PREFACE Assalamualaikum Wr.

Wb Firstly, I would like to thank God for this English paper had been finished at the perfect time. This assignment had been made as a requirement to pass the English lesson in this 6th semester in Faculty of Medicine Trisakti University. Second of all, I would like to thank to my parent for their support and also to dr. Sylvia Y Muliawan,Sp.MK.Ph.D as my supervisor for her guidance and some critics to my articles so that I can finished it easily. For all of my friends, I really appreciate their great time to accompany me and discuss the materials of the articles as long as I had difficulties in making this article. Last but not least, I realize to accomplish this assignment is far away from being perfect because of lack of my knowledge and grammatically language. Please feel free to give me feedback or criticism so I could improve this paper. And hopefully this article is worth for all. Wassalamualaikum Wr. wb

Jakarta, July 2011

Tri Wahyuningsih 030.08.244

ABSTRACT

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

TABLE OF CONTENT Chapter I Chapter II II.1 II.2 II.3 II.4 II.5 II.6 II.7 II.8 II.9 : Introduction : Breast Cancer : Definition : Causes . 4 .. 3

: Epidemiology and Pathophysiology .............................................. :Risk Factors : Symptoms : Test and Diagnosis : Treatments : Complications : Prevention .. .. . ..... ..... . ........................................ .

II.10 : Prognosis Conclusion References

CHAPTER I INTRODUCTION

Breast cancer is the top cancer in women both in the developed and the developing world. The incidence of breast cancer is increasing in the developing world due to increase life expectancy, increase urbanization and adoption of western lifestyles. Although some risk reduction might be achieved with prevention, these strategies cannot eliminate the majority of breast cancers that develop in low- and middle-income countries where breast cancer is diagnosed in very late stages. Therefore, early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control.(1)

The recommended early detection strategies for low- and middle-income countries are awareness of early signs and symptoms and screening by clinical breast examination in demonstration areas. Mammography screening is very costly and is recommended for countries with good health infrastructure that can afford a long-term programme.(1)

Many low- and middle-income countries that face the double burden of cervical and breast cancer need to implement combined cost-effective and affordable interventions to tackle these highly preventable diseases. (1)

Breast cancer incidence increases with age, with the vast majority of women diagnosed after the age of 40 years. Nevertheless, approximately 7% of women diagnosed with breast cancer between 2000 and 2005 were below the age of 40(2). Interestingly, breast cancer risk factors, clinical outcomes, and tumor biology are somewhat different in the subgroup of women below 40, suggesting that breast cancer in young women represents a distinct entity.(3)

CHAPTER II

BREAST CANCER

II.1. DEFINITION

Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare. The normal breast (4)

To understand breast cancer, it helps to have some basic knowledge about the normal structure of the breasts, shown in the diagram below.

The female breast is made up mainly of lobules (milk-producing glands), ducts (tiny tubes that carry the milk from the lobules to the nipple), and stroma (fatty tissue and connective tissue surrounding the ducts and lobules, blood vessels, and lymphatic vessels).

Most breast cancers begin in the cells that line the ducts (ductal cancers). Some begin in the cells that line the lobules (lobular cancers), while a small number start in other tissues.

II.2. CAUSES(5)

Many women who develop breast cancer have no risk factors other than age and sex. Gender is the biggest risk because breast cancer occurs mostly in women. Age is another critical factor. Breast cancer may occur at any age, though the risk of breast cancer increases with age. The average woman at age 30 years has one chance in 280 of developing breast cancer in the next 10 years. This chance increases to one in 70 for a woman aged 40 years, and to one in 40 at age 50 years. A 60-year-old woman has a one in 30 chance of developing breast cancer in the next 10 years. Women who start their periods at an early age (11 or younger) or experience a late menopause (55 or older) have a slightly higher risk of developing breast cancer. Conversely, being older at the time of the first menstrual period and early menopause tend to protect one from breast cancer.

II.3 EPIDEMIOLOGY AND PATHOGENESIS

EPIDEMIOLOGY

Breast cancer is the most common cancer in women worldwide, comprising 16% of all female cancers. It is estimated that 519 000 women died in 2004 due to breast cancer, and although breast cancer is thought to be a disease of the developed world, a majority (69%) of all breast cancer deaths occurs in developing countries(6)

Incidence rates vary greatly worldwide, with age standardized rates as high as 99.4 per 100 000 in North America. Eastern Europe, South America, Southern Africa, and western Asia have moderate incidence rates, but these are increasing. The lowest incidence rates are found in most African countries but here breast cancer incidence rates are also increasing.

