Breast cancer - An Overview

Breast cancer refers to cancers that originate from breast tissue, most commonly from the inner lining of milk ducts or lobules. There are different types of breast cancer, with different stages (spread), aggressiveness, and genetic makeup. Survival varies greatly depending on those factors; with best treatment, 10-year disease-free survival varies from 98% to 10%. Treatment includes surgery, drugs (hormonal therapy and chemotherapy), and radiation

Worldwide, breast cancer comprises 10.4% of all cancer incidence, making it the second most common type of cancer (after lung cancer) and the fifth most common cause of cancer death.[2] In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).[3] Breast cancer is about 100 times more common in women than in men, but survival rates are equal in both sexes.

Some breast cancers require the hormones estrogen and progesterone to grow, and have receptors for those hormones. After surgery those cancers are treated with drugs that interfere with those hormones, usually tamoxifen, and with drugs that shut off the production of estrogen in the ovaries or elsewhere; this may damage the ovaries and end fertility. Low-risk, hormone-sensitive breast cancers may be treated with hormone therapy and radiation alone. Breast cancers without hormone receptors, or which have spread to the lymph nodes in the armpits, or which express certain genetic characteristics, are higher-risk, and are treated more aggressively. One standard regimen, popular in the U.S., is cyclophosphamide plus doxorubicin (Adriamycin), known as CA; these drugs damage DNA in the cancer, but also in fast-growing normal cells where they cause serious side effects. Sometimes a taxane drug, such as docetaxel, is added, and the regime is then known as CAT; taxane attacks the microtubules in cancer cells. An equivalent treatment, popular in Europe, is cyclophosphamide, methotrexate, and fluorouracil (CMF).[7] Monoclonal antibodies, such as trastuzumab, are used for cancer cells that have the HER2 mutation. Radiation is usually added to the surgical bed to control cancer cells that were missed by the surgery, which usually extends survival, although radiation exposure to the heart may cause damage and heart failure in the following years Classification
Main article: Breast cancer classification

Breast cancers are classified by four different schemes:

* Stage. The TNM classification for breast cancer is based on the size of the tumor (T), whether or not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has metastasized (M) or spread to a more distant part of the body. Larger size, nodal spread, and metastasis have a worse prognosis.

* Pathology. Most often, breast cancer cells are derived from the epithelium lining the ducts. Frequently they are derived from the epithelial lining of the lobules. Less commonly, they are derived from nonepithelial tissue. Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of the surrounding tissue. Invasive carcinoma invades the surrounding tissue.

* Grade (Bloom-Richardson grade). When cells become differentiated, they take different shapes and forms to function as part of an organ. Cancerous cells lose that differentiation. Cells that normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade). Poorly-differentiated cancers have a worse prognosis.
* Receptor status. Breast cancer cells have receptors on their surface. Chemical messengers such as hormones bind to receptors, and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Cells with these receptors are called ER positive (ER+), ER negative (ER-) PR positive (PR+) PR negative (PR-) HER2 positive (HER2+) and HER2 negative (HER2-). Cells with none of these receptors are called basal-like or triple negative. ER+ cancer cells depend on estrogen for their growth, so they can be treated with drugs to reduce estrogen, and generally have a better prognosis. HER2+ cancer cells respond to drugs such as trastuzumab. Generally, HER2+ has a worse prognosis. These receptors are identified by immunohistochemistry.

Receptor status is used to divide breast cancer into four molecular classes: (1) Basal-like, which are ER-, PR- and HER2- (triple negative, TN). Most BRCA1 breast cancers are basal-like TN. (2) Luminal A, which are ER+ and low grade (3) Luminal B, which are ER+ but often high grade (4) HER2+, which have amplified ERBB2.

DNA microarrays have compared normal cells to breast cancer cells and found differences in hundreds of genes, but the significance of most of those differences is unknown. Several screening tests are commercially marketed, but the evidence for their value is limited. The only test supported by Level II evidence is Oncotype DX, which is not approved by the U.S. Food and Drug Administration (FDA) but is endorsed by the American Society of Clinical Oncology. MammaPrint is approved by the FDA but is only supported by Level III evidence. Two other tests have Level III evidence: Theros and MapQuant Dx. No tests have been verified by Level I evidence (a prospective, randomized controlled trial in which patients who used the test had a better outcome than those who did not). In a review, Sotirou concluded, "The genetic tests add modest prognostic information for patients with HER2-positive and triple-negative tumors, but when measures of clinical risk are equivocal (e.g., intermediate expression of ER and intermediate histologic grade), these assays could guide clinical decisions."

Breast cancer is usually, but not always, primarily classified by its histological appearance. Rare variants are defined on the basis of physical exam findings. For example, inflammatory breast cancer (IBC), a form of ductal carcinoma or malignant cancer in the ducts, is distinguished from other carcinomas by the inflamed appearance of the affected breast.[11] In the future, some pathologic classifications may be changed.
Signs and symptoms

The first symptom, or subjective sign, of breast cancer is typically a lump that feels different from the rest of the breast tissue. According to the The Merck Manual, more than 80% of breast cancer cases are discovered when the woman feels a lump.According to the American Cancer Society, the first medical sign, or objective indication of breast cancer as detected by a physician, is discovered by mammogram. Lumps found in lymph nodes located in the armpits can also indicate breast cancer.

