavros, 2004) (benedetto et al, 2016).

2. The Immune System in Cancer

The link between the immune system and cancer has been widely
appreciated for over century and was first highlighted by Rudolph Virchow over
150 years ago (J.L.Adams et al.,2015). The underlying basis for this relationship
between cancer and immunity involves three basic principles of how the immune
system acts to defend and protect an individual: it detects “nonself ” antigens
from pathogens or infected/malignant cells; it encompasses effecto functions to
specifically target and destroy the pathogen or infected/malignant cells while
protecting the host; and it develops immunological memory via the adaptive
immune responses for subsequent defense mechanisms following an injury or an
attack against the host [K. Murphy et al., 2008].

Through this process, the immune system has acquired characteristics

that give the paradigm known as immunoediting, which provides a balance
between immune surveillance and cancer progression in the realm of oncology.
This multifaceted mechanism consists of the three primary phases: elimination,
equilibrium, and escape, that contribute to cancer elimination, dormancy, and
progression, respectively [M. D. Vesely., 2011] Interestingly this ability of
cancers to evade or escape the immune response is nowrecognized tobeoneof the
most distinguished cancer hallmarks, which provides the platform for treatments
within the context of immunotherapies. Although the initial utilization of
immunotherapy for cancer treatments dates back to the early nineteenth century,
suggestive of work done b William B. Coley and colleagues (J.L.Adams et
al.,2015)., it was the more recent scientific advances that have helped elucidate
innovative approaches for implementing immunotherapies to eradicate and/or
treat various cancers. These advances have made the concept of
immunooncology and cancer immunotherapy more clinically relevant. This
review highlights the emerging and evolving findings that contribute to the
understanding of immunooncology, as well as emphasizing the importance of
relevant immunotherapies for potential therapeutic interventions in cancer
treatments.

a. Innate Immunity and Cancer

During cancer pathogenesis several components of the innate immunity

are activated in efforts to minimize cancermediated inflammation . This process
also initiates adaptive immune responses for targeting the cancer via mor specific
immune mechanisms [D. S. Chen et al.,2011]. Several studies suggest the role
for geneti and epigenetic modifications in cancer cells . Notably, these alterations
in th cancer cells correlate with the changes observed in the composition of their
cel surface proteins, resulting in expression of tumorassociated antigens which
can b recognized by complement proteins and thereby predisposing the cancer
cells to complement-mediated death . Activation of complement proteins has bee
reported in local and/or systemic biological fluids of cancer patients, as well as
in cancer tissues from patients diagnosed with neuroblastoma, lung cancer,
ovarian cancer, and a variety of others [R. Pio et al.,2014].

While complement activation promotes mechanisms that aid in

eradicating cancer cells, the presence of soluble an membrane-bound
complement regulatory proteins (CRPs) that inhibit various steps in the multiple
complement signaling pathways help Journal of Immunology Research 5 protect
cancer cells against complement-mediated injury . Inhibition of the complement
cascade also hinders some of the effects of adaptive immune responses because
complement proteins have also been reported to play a role in Band T cell
activation/survival .Therefore, CRP-mediated complemen inhibition may also
result in insufficient activation and expansion of B and T cell that can
specifically target the cancer cells . As previously mentioned, geneti and
epigenetic modifications result in modified cell surface markers and patterns on
the surface of the cancer cell . Notably, one such cell surface marker is MH class
I whose expression becomes altered or reduced in cancer cells [I. Waldhauer and
A. Steinle ,2008].

This aberrant or reduced MHC class I expression leads to activation of

NK cells vi activating receptors present on NK cell surface such as NKG2D
which bind to surface glycoproteins known as MICA/B thatmay be present on
the tumor .NK-induced programmed cell death (apoptosis) can occur by several
mechanisms such as tumor-necrosis factor-alpha- (TNF-𝛼-) dependent release of
cytoplasmic granules (perforin and granzymes) that form pores in cell
membranes; by antibodydependent complement cytotoxicity due to the presence
antibody receptor (CD16) on NK cell surface; and by the release of cytokines
such as IFN-𝛾 which mediates activation andmaturation of antigen-presenting
cells such as dendritic cells . Cells are resistant to NK-mediated lysis due to
normal expression o MH class I that activates inhibitor receptors on NK cells
which prevents NK cell induced apoptosis . Other mechanisms by which the
innate immunity contributes to cancer pathogenesis include neutrophils which
have been more widely known t promote cancer progression [A.D. Gregory and
A. M. Houghton ,2011].

