MED 399

TITLE:

THE TREATMENT AND MANAGEMENT METHODS OF

BREAST CANCER, THEIR SUCCESS RATES, AND
ASSOCIATED SETBACKS

AUTHOR: NANA KWAME OBENG BEMPONG

SM/SMS/ 16/0038

FACILITATOR: DR. AKWASI ANYANFUL

Date: 1st DECEMBER, 2018.

 TABLE OF CONTENT

1. Title

2. Acknowledgement

3. Abstract

4. Introduction

5. Body

6. Conclusion

7. Recommendations

8. References
 ACKNOWLEDGEMENT

I was blessed to have the help and support of many talented people to whom I want to express
my sincere thanks:

To my facilitator, Dr. Akwasi Anyanful, for his guidance, advise, and immense
contribution to this work.

To Eliza Akosua Asaa Gyebi, and Samuel Okyere, all students of the Level 300
UCCSMS class, for their insight, feedback and expertise.

To UCCSMS Class of 2022 students, who are worthy of honourable mention, for their
tremendous help.

To Kwadwo Boadu, and the wonderful staff at the UCCSMS library their tireless and
committed efforts.

To my father, Richard Bempong, my sisters, Georgette and Caroline, and my mother,

Sylvia, for their support and feedback.

And finally, to the many individuals who have in their own special ways contributed
to the creation of this work.
 ABSTRACT

The purpose of this work is to discuss current therapies used in the treatment of breast cancer
or its management. Breast cancer is the most common type of cancer that affects women. One risk
factor of developing breast cancer is age. Women over the age of 50 years record the most cases.
Breast cancer affects men as well as women, but male breast cancer accounts for less than 1 percent
of all breast cancer cases. About 5% of cancer cases, studies have found, are due to mutations in
genes such as BRCA-1 and BRCA-2, and also the tumour suppressor gene p53. In a third of all breast
cancer cases, oncogenes produce the protein HER-2. Other risk factors of breast cancer include a
genetic history of the disease in one’s family, early menstruation, delayed onset of menopause,
never giving birth, or giving birth to the first child after age 30, and some conditions such as tumours
that extend the duration of estrogen action in the body. Most breast cancers are first detected as
an unusual mass or lump in the breast. The earlier the cancer is detected, the greater the
chances of recovering fully from it. Oncologists select from a number of options when
treating cancer, depending on the stage of the tumour. The major treatments currently
available are surgery, radiation therapy, chemotherapy, and hormone therapy. Often,
targeting cancerous tumours requires the artistic combination of more than one type of cancer
therapy.
 INTRODUCTION

Cells, as we know them to be, are the building blocks of the body of any organism,
whether unicellular or multicellular. This is overemphasised in the cell theory proposed by
Theodor Schwann and Matthias Jakob Schleiden. Just like the organism they form, these cells
are not everlasting; while some cells, like neurons, last throughout the lifetime of the
organism, majority are quite short-lived. For cells of the latter group, there is the need for
them to divide to create a replacement for when they are gone. This was what Rudolph
Virchow observed, and he postulated, as part of the cell theory that new cells arise from pre-
existing cells. In essence, cell division is important to replace cells which have become too
old, mutated or have reduced performance from wear and tear. (1).

Cell replacement is achieved by cell division which is essential for life. In the process
of dividing, it is essential that the cell passes identical genetic material to the daughter cells.
Thus before a cell divides, it must duplicate or replicate its DNA, allocate the two DNA
copies to opposite ends of the cell and then split in the middle to daughter cells. This enables
each daughter cell to have its own set DNA to provide the operational instructions. This
ordered series of events that culminates in the cell growing and dividing to produce new
daughter cells is called the cell cycle. The cell cycle is divided into two main stages called
interphase and the M-stage, where M stands for mitotic. (1).

Interphase is basically the part of the cell cycle when no activities involved in cell
division occurs. Although regarded as a resting stage, the cell is engaged in several activities.
It is essentially divided into three phases. These are the Gap 1 phase (G1) where cytoplasmic
organelles like mitochondria, endoplasmic reticula, and centrioles are duplicated, the
Synthetic phase (S) where the DNA of the parent cell is replicated, and finally the Gap 2
phase (G2), where the cell “double checks” the duplicated DNA for any errors, making the
needed repairs. (1). For about 95% of the cycle, the cell is in interphase. The M-stage is the
stage for actual division of the cell to yield two daughter cells, and it lasts very short, for
about an hour or so. It is also subdivided into four phases; prophase, metaphase, anaphase,
and telophase. The M-stage is sharply followed by cytokinesis, in essence, formation of a
cleavage furrow to divide the parent cell’s cytoplasm into two daughter cells.