Indications of breast cancer other than a lump may include changes in breast size or shape, skin dimpling, nipple inversion, or spontaneous single-nipple discharge. Pain ("mastodynia") is an unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other breast health issues.

When breast cancer cells invade the dermal lymphatics—small lymph vessels in the skin of the breast—its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer (IBC). Symptoms of inflammatory breast cancer include pain, swelling, warmth and redness throughout the breast, as well as an orange-peel texture to the skin referred to as peau d'orange.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes such as redness and mild flaking of the nipple skin. As Paget's advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget's also have a lump in the breast.

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. Common sites of metastasis include bone, liver, lung and brain.[16] Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are "non-specific", meaning they can also be manifestations of many other illnesses.
Most symptoms of breast disorder do not turn out to represent underlying breast cancer. Benign breast diseases such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms. The appearance of a new symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.
Causes and risk factors
Main article: Risk factors of breast cancer

The primary risk factors that have been identified are sex,age, childbearing, hormones, a high-fat diet, alcohol intake, obesity, and environmental factors such as tobacco use, radiation , endocrine disruptors and shiftwork.
Well established risk factors account for 47% of cases while 5% are attributable to hereditary syndromes.[28] In particular, carriers of the breast cancer susceptibility genes, BRCA1 and BRCA2, are at a 30-40% increased risk for breast and ovarian cancer, depending on in which portion of the protein the mutation occurs.
* Personal history of breast cancer: A woman who had breast cancer in one breast has an increased risk of getting cancer in her other breast.
* Family history: A woman's risk of breast cancer is higher if her mother, sister, or daughter had breast cancer. The risk is higher if her family member got breast cancer before age 40. Having other relatives with breast cancer (in either her mother's or father's family) may also increase a woman's risk.
* Certain breast changes: Some women have cells in the breast that look abnormal under a microscope. Having certain types of abnormal cells (atypical hyperplasia and lobular carcinoma in situ [LCIS]) increases the risk of breast cancer.
* Race: Breast cancer is diagnosed more often in Caucasian women than Latina, Asian, or African American women.
* No physical activity: Women who are physically inactive throughout life may have an increased risk of breast cancer. Being active may help decrease risk.

Abortion has not been found to be a risk factor for breast cancer. The breast cancer abortion hypothesis however continues to be promoted by some pro-life groups. Bras and tight fitting clothing has not been found to be related to breast cancer.
United Kingdom being member of International Cancer Genome Consortium is leading efforts to map breast cancer's complete genome.
Pathophysiology
Main article: Carcinogenesis

Breast cancer, like other forms of cancer, is the outcome of multiple environmental and hereditary factors. Some of these factors include:

1. Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and TP53.
2. Lesions to DNA such as genetic mutations. Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.
3. Failure of immune surveillance, a theory in which the immune system removes malignant cells throughout one's life.
4. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth.[citation needed]

People in less-developed countries report lower incidence rates than in developed countries.
In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian cancer have a first- or second-degree relative with one of these diseases. Mutations in either of two major susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. However, mutations in these genes account for only 2 to 3 percent of all breast cancers.
Diagnosis
While screening techniques discussed above are useful in determining the possibility of cancer, a further testing is necessary to confirm whether a lump detected on screening is cancer, as opposed to a benign alternative such as a simple cyst.

In a clinical setting, breast cancer is commonly diagnosed using a "triple test" of clinical breast examination (breast examination by a trained medical practitioner), mammography, and fine needle aspiration cytology. Both mammography and clinical breast exam, also used for screening, can indicate an approximate likelihood that a lump is cancer, and may also identify any other lesions. Fine Needle Aspiration and Cytology (FNAC), which may be done in a GP's office using local anaesthetic if required, involves attempting to extract a small portion of fluid from the lump. Clear fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, these three tools can be used to diagnose breast cancer with a good degree of accuracy.

Other options for biopsy include core biopsy, where a section of the breast lump is removed, and an excisional biopsy, where the entire lump is removed.
Screening
Main article: Breast cancer screening
Mammograms showing a normal breast (left) and a breast cancer (right).

Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes. A number of screening test have been employed including: clinical and self breast exams, mammography, genetic screening, ultrasound, and magnetic resonance imaging.

A clinical or self breast exam involves feeling the breast for lumps or other abnormalities. Evidence however does not support its use. Mammographic screening for breast cancer is also controversial. It uses x-rays to examine the breast for any uncharacteristic masses or lumps. The Cochrane collaboration in 2009 concluded that it is unclear whether screening does more good than harm.[39] Many national organizations however recommend it. If mammography is decided upon it should only be done every two years in women between the ages of 50 and 74.