Proteases such as neutrophil elastase present in neutrophil granules

facilitate growth of cancer cells . Other proteases in the neutrophil granules assist
in cleaving extracellular matrix proteins, thus allowin cancer invasion and
metastasis . As previously mentioned, these neutrophils also contain
phagolysosomes which contain enzymes like NADPH oxidase which oxidizes
superoxide radicals and other reactive oxygen species (ROS). It is well
documented that ROS have been reported to not only promote cancer by genetic
modifications via DNA damage, but also initiate cytotoxicity through disruption
o the cell membrane on the tumors[A.D. Gregory and A. M. Houghton ,2011].

b. Adaptive Immunity and Cancer

Similar to innate immunity, the adaptive immunity is comprised of

several components that can either eradicate cancer cells or promote their
proliferation [39].This formof immune response is capable of targeting antigens
specific to the cance cells by exploiting the effector functions of antibodies, T
cells B cells, and antigen-presenting cells (R. Warrington et al.,2011).
 The central dogma behind the cancer immunity concept involves the
formation of neoantigens, such as the new antigens that are formed due to
tumorigenesis/oncogenesis, which are phagocytosed by antigen-presenting cells
(APCs) or pinocytosed by dendritic cells for antigen processing [39]. MHC class
II molecules present exogenous peptides of tumor antigens, whereas MHC class
I molecules present endogenous peptides derived from cancer antigens [38]. The
processed tumor-associated antigens are then presented by MHC class II and
MHC class I molecules on the APC to the antigen-specific T cell receptor on
CD4+ T cells or CD8+ T cells, respectively [39]. Activation of CD4+ T cells
byMHC class II on APC primes them for subsequent exposures to that particular
antigenic peptide/MHC class II complex, thus formingmemory T cells(R.
Warrington et al.,2011).

IL-2 is also produced when T cells are activated and further promotes T
cell proliferation [47]. The cytokine milieu present within the tumor environment
at the time 6 Journal of Immunology Research of CD4+ T cell activation dictates
the T cell differentiation pathway as previouslymentioned [39].While it is known
that B cells can act asAPCs tona¨ıve T cells, activated CD4+ T cells (also known
as helper T cells) can also interact with na¨ıve B cells to promote their
activation .This process is known as thymus-dependent activation of B cells and
encompasses two types of signals between T helper cells and B cells: TCRMHC
class II with tumor antigen and a costimulatory signal between CD40 ligand and
CD40 (R. Warrington et al.,2011).

In the absence of this costimulatory signal, the B cells are not able to be
activated or proliferate . B cells can also be activated by thymusindependent (TI)
mechanisms which involve antigens with highly repetitive structures [31].
Following TI-independent B cell activation, antibodies are secreted which can
bind to the tumor-derived antigen. This can initiate tumor cell lysis via ADCC or
CDC and also by [32] binding to Fc receptors on NK cells [25]. Similarly,
activation of CD8+ T cells occurs by interaction of antigen-specific T cell
receptors with MHC class I/tumor antigen complexes leading to induction of
cytolytic CD8+ T cell-mediated lysis of cancer cells [39]. Within this central
dogma of cancer immunity, there are several regulatory factors that act as
immune checkpoints in the context of adaptive immune responses to mediate
either cancer progression or regression. For instance, during the first encounter
with antigen/MHC class II on the antigenpresenting cells, it is critical to have
two signals delivered between the APC and T cell: antigen-bound MHC class II
interacting with the T cell receptor and costimulatory signals (R. Warrington et
al.,2011).

Some of these costimulatory signals include CD28, ICOS, and CD80

(B7.1)/CD86 (B7.2) . The ICOS ligand onAPCs interacts with ICOS receptor on
T cells,whereas CD28 on T cells interacts with CD80 (B7.1)/CD86 (B7.2) on
APCs for costimulation . If these costimulatory signals are not present when
activating the na¨ıve T cells, then they will not differentiate or proliferate . Lack
of an appropriate costimulatory signal ultimately results in T cell anergy and a
state of immune tolerance to cancer cellassociated antigens; under this scenario,
adaptive immunity is shut down and cancer progresses [48]. Similarly, immune
tolerance is also initiated by CTLA4 on T cells binding to the CD80/CD86
proteins on APCs . Contrary to the binding of CD28 with these proteins,
interaction of CTLA4 on CD4+ T cells with CD80/CD86 on APCs results in T
cell inhibition and mediates downregulation of immune responses . CTLA4 is
also expressed by several cancers/tumors and this mechanism corresponds with
immune tolerance as seen in cancer progression . Interestingly, the T cells also
have a cell surface receptor molecule known as programed cell death protein 1
(PD-1) which can bind to its ligand, PD-L1, on APCs and mediates
immunosuppression . Notably, the PD-1 expression has also been reported in
multiple other immune cells such as B cells, NK cells, monocytes, dendritic
cells, and Tregs (J. R. Podojil and S. D. Miller, 2009)