The breasts are the most visible features in the anterior thoracic wall, especially in
women. They consist of glandular tissue, which is the breast parenchyma, and supporting
fibrous tissue embedded within a fatty matrix, together with blood vessels, lymphatic vessels
and nerves. (2). The breasts are responsible for secreting milk during lactation, and are also
organs of sexual desire. Both men and women have breasts, though they are well developed
in women, and only rudimentary in men. At the greatest prominence of the breast is the
nipple, surrounded by a circular pigmented area of skin, the areola, within which there are
small round projections, called Montgomery tubercles. In a non-lactating woman, the amount
of fat surrounding the glandular tissue determines the size of the breast.

Each breast lies on the bed of the breast, which is made up of the pectoralis fascia,
and the fascia overlying the serratus anterior. Between the breast and the pectoralis facia is
the retromammary space, which contains a small amount of fat and allows the breast to slide
on the underlying fascia. The glandular tissue, often called the mammary glands, is firmly
attached to the overlying dermis by the suspensory ligaments of Cooper. The glands consist
of lobules, which produce the milk, and ducts, which drain the milk into the nipple. This
glandular tissue projects along the superolateral margin of the pectoralis major into the axilla
as the tail of Spence. (3). The breast is supplied with blood by the medial mammary
perforating branches of the internal thoracic artery, the lateral thoracic and thoracoacromial
branches of the axillary artery, and the second, third, and fourth intercostal branches of the
thoracic aorta. Venous blood from the breast is drained into the axillary vein.

Lymphatic drainage of the breast is important because of its role in the metastasis of
cancer cells. For the sake of understanding, the breast is divided into four quadrants. Lymph
passes from the nipple, areola and lobules of the subareolar plexus. From this plexus, most
lymph, usually from the lateral quadrants, drains to the axillary lymph nodes. Most of the
remaining lymph, particularly from the medial quadrants, drains into the parasternal lymph
nodes or to the opposite breast. Lymph from the inferior quadrants reach the abdominal
lymph nodes. Lymph from the skin of the breast drains into the ipsilateral axillary lymph
nodes, inferior deep cervical lymph nodes, and the infraclavicular lymph nodes. The breasts
are segmentally innervated by the anterior cutaneous branches of the fourth to sixth
intercostal nerves. (2).

Cancer occurs as a result of mutations, or abnormal alterations, in the genes that

control cell division and keep them healthy. Normally, bodily cells replace themselves
through mitosis, an orderly process of cell growth. Healthy new cells replace the old ones
which die off. But over time, these mutations can activate or suppress certain genes in a cell.
(4). The altered cell then gains the ability to proliferate without control, producing more cells
of its kind and forming a tumour. A tumour can either be malignant or benign. Benign tumors
are generally not considered cancerous. Their cells are not very different from the normal in
appearance, their growth is slow, and they do not invade surrounding tissues or spread to
other body parts. Malignant tumors, on the other hand, are cancerous. If they are left
unchecked, these cells can spread beyond their original site to other parts of the body.

The term “breast cancer” refers to a malignant tumour that has developed from the
breast tissue. Usually, it either begins in the cells of the lobules, or in the cells of the ducts.
Less commonly, breast cancer can begin in the surrounding fibrofatty tissue of the breast.
With time, cancer cells can invade nearby healthy breast tissue and find their way into the
axillary lymph nodes. If cancer cells get into the lymph nodes, they can travel through the
lymph in the vessels to other parts of the body. (5). The breast cancer’s stage refers to how far
the cancer cells have spread beyond the original tumour site.

Doctors have found a lot of ways to determine what stage a breast cancer has reached.
Clues from physical examination of the breast, radiographic images, bone scans, biopsies and
blood tests.
 BODY

STAGES OF BREAST CANCER

Stage 0 describes breast cancers that have not invaded any tissue yet, such as DCIS
(ductal carcinoma in situ) and LCIS (lobular carcinoma in situ). In general, stage 0 breast
cancers are localized in the ductile and lobular systems of the breast, but not in the fatty
tissue. Stage 0 cancers are described as being precancerous, and are not considered life-
threatening, but can become invasive over time. (6).