Breast cancer survival rates vary greatly worldwide, ranging from 80% or over in North America, Sweden and Japan to around 60% in middle-income countries and below 40% in low-income countries(7). The low survival rates in less developed countries can be explained mainly by the lack of early detection programmes, resulting in a high proportion of women presenting with late-stage disease, as well as by the lack of adequate diagnosis and treatment facilitie

PATHOGENESIS

Breast cancer, like other cancers, occurs because of an interaction between the environment and a defective gene. Normal cells divide as many times as needed and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when mutations destroy their ability to stop dividing, to attach to other cells and to stay where they belong. When cells divide, their DNA is normally copied with many mistakes. Error-correcting proteins fix those mistakes. The mutations known to cause cancer, occur in the error-correcting mechanisms. These mutations are either inherited or acquired after birth. Presumably, they allow the other mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs. Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until then, they are protected from cell suicide by several protein clusters and pathways. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently "on", rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that causes cancer in combination with other mutations.

Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.

Failure of immune surveillance, the removal of malignant cells throughout one's life by the immune system.

Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. II.4 RISK FACTOR(8)

A risk factor is anything that makes it more likely you'll get a particular disease. But having one or even several risk factors doesn't necessarily mean you'll develop cancer many women who develop breast cancer have no known risk factors other than simply being women.

Factors that are associated with an increased risk of breast cancer include:

Being female. Women are much more likely than men are to develop breast cancer. Increasing age. Risk of breast cancer increases as age. Women older than 55 have a greater risk than do younger women.

A personal history of breast cancer A family history of breast cancer Inherited genes that increase cancer risk. Certain gene mutations that increase the risk of breast cancer can be passed from parents to children. The most common gene mutations are referred to as BRCA1 and BRCA2. These genes can greatly increase risk of breast cancer and other cancers, but they don't make cancer inevitable.

Radiation exposure. Received radiation treatments to chest as a child or young adult, more likely to develop breast cancer later in life.

Obesity. Being overweight or obese increases risk of breast cancer because fat tissue produces estrogen that may help fuel certain cancers.

Beginning your period at a younger age. Beginning period before age 12 increases your risk of breast cancer.

Beginning menopause at an older age. Menopause after age 55, more likely to develop breast cancer.

Having your first child at an older age. Women who give birth to their first child after age 35 may have an increased risk of breast cancer.

Postmenopausal hormone therapy. Women who take hormone therapy medications that combine estrogen and progesterone to treat the signs and symptoms of menopause have an increased risk of breast cancer.

Drinking alcohol. Drinking alcohol increases the risk of breast cancer. Experts recommend no more than one alcoholic beverage a day for women.

Other risk factors that have been suggested, but don't play any role in the development of breast cancer include tightfitting bras, antiperspirants, breast implants and shift work. II.5. SYMPTOMS(9)

Early breast cancer usually does not cause symptoms. This is why regular breast exams are important. As the cancer grows, symptoms may include:

Breast lump or lump in the armpit that is hard, has uneven edges, and usually does not hurt

Change in the size, shape, or feel of the breast or nipple -- for example, you may have redness, dimpling, or puckering that looks like the skin of an orange

Fluid coming from the nipple -- may be bloody, clear to yellow, green, and look like pus

Symptoms of advanced breast cancer may include:

Bone pain Breast pain or discomfort Skin ulcers Swelling of one arm (next to the breast with cancer) Weight loss

II.6. TEST AND DIAGNOSIS(10)

Tests and procedures used to diagnose breast cancer include:

Breast exam. check both of breasts, feeling for any lumps or other abnormalities. Yo Mammogram. A mammogram is an X-ray of the breast. Mammograms are commonly used to screen for breast cancer. If an abnormality is detected on a screening mammogram,

Breast ultrasound. Ultrasound uses sound waves to produce images of structures deep within the body. Ultrasound help determine whether a breast abnormality is likely to be a fluid-filled cyst or a solid mass, which may be either benign or cancerous. Breast ultrasound is helpful to guide radiologic biopsy to get a sample of breast tissue if a solid mass is found.

Removing a sample of breast cells for testing (biopsy). A biopsy to remove a sample of the suspicious breast cells helps determine whether cells are cancerous. The sample is sent to a laboratory for testing. A biopsy sample is also analyzed to
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determine the type of cells involved in the breast cancer, the aggressiveness (grade) of the cancer and whether the cancer cells have hormone receptors.

Breast magnetic resonance imaging (MRI). An MRI machine uses a magnet and radio waves to create pictures of the interior of breast. Before a breast MRI, patien receive an injection of dye. This test may be ordered after a breast biopsy confirms cancer, but before surgery to give doctor an idea of the extent of the cancer and to see if there's any evidence of cancer in the other breast.