Similar to expression of CTLA4, this PD-L1 protein is also expressed by

various types of cancer cells which may be a mechanism for how the cancer
escapes immunity . Immune responses in oncogenic environment can also be
suppressed by Tregs . Tumors/cancer cells can secrete chemokines like CCL22
that recruit Tregs to the oncogenic site and help suppress effector functions of
other T cells that may be necessary to eradicate cancer cells . Collectively, the
role of these innate and adaptive immune responses in oncogenesis serves to be
the underlying basis for immune surveillance and cancer immunoediting
(J.L.Adams et al.,2015.

3. Epidemiology of Breast Cancer

Breast cancer is the most common female cancer, the second most
common cause of cancer death in women, and the main cause of death in women
ages 40 to 59 . It has been reported that mortality rate from breast cancer has
been significantly greater in women whose cancer was first diagnosed during
pregnancy compared with those who had never pregnant (K. Murphy et al.,
2008). Nowadays, many women all over the world faced the challenge of living
with breast cancer. The lifetime probability of developing breast cancer is one in
six overall . High prevalence of breast cancer and high mortality rate of women
who stricken by, appoint it among the most challenging subjects in the area of
experiments. The two major types of breast cancer risks are objective and
subjective factors. Objective breast cancer risk is defined as an estimated chance
for bearing breast cancer based on scientifically established risk factors for the
disease and is predictive of resultant health outcomes. Subjective breast cancer
risk is identified as an individual’s realization of her chance for getting breast
cancer based on her own cognitive appraisal and is affected by depressive
conditions. Objective BC risk had a limited but significant relationship with
immune response and natural killer cell activity (NKCA), whereas Subjective
risk was highly associated with psychological distress but was not associated
with NKCA also the results are still controversial (J.L.Adams et al.,2015).
Breast cancer is the most commonly occurring cancer in women,
comprising almost one third of all malignancies in females. It is second only to
lung cancer as a cause of cancer mortality, and it is the leading cause of death for
American women between the ages of 40 and 55.1 The lifetime risk of a woman
developing invasive breast cancer is 12.6 % 2 one out of 8 females in the United
States will develop breast cancer at some point in her life. The death rate for
breast cancer has been slowly declining over the past decade, and the incidence
has remained level since 1988 after increasing steadily for nearly 50 years.
Twenty-five percent to 30% of women with invasive breast cancer will die of
their disease. 1 But this statistic, as grim as it is, also means that 70% to 75% of
women with invasive breast cancer will die of something other than their breast
cancer. Hence, a diagnosis of breast cancer, even invasive breast cancer, is not
necessarily the ‘‘sentence of death’’ that many women (and their insurance
companies) imagine. Mortality rates are highest in the very young (less than age
35) and in the very old (greater than age 75). It appears that the very young have
more aggressive disease, and that the very old may not be treated aggressively or
may have comorbid disease that increases breast cancer fatality.5 Although 60%
to 80% of recurrences occur in the first 3 years, the chance of recurrence exists
for up to 20 years.