Stage I is used to describe breast cancer that has the ability to invade the surrounding
tissue. The size of a stage 1 cancer lies between 0.2mm and 2cm. Such cancers usually exist
as a large lump which can grow up to 2cm, or small masses of cells, which do not exceed
2mm in size. These cancers have not exited the breast yet, and may be found in the lymph
nodes. Stage I cancers are almost always curable. (6).

Stage II cancer is a medium-to-larger-sized tumour, usually one that has a size

between 2cm and 5cm. It has spread to 1 to 3 axillary lymph nodes, or parasternal lymph
nodes, and has invaded the surrounding fibrofatty supporting tissue of the breast. With
advances in the treatment of breast cancer, stage II cancers are often curable, but many
require additional treatments to achieve this goal. (6).

Stage III cancer is one that has spread to 4 to 9 axillary lymph nodes, more parasternal
lymph nodes and the infraclavicular lymph nodes. It can be of any size, though by this stage
the cancer usually gets larger than 5cm. It affects the fatty tissue and causes local
inflammation on the skin of the breast, characterized by pain, redness, swelling and heat. In
most cases, at this stage of breast cancer, because the cancer has advanced so much by
forming its own vasculature, it becomes increasingly difficult to combat. (6).

Stage IV of breast cancer is the most dangerous of all. Cancers in this stage are
commonly called metastatic or invasive. Here, the cancer cells spread beyond the breast and
nearby lymph nodes to other organs of the body such as the bones, brain, liver and lungs.
This stage of cancer is the most difficult to manage because of its metastasis. (6).
TYPES OF THERAPY USED IN BREAST CANCER TREATMENT

CHEMOTHERAPY: Chemotherapy treatment uses medicines to weaken and destroy

cancer cells in the body, including cells at the site of origin of the cancer and any cancer cells
that may have metastasized. Chemotherapy, often shortened to just "chemo" is a systemic
therapy, which means it affects the whole body by going through the bloodstream. (7). It is
important in the treatment of early-stage invasive breast cancer, or advanced-stage breast
cancer to destroy or damage the cancer cells as much as possible.

It is often common for doctors to give chemotherapy after surgery, in the treatment of
early-stage invasive breast cancer, to kill any cancer cells that may be left behind after
surgery and to reduce the risk of the cancer coming back. This form of chemotherapy is
called adjuvant chemotherapy, (8) because it is given in addition to surgery, which is
considered the primary treatment. Other times too, chemotherapy is given before surgery to
shrink the cancer so that less tissue will have to be removed during the surgery. This form of
chemotherapy before surgery is called neoadjuvant chemotherapy. (9).

Many drugs are used as anti-tumour medicines in chemotherapy. Some examples of

chemotherapy medicines include Methotrexate, Adriamycin, 5-Fluorouracil (5-FU),
Dororubicin, Epiburicin, Abraxane, Cyclophosphamide, Mitomycin, Taxol, Tamotere,
Ixempra, Gemcitabine and Epirubicin. All of these drugs have different mechanisms of
action. (10). For example, methotrexate interferes with folate metabolism by competitively
inhibiting dihydrofolate reductase. By starving cells of tetrahydrofolate, rapidly growing
cancer cells are unable to synthesize thymidine monophosphate (TMP) in addition to purines
and die out. Adriamycin, another anticancer drug, exerts its effects by intercalating between
the strands of DNA and preventing replication and transcription. Yet another, like 5-FU,
works by being converted in vivo to 5- deoxyuridine monophosphate (5-dUMP). This
analogue binds to the enzyme thymidylate synthetase irreversibly and thus, acts as a suicide
inhibitor. The inhibition prevents the enzyme from converting deoxyuridine monophosphate
(dUMP) to thymidine monophosphate (TMP). Since rapidly dividing cells require abundance
of this TMP, 5-FU starves them out of this and they die out. (11).