Staging breast cancer

Cancer's stage helps determine

prognosis and the best treatment options. Complete

information about cancer's stage may not be available until after patien undergo breast cancer surgery.

Tests and procedures used to stage breast cancer may include:

Blood tests, such as a complete blood count Mammogram of the other breast to look for signs of cancer Chest X-ray Breast MRI Bone scan Computerized tomography (CT) scan Positron emission tomography (PET) scan

Not all women will need all of these tests and procedures. doctor selects the appropriate tests based on specific circumstances.

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Breast cancer stages range from 0 to IV, with 0 indicating cancer that is very small and noninvasive. Stage IV breast cancer, also called metastatic breast cancer, indicates cancer that has spread to other areas of the body. STAGING(11)

The American Joint Committee on Cancer (AJCC) staging system groups patients into 4 stages based on tumor size (T), lymph node status (N), and distant metastasis (M). See Table 5, below(19).

Primary tumor (T), Tumor size definitions are as follows:

Tx: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: (DCIS) Carcinoma in situ Tis: (LCIS) Carcinoma in situ Tis: Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor.)

T1: Tumor 2 cm or smaller in greatest diameter T1mic: Microinvasion 0.1 cm or less in greatest dimension T1a: Tumor >0.1 but not >0.5 cm in greatest diameter T1b: Tumor >0.5 but not >1 cm in greatest diameter T1c: Tumor >1 cm but not >2 cm in greatest diameter T2: Tumor >2 cm but not >5 cm in greatest diameter T3: Tumor >5 cm in greatest diameter T4: Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described below
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T4a: Extension to the chest wall, not including the pectoralis muscle T4b: Edema (including peau dorange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast

T4c: Both T4a and T4b T4d: Inflammatory disease

Regional lymph nodes (N), Regional lymph node definitions are as follows:

Nx: Regional lymph nodes cannot be assessed (eg, previously removed) N0: No regional lymph node metastasis N1: Metastasis in movable ipsilateral axillary lymph node(s) N2: Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis

N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures

N2b: Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes

N3: Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node

N3a: Metastasis in ipsilateral infraclavicular lymph node(s) N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

N3c: Metastasis in ipsilateral supraclavicular lymph node(s)

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Distant metastasis, Metastases are defined as follows:

Mx: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

TNM Staging System for Breast Cancer

Stage Stage 0 Stage I Stage IIA Tis T1 T0 T1 T2 Stage IIB T2 T3 Stage III T0 T1 T2 T3 Stage IIIB T4 T4 T4 Stage IIIC Stage IV Any T Any T Tumor N0 N0 N1 N1 N0 N1 N0 N2 N2 N2 N1-2 N0 N1 N2 N3 Any N Node Metastases M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

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II.7. TREATMENT(12)

Many women have treatment in addition to surgery, which may include radiation therapy, chemotherapy, or hormonal therapy. The decision about which additional treatments are needed is based upon the stage and type of cancer, the presence of hormonal and/or HER2/neu receptors, and patient health and preferences.

1. Radiation therapy is used to kill tumor cells if there are any left after surgery.

Radiation is a local treatment and therefore works only on tumor cells that are directly in its beam.

Radiation is used most often in people who have undergone conservative surgery such as lumpectomy. Conservative surgery is designed to leave as much of the breast tissue in place as possible.

Radiation therapy is usually given five days a week over five to six weeks. Each treatment takes only a few minutes.

Radiation therapy is painless and has relatively few side effects. However, it can irritate the skin or cause a burn similar to a bad sunburn in the area.

2. Chemotherapy consists of the administration of medications that kill cancer cells or stop them from growing. In breast cancer, three different chemotherapy strategies may be used:

1. Adjuvant chemotherapy is given to people who have had curative treatment for their breast cancer, such as surgery and radiation. It is given to reduce the possibility that the cancer will return.

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2. Presurgical chemotherapy is given to shrink a large tumor and/or to kill stray cancer cells. This increases the chances that surgery will get rid of the cancer completely. 3. Therapeutic chemotherapy is routinely administered to women with breast cancer that has spread beyond the confines of the breast or local area.

3. Hormonal therapy may be given because breast cancers (especially those that have ample estrogen or progesterone receptors) are frequently sensitive to changes in hormones. Hormonal therapy may be given to prevent recurrence of a tumor or for treatment of existing disease.

4. Monoclonal antibodies are antibodies against proteins in or around a cancer cell. Antibodies recognize an "invader" in this case, a cancer cell and attack it.

5. Surgery is generally the first step after the diagnosis of breast cancer. The type of surgery is dependent upon the size and type of tumor and the patient's health and preferences. II.8. COMPLICATIONS(13)

Complications of breast cancer include:

Destruction of the breast Destruction of the chest wall surrounding the breast Mastitis Nipple discharge Chest pain
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Radiation therapy side effects Chemotherapy side effects

Additional complications occur when the cancer spreads to other parts of the body, called metastasis. The most common sites include the lungs, liver and bones.