4. Pathophysiology of Breast Cancer

Breast cancer usually occurs due to an interaction between environmental
and genetic factors. PI3K/AKT pathway and RAS/MEK/ERK pathway protect
normal cells from cell suicide. When the genes encoding these protective
pathways are mutated, the cells become incapable of committing suicide when
they are no longer needed which then leads to cancer development. These
mutations were proven to be experimentally linked to estrogen exposure. It was
suggested that abnormalities in the growth factors signaling can facilitate
malignant cell growth. Over expression of leptinin breast adipose tissue leads to
increased cell proliferation and cancer.(Kabel M.A, Baali F.H. 2015)
The familial tendency to develop breast cancers is called hereditary
breast–ovarian cancer syndrome. Some mutations associated with cancer, such as
p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA
leading to uncontrolled division, lack of attachment, and metastasis to distant
organs. The inherited mutation in BRCA1 or BRCA2 genes can interfere with
repair of DNA cross links and DNA double strand breaks. GATA-3 directly
controls the expression of estrogen receptor (ER) and other genes associated with
epithelial differentiation. Loss of GATA-3 leads to inhibition of differentiation
and poor prognosis due to increased cancer cell invasion and distant metastasis.
(Kabel, Baali. 2015)
Ninety-five percent of breast cancers arecarcinomas, ie, they arise from
breast epithelial elements. Breast cancers are divided into 2 major types, in situ
carcinomas and invasive (or infiltrating) carcinomas. The in situ carcinomas may
arise in either ductal or lobular epithelium, but remain confined there, with no
invasion of the underlying basement membrane that would constitute extension
beyondepithelial boundaries. As would be expected with such localized and
confined malignancy, there is negligible potential for metastases. When there is
extension of the ductal or lobular malignancy beyond the basement membrane
that constitutes the epithelial border, then the malignancy is considered invasive
(or infiltrating) ductal or lobular carcinoma. The potential for metastases and
ultimately death occurs in invasive disease.
Many factors including prenatal conditions, diet, physical activity,
estrogen exposure, body mass index, depression and quality of life have been
mentioned as breast cancer risk factors. A positive family history is the main risk
factor. Diet with high amounts of alcohol, fat, caffeine and red meat is a positive
risk factor for bearing breast cancer, whereas phytoestrogens and high amounts
of calcium/vitamin D can be effective to reduce it
(A.HoosandC.M.Britten ,2012). Hormonal conditions stand among the most
important factors. Prolonged exposure to and higher concentrations of
endogenous estrogen; which is controlled and modulated by menarche,
pregnancy, and menopause; increase the risk of breast cancer. Testosterone level
has also showed some parallelism with higher rate of breast cancer in some
studies, although not in all of them. Younger age of menarche and older age of
first full-term pregnancy are associated with a higher risk of breast cancer. The
data about the effects of oral contraceptives on breast cancer risk are
controversial. Some studies show an increased risk of breast cancer in oral
contraceptive users, whereas in some other researches, no significant difference
was seen. The two newer researches didn’t give any data which show that oral
contraceptives cause any increase in breast cancer risk. Long term use of
postmenopausal hormone therapy is associated with higher risk of breast cancer.
In contrast, short-term HT appears not to increase the risk significantly, although
it may make mammographic detection more difficult. Environmental toxic
agents such as Organochlorines include polychlorinated biphenyls (PCB's),
dioxins, and organochlorine pesticides such as DDT are weak estrogens with
high lipophilic properties and as a result, can store in adipose tissues. Some
studies suggest that exposure to these chemicals will increase the risk of bearing
breast cancer, however the data are controversial and more researches should be
done.

5. Classification
Nowadays, beside conventional use of grade, histology, and
immunohistochemical analysis, changes in gene expression during bearing
tumors are used as an instrument to classify breast cancer. Molecular profiling
make us capable for better understanding of breast cancer, more precision in
determining subtypes and better prediction of clinical outcome and response to
therapy. New instruments like microarray kits provide the possibility for
simultaneous studying of the expression of thousands of genes in a breast cancer
cells and finding out the Gene expression profile. Future applications will take
the same approach to proteins (proteomics), genome-wide germline variability
(single nucleotide polymorphisms), or cellular metabolism (metabolomics).
Based on these methods, several distinct breast cancer subtypes have been
identified including two main subtypes of estrogen receptor (ER)-negative
tumors and basal-like and human epidermal growth factor receptor-2 (HER2)-
enriched, and two subtypes of ER-positive tumors including luminal A and
luminal B. These subtypes differ markedly in prognosis and in the therapeutic
targets they express.The luminal cancers, luminal A and luminal B, so called
because they are characterized by expression of genes also expressed by normal
breast luminal epithelial cells, have overlap with ER-positive breast cancers.
There are also several subtypes characterized by low expression of hormone
receptor-related genes (ER-negative), one of which is called the "HER2-
enriched" subtype (previously called HER2+/ER-) and another called the "basal-
like" subtype. The basal-like subtype is named because it expresses many genes
characteristic of normal breast basal epithelial cells.