In many cases, chemotherapy medicines are given in combination, which means you
get two or three different medicines at the same time. (12). These combinations are known as
chemotherapy regimens. In early stage breast cancer, standard chemotherapy regimens lower
the risk of the cancer coming back. In advanced breast cancer, chemotherapy regimens make
the cancer shrink or disappear in about 30-60% of people treated. Examples of chemotherapy
regimens include:

 CMF: Cyclophosphamide, methotrexate, and 5-Fluorouracil

 CEF: Cyclophosphamide, Epirubicin, and 5-Fluorouracil
 FAC: 5-Fluorouracil, Adriamycin, and Cyclophosphamide

The fact that chemotherapy is revered in breast cancer treatment does not mean it is
devoid of problems. As with every pharmacology beneficial drug, there is the problem of side
effects. Most normal cells grow and divide in a precise, orderly way. Still, some normal cells
do divide quickly, including cells in hair follicles, nails, the mouth, digestive tract, and bone
marrow. Chemotherapy, thus, can unintentionally harm these other types of rapidly dividing
cells, possibly causing chemotherapy side effects. Common side effects associated with these
drugs include hair loss (alopecia), fatigue, infertility, mouth, throat and vaginal sores, nail
changes, weight changes and anaemia. (13).

Multidrug resistance is a major obstacle to successful cancer chemotherapy. One

important mechanism of multidrug resistance involves the multidrug transporter, P-
glycoprotein (Pgp). Pgp belongs to the ATP-binding cassette (ABC) family of transporter
molecules which require hydrolysis of ATP to run the transport mechanism. (14). This
transporter confers upon cancer cells the ability to resist lethal doses of certain cytotoxic
drugs by pumping the drugs out of the cells and thus reducing their cytotoxicity. This is
another setback to chemotherapy in breast cancer treatment.

RADIOTHERAPY: This type of breast cancer treatment involves the use of a special
kind of high-energy beam of rays to treat cells. This high-energy beam destroys the DNA of
the cell which is required for cell growth and cell division. There are two ways by which the
radiation is delivered to the cancer cells. The first way is to use a machine that delivers the
radiation from outside the body. (15). This machine is called a linear accelerator. In the
second way, seeds or pellets, small materials of radioactive material capable of giving off
radiation are put inside the body. In some cases, hyperthermia is recommended together with
radiotherapy. Hyperthermia involves heating up cancer cells with an energy source such as
ultrasound or microwave to about 45 degrees Celsius. What hyperthermia does is that it
increases the sensitivity of the cancer cells to radiation. (16). Radiotherapy is often used after
surgery to prevent the risk of recurrence, and just like chemotherapy, there is adjuvant
radiotherapy and neoadjuvant chemotherapy. (17).

There are three main types of radiation used in radiotherapy. The first type is called
external whole-breast radiation. In this technique, the linear accelerator is used to generate
and focus the high-energy radiation unto the affected breast. The schedule for this type of
radiotherapy is 5-7 weeks for slow treatment, and 3-5 weeks for accelerated treatment. The
second type of radiotherapy is called internal radiation. It is sometimes also referred to as
partial-breast radiotherapy or brachytherapy. This type of radiotherapy is not in used
extensively, as it is still undergoing much study to be used after lumpectomy. It involves the
insertion of tiny tubes called catheters in the skin. The seeds are then passed through the
catheter into the site of the cancer. The third type of radiotherapy is called intra-operative
radiation. In this type, a single dose of radiation is delivered by the linear accelerator during
surgery. During surgery, after the skin of the breast has been opened, the underlying tissue
has been exposed, and the cancerous mass has been resected, the surrounding tissue is
exposed to radiation to prevent risk of recurrence of the cancer. (18).

Radiation is used for local treatment of cancer. Since it does not use drugs, it is devoid
of the problems of chemotherapy. However, it also has its own problems. Over time, the
radiation damages cells that are in the path of its beam- normal cells as well as cancer cells.
The most annoying and uncomfortable problem of radiotherapy involves the skin of the area
being treated. In many cases, the side effect of radiotherapy presents on the skin in a way
similar to sunburn. It is characterised by itching, redness, swelling, pain, and at times possible
peeling. Unlike sunburn, this reaction to the radiation is more gradual and occurs in patches
on the skin. In some cases, there may be hyperpigmentation of the skin involved. Other side
effects may come as fatigue, heart problems, armpit discomfort, chest pain, and lower white
blood cell counts.

SURGERY: Surgery is usually the first line of attack against breast cancer. It is the
physical resection of the tumour and some amount of healthy surrounding tissue of the breast.
Surgery is also useful in the assessing the lymph nodes under the arm for cancer cells. (19).
The decision to use surgery for breast cancer treatment depends on several factors such as the
stage of the cancer, and the willingness of the individual to keep her breasts. Generally, the
smaller the tumour, the more surgical options the patient has. There are mainly two types of
surgery for breast cancer. These are lumpectomy; removal of the tumour with a small amount
of the healthy tissue around it, often called the margins, and mastectomy; surgical removal of
the entire breasts. (20).