Complications of metastasis include:

Pneumonia Collapsed lung Respiratory failure Liver failure Bone fractures

II.9. PREVENTION

Control of specific modifiable breast cancer risk factors as well as effective integrated prevention of non-communicable diseases which promotes healthy diet, physical activity and control of alcohol intake, overweight and obesity, could eventually have an impact in reducing the incidence of breast cancer in the long term.

Early detection

Although some risk reduction might be achieved with prevention, these strategies cannot eliminate the majority of breast cancers that develop in low- and middle-income countries. Therefore, early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control.(14)

There are two early detection methods:

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early diagnosis or awareness of early signs and symptoms in symptomatic populations in order to facilitate diagnosis and early treatment, and

screening that is the systematic application of a screening test in a presumably asymptomatic population. It aims to identify individuals with an abnormality suggestive of cancer.

A screening programme is a far more complex undertaking that an early diagnosis programme.(15)

Irrespective of the early detection method used, central to the success of population based early detection are careful planning and a well organized and sustainable programme that targets the right population group and ensures coordination, continuity and quality of actions across the whole continuum of care. Targeting the wrong age group, such as, younger women with low risk of breast cancer, could cause a lower number of breast cancers found per woman screened and therefore reduce its cost-effectiveness. In addition, targeting younger women would lead to more evaluation of benign tumours, which causes unnecessary overload of health care facilities due to the use of addition diagnostic resources. Early diagnosis (16)

Early diagnosis remains an important early detection strategy, particularly in low- and middleincome countries where the diseases is diagnosed in late stages and resources are very limited. There is some evidence that this strategy can produce "down staging" (increasing in proportion of breast cancers detected at an early stage) of the disease to stages that are more amenable to curative treatment.

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Mammography screening(16)

Mammography screening is the only screening method that has proven to be effective. It can reduce breast cancer mortality by 20 to 30% in women over 50 yrs old in high-income countries when the screening coverage is over 70% (IARC, 2008). Mammography screening is very complex and resource intensive and no research of its effectiveness has been conducted in low resource settings. Breast self examination (BSE)(17)

There is no evidence on the effect of screening through breast self-examination (BSE). However, the practice of BSE has been seen to empower women, taking responsibility for their own health. Therefore, BSE is recommend for raising awareness among women at risk rather than as a screening method. HOW TO DO A BREAST SELF-EXAM (18) In the Shower Fingers flat, move gently over every part of each breast. Use your right hand to examine the left breast, left hand for the right breast. Check for any lump, hard knot, or thickening. Carefully observe any changes in your breasts.

Before a Mirror Inspect your breasts with your arms at your sides. Next, raise your arms high overhead.

Look for any changes in the contour of each breast, a swelling, a dimpling of the skin, or changes in the nipples. Then rest your palms on your hips and
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press firmly to flex your chest muscles. Left and right breasts will not exactly matchfew women's breasts do.

Lying Down Place a pillow under your right shoulder and put your right arm behind your head. With the fingers of your left hand flat, press your right breast gently in small circular motions, moving vertically or in a circular pattern covering the entire breast.

Use light, medium, and firm pressure. Squeeze the nipple; check for discharge and lumps. Repeat these steps for your left breast. II.10. PROGNOSIS(19)

Five-year survival rates are highly correlated with tumor stage, as follows:

Stage 0: 99-100% Stage I: 95-100% Stage II: 86% Stage III: 57% Stage IV: 20%

This prognostic information can guide physicians in making therapeutic decisions. Pathologic review of the tumor tissue for histological grade along with the determination of estrogen/progesterone receptor status, HER2 status, and lymph node involvement as determined by sentinel lymph node biopsy or axillary lymph node dissection is necessary for determining prognosis.
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CHAPTER V CONCLUSION There are two important aspects in breast cancer prevention: early detection and risk reduction. Screening may identify early noninvasive cancers and allow treatment before they become invasive or identify invasive cancers at an early treatable stage. But screening does not, per se, prevent cancer. Breast cancer prevention really must be understood as risk reduction. In extremely high-risk patients, such as those who have breast cancer-associated (BRCA)mutations, risk reduction may involve prophylactic surgical removal of the breasts and ovaries. For the average patient, lifestyle modifications (diet, exercise, weight loss, etc.) may be easily recommended and have many other benefits. For patients who have an increased risk based on other factors, the use of hormone-blocking agents, in addition to the usual lifestyle recommendations, may also be considered.

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