6. Etiology Of Breast Cancer

Breast cancer incidence is highest in North America and Northern Europe
and lowest in Asia and Africa. Studies of migration patterns to the United States
suggest that genetic factors alone do not account for the incidence variation
among countries, as the incidence rates of second-, third- and fourth-generation
Asian immigrants increase steadily in this country. Thus, environmental and/or
lifestyle factors appear to be important determinants of breast cancer risk. (R.
Warrington et al.,2011). Gender is by far the greatest risk factor. Breast cancer
occurs 100 times more frequently in women than men. In women, incidence
rates of breast cancer rise sharply with age (see Table 1) until ages 45 to 50,
when the rise becomes less steep.4 This change in slope probably reflects the
impact of hormonal change (menopause) that occurs about this time. By ages 75
to 80, the curve actually flattens and then decreases.
Despite the steepness of the incidence curve at younger ages, the more
important issue is the increasing prevalence of breast cancer with advancing age,
and the takehome message for physicians and underwriters alike is that any
breast mass in a postmenopausal woman should be considered cancer until
proven otherwise.8 Genetics plays a limited but important role as a risk factor for
breast cancer. Only 5% to 6% of breast cancers are considered hereditary. 9
BRCA-1 and BRCA-2 account for an estimated 80% of hereditary breast cancer,
but again, this only represents 5% to 6% of all breast cancers. BRCA-1 and/or
BRCA-2 positive women have a 50% to 85% lifetime risk of developing breast
cancer (see Table 1), and a 15% to 65% risk of developing ovarian cancer,
beginning at age 25.10 Familial breast cancer is considered a risk though earlier
studies suggested that this increased risk of cancer was offset by the fact that the
cancers induced by HRT were of more benign pathology and had a more
favorable prognosis,4 reevaluation of the WHI data reveals this impression to be
incorrect. Invasive breast cancers associated with estrogen plus progestin use
were larger (l.7 cm vs 1.5 cm, p 5 0.04), were more likely to be node positive
(26% vs 16%, p 5 0.03), and were diagnosed at a significantly more advanced
stage (regional/metastatic 25.4% vs 16%, p 5 0.04).
The percentages and distribution of invasive ductal, invasive lobular,
mixed ductal, and lobular as well as tubular carcinomas were similar in the
estrogen plus progestin group vs the placebo group.15 Over observation time as
short as a year, there was a statistically significant increase in breast density in
the estrogen plus progestin group, resulting in increased incidence of abnormal
mammograms (9.4% vs 5.4%, p,0.001).15 As noted by Gann and Morrow in a
JAMA editorial, ‘‘the ability of combined hormone therapy to decrease
mammographic sensitivity creates an almost unique situation in which an agent
increases the risk of developing a disease while simultaneously delaying its
detection.’’16 Li et al reported that women using unopposed estrogen
replacement therapy (ERT) had no appreciable increase in the risk of breast
cancer. However, use of combined estrogen and progestin hormone replacement
therapy had an overall 1.7-fold (95% CI 1.3– 2.2) increased risk of breast cancer,
including a 2.7-fold (95% CI 1.7–4.3) increased risk of invasive lobular
carcinoma, a 1.5-fold (95% CI, 1.1–2.0) increased risk of invasive ductal
carcinoma, and a 2-fold (95% CI 1.5–2.7) increased risk of ER1/PR1 breast
cancers.17 Other risk factors for breast cancer include alcohol, which has been
linked to increased blood levels of estrogen interfering with folate metabolism
that protects against tumor growth.
Women who drink 2 ounces of alcohol per day are 40% more likely to
develop breast cancer than women who drink no alcohol. 18 The Nurses’ Health
Study found that in postmenopausal women a weight gain of more than 45
pounds after age 18 was linked as an independent risk factor for breast cancer
(fat tissue produces hormones that are converted to estrogen). This association
was stronger in postmenopausal women who had never taken estrogen
replacement therapy. The relative risk of developing breast cancer was 1.6 with a
10–20 kg weight gain, and 2.0 with a weight gain of more than 20 kg, compared
to women with minimal weight gain. In contrast, among women taking estrogen,
those who gained weight did not have an increased risk of breast cancer.
The differing effects of obesity and weight gain in premenopausal and
postmenopausal women is thought to be because obesity decreases estradiol and
progesterone concentrations in premenopausal women because of an increased
frequency of anovulation.20 Thus, less circulating estrogen is available to target
tissues such as the breast. The Nurses’ Health Study also found that
postmenopausal women who got at least 1 hour of physical exercise per week
were 15% 20% less likely to develop breast cancer than those who were
completely sedentary. In regularly exercising women, participants in a health-
screening program in Norway, the reduction in risk was greater in
premenopausal women than in postmenopausal women (relative risk 0.38; 95%
CI 0.19–0.79).21 Thereason for the reduction of risk in exercising women may
be related to delayed menarche in young girls involved in strenuous physical
activity. Also, moderate levels of physical activity in premenopausal women are
associated with anovulatory cycles, which also are associated with decreased
risk.
Women treated for breast cancer have about a 1% greater chance per year
of developing a new second cancer in either the treated breast or the other breast.
Therefore, previous breast cancer is an accepted risk factor for development of
breast cancer.23 Ten percent of women with breast cancer develop a second
breast cancer, and women with breast cancer have a 3- to 7-fold increased
relative if a first-degree relative develops breast cancer before menopause, if it
affected both breasts, or if it occurred in conjunction with ovarian cancer.11
There is a 2-fold relative risk of breast cancer if a woman has a single firstdegree
relative (mother, sister or daughter). There is a 5-fold increased risk if 2 first-
degree relatives have had breast cancer.12 A woman’s hormonal history appears
to be a risk factor, as the relative risk of breast cancer seems to be related to the
breast’s cumulative exposure to estrogen and progesterone. Early menarche
(onset of menstruation , age 13), having no children or having them after age 30,
and menopause after age 50 and especially age 55—all these mean more
menstrual cycles and thus greater hormone exposure. (J.L.Adams et al.,2015)
The Women’s Health Initiative (WHI), a randomized controlled trial of
16,608 postmenopausal women comparing effects of estrogen plus progestin
with placebo on chronic disease risk, confirmed that combined estrogen plus
progestin use increases the risk of invasive breast cancer.14 Hormone
replacement therapy (HRT) users have a breast cancer risk that is 53% higher for
combination therapy and 34% higher for estrogen alone, especially if used for
more than 5 years. Al risk of cancer developing in the opposite breast. Women
who have had high doses of radiation to the chest before age 45—usually for
Hodgkin’s disease—are at significantly increased risk of breast cancer as adults.
Radiation after age 45 does not confer increased risk.
The most vulnerable ages appear to be the prepubertal years of 10 to 14.
These women should have yearly mammograms and clinical breast exams
beginning either 10 years after the radiation treatments or by age (R. Warrington
et al.,2011).