The main advantage of lumpectomy is that the appearance and sensation of the breast
is preserved. Also, it is a less invasive procedure, so recovery time is shorter and it is easier to
perform. However, there are few potential disadvantages in that the probability of local
recurrence of cancer is high, and the patient is likely to have 5 to 7 weeks of adjuvant
radiotherapy. For mastectomy, the main advantage is that recurrence of the cancer usually
does not occur. It also does not require subsequent surgeries to check the cancer. The
disadvantages include a permanent loss of the breast, and it is more expensive than
lumpectomy. In high-risk people, there are other options as prophylactic mastectomy which is
the preventive removal of the breasts, and prophylactic ovary removal, which is the removal
of the ovary to reduce the amount of estrogen in the body and make it harder to stimulate the
development of breast cancer. (20).

During lumpectomy or mastectomy, the pathologist takes biopsies from lymph nodes.
If these biopsies show that the cancer cells have spread from the breast parenchyma to the
lymph nodes, then some axillary lymph nodes would be removed to prevent further spread of
the cancer. In all cases, breast reconstructive surgery can be performed to rebuild the breast
using tissue from another part of the body, or using synthetic implants. This can be done
while mastectomy is being performed, called immediate reconstruction, or at some other time
in the future, called delayed reconstruction. Some women decide against reconstructive
surgery, and rather opt for a prosthesis. This artificial breast is made from silicone or soft
material, and fitted into a mastectomy bra. (21).

HORMONE THERAPY: This is also called endocrine therapy. It is effective for the
treatment of tumours that have viable receptors for estrogen and progesterone (ie, ER-
positive or PR-positive). The breast is both ER-positive and PR-positive. (22). Stimulation of
the estrogen receptors leads to the development of the ductile system, while stimulation of the
progesterone receptors of the breast induces the lobular system to develop. (23). Such
tumours are fuelled by these steroid reproductive hormones, hence blocking their synthesis or
circulation will starve and kill cancer cells. One common drug used for this therapy is
tamoxifen. It is an estrogen analogue that binds to estrogen receptors on the breast and
prevents the binding of estrogen. It is effective for preventing recurrence of cancer in the
breast that had it. It works well in women who have been through menopause and those who
have not. Tamoxifen is an oral pill, and should only be taken based on prescription of a
physician, as certain substances interfere with its action. Common side effects of tamoxifen
include hot flashes, vaginal dryness, vaginal discharge, formation of blood clots, and
cataracts. (24).

Another group of drugs are called aromatase inhibitors. After menopause, estrogen is
produced no more in the ovaries, but rather in other tissues such as the adrenal glands. In
these tissues, androgens are converted by the enzyme aromatase into estrogen. These drugs,
which include Aromasin, Arimidex and Femara, inhibit this enzyme and therefore decrease
the production of estrogen in post-menopausal women. Aromatase inhibitors are used either
alone, or together with tamoxifen. (25) The side effects associated with their use are
osteoporosis, increased cholesterol levels, hot flashes, vaginal dryness and vaginal discharge.

In premenopausal women, estrogen production can be decreased by administering

drugs that suppress the secretion of estrogen by the ovaries. Drugs for ovarian suppression
are agonists of gonadotrophin releasing hormone (GnRH) receptors in the anterior pituitary
gland. Examples are Zoladex and Lupron. These drugs effectively stimulate the release of the
gonadotrophins, follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the
anterior pituitary. The gonadotrophins are carried in circulation to the ovary where the induce
secretion of estrogen and progesterone. Since the production of estrogen is induced by drugs,
the physiological feedback mechanisms are lost. Hence, there is an initial surge in estrogen
levels, after which estrogen drops to negligible levels in blood. They are given by injection
and prevent the ovary from making estrogen for 1 to 3 months. (26).
 CONCLUSION

The preferred therapy for breast cancer in a particular patient depends on several
factors. These include primary factors such as the stage of the breast cancer, the advantages
and disadvantages of the therapy, patient’s age and health, and known mutations in inherited
breast cancer genes such as BRCA-1 or BRCA-2. There are also secondary factors such as
patient’s preference and cost of therapy.
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