7. Detection Of Breast Cancer

As breast cancer rarely causes pain, a painless mass is much more
worrisome for malignancy than is one causing symptoms. Mammography done
yearly beginning at age 40 is the current recommendation for women with no
risk factors. The most commonly encountered categorization of mammography
findings is summarized. Although mammograms may detect malignancy as
small as 0.5 cm, 10% to 20% of malignancies elude detection by mammography,
even when they occur at a much larger size. In a patient with a solid, dominant
mass (suspicious mass) the primary purpose of the mammogram is to screen the
normal surroundin breast tissue and the opposite breast for nonpalpable cancers,
not to make a diagnosis of the palpable mass.8 Thus, a negative mammogram is
no guarantee of absence of malignancy, and a mass that does not disappear or
collapse with aspiration must be assumed be a malignancy and biopsied.( J. R.
Dunkelberger and W.-C. Song)

CHAPTER III
CONCLUSION
 Breast cancer is a disease that occurs when there is genetic damage to DNA from
breast epithelial cells. There are many types of breast cancer. Genetic changes are found
in epithelial cells, radiating into the duct or lobular tissue. The rate of cancer growth
depends on the effects of estrogen and progesterone. Cancer can be either invasive
(infiltration) or noninvasive (in situ). Invasive breast cancer or infiltration can progress
to the ductal wall and surrounding tissue, so far the most prevalent cancer is invasive
ductus carcinoma. The carcinoma duct originates from the lactiferous ducts and is
shaped like a tentacle that attacks the surrounding breast structure. Tumors are usually
unilateral, can not be described, solid, non mobile, and nontender. Lobular carcinoma is
derived from the breast lobes. Usually bilateral and not palpable. Nipple carcinoma
(paget's disease) originates from the nipple. Usually occurs with invasive ductal
carcinoma. Bleeding and nipple hardening.
This article reviews the evidence that the functioning of both the innate and the
adaptive immune system plays a role in preventing relapse in women with breast cancer.
Lymphocytes, including T cells, T regulatory cells, and natural killer cells, and their
cytokine release patterns are implicated in both primary prevention and recurrence of
breast cancer. Cancer prognosis may be related to immune system functional status. The
hypothesis that the immune system has a causal role in breast cancer etiology is
supported by epidemiologic, preclinical, and clinical research. Empirical support for the
concept that immune status and immunomodulatory therapy have important roles in
comprehensive breast cancer treatment is provided.

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