In women at high risk, such as those with a strong family history of cancer, additional testing may include genetic screening and / or magnetic resonance imaging. Genetic screening involves testing for mutations in the BRCA genes.
Management
Main article: Breast cancer treatment
Chest appearance after right breast mastectomy.

The mainstay of breast cancer treatment is surgery. Adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor) is given when the tumor expresses estrogen receptors or progesterone receptors. Chemotherapy is given for more advanced stages of disease. Monoclonal antibodies are sometimes used, especially for HER2-positive tumors. Radiotherapy is given after surgery to the region of the tumor bed, to destroy microscopic tumors that may have escaped surgery. Treatments are constantly being evaluated in randomized, controlled trials, to evaluate and compare individual drugs, combinations of drugs, and surgical and radiation techniques. The latest research is reported annually at scientific meetings such as that of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposium,and the St. Gallen Oncology Conference in St. Gallen, Switzerland. These studies are reviewed by professional societies and other organizations, and formulated into guidelines for specific treatment groups and risk category.

Radiation therapy is also used to help destroy cancer cells that may linger after surgery. Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal radiotherapy). Radiation can reduce the risk of recurrence by 50-66% (1/2 - 2/3rds reduction of risk) when delivered in the correct dose.
Prognosis

A prognosis is the medical team's "best guess" in how cancer will affect a patient. There are many prognostic factors associated with breast cancer: staging, tumor size and location, grade, whether disease is systemic (has metastasized, or traveled to other parts of the body), recurrence of the disease, and age of patient.

Stage is the most important, as it takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the worse the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging unless the cancer is invasive. Ductal Carcinoma in situ throughout the entire breast is stage zero.

Grading is based on how biopsied, cultured cells behave. The closer to normal cancer cells are, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used).

Younger women tend to have a poorer prognosis than post-menopausal women due to several factors. Their breasts are active with their cycles, they may be nursing infants, and may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biologic factors contributing to a higher risk of disease recurrence for younger women with breast cancer.

The presence of estrogen and progesterone receptors in the cancer cell, while not prognostic, is important in guiding treatment. Those who do not test positive for these specific receptors will not respond to hormone therapy.

Likewise, HER2/neu status directs the course of treatment. Patients whose cancer cells are positive for HER2/neu have more aggressive disease and may be treated with trastuzumab, a monoclonal antibody that targets this protein.

Elevated CA15-3, in conjunction with alkaline phosphatase, was shown to increase chances of early recurrence in breast cancer.Psychological aspects

The emotional impact of cancer diagnosis, symptoms, treatment, and related issues can be severe. Most larger hospitals are associated with cancer support groups which provide a supportive environment to help patients cope and gain perspective from cancer survivors. Online cancer support groups are also very beneficial to cancer patients, especially in dealing with uncertainty and body-image problems inherent in cancer treatment.

Not all breast cancer patients experience their illness in the same manner. Factors such as age can have a significant impact on the way a patient copes with a breast cancer diagnosis. Premenopausal women with estrogen-receptor positive breast cancer must confront the issues of early menopause induced by many of the chemotherapy regimens used to treat their breast cancer, especially those that use hormones to counteract ovarian function.

On the other hand, a recent study conducted by researchers at the College of Public Health of the University of Georgia showed that older women may face a more difficult recovery from breast cancer than their younger counterparts. As the incidence of breast cancer in women over 50 rises and survival rates increase, breast cancer is increasingly becoming a geriatric issue that warrants both further research and the expansion of specialized cancer support services tailored for specific age groups.Epidemiology
Age-standardized death from breast cancer per 100,000 inhabitants in 2004.[48]
no data less than 2 2-4 4-6 6-8 8-10 10-12 12-14 14-16 16-18 18-20 20-22 more than 22

Worldwide, breast cancer is the most common cancer in women after skin cancer representing 16% of all female cancers. The rate is more than twice that of colorectal cancer and cervical cancer and about three times that of lung cancer.[citation needed] Mortality worldwide is 25% greater than that of lung cancer in women.[2] In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).[3] The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.

The incidence of breast cancer varies greatly around the world, being lower in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized incidence rates per 100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-Eastern Asia, 26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49; Southern Europe, 56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90.

Breast cancer is strongly related to age with only 5% of all breast cancers occur in women under 40 years old.
United States

The lifetime risk for breast cancer in the United States is usually give as 1 in 8 (12.5%) with a 1 in 35 (3%) chance of death.[54] A recent analysis however has called this estimate into question when it found a risk of only 6% in healthy women.

The United States have the highest annual incidence rates of breast cancer in the world; 128.6 per 100,000 in whites and 112.6 per 100,000 among African Americans.It is the second-most common cancer (after skin cancer) and the second-most common cause of cancer death (after lung cancer). In 2007, breast cancer was expected to cause 40,910 deaths in the US (7% of cancer deaths; almost 2% of all deaths).
This figure includes 450-500 annual deaths among men out of 2000 cancer cases.

In the US, both incidence and death rates for breast cancer have been declining in the last few years in Native Americans and Alaskan Natives. Nevertheless, a US study conducted in 2005 by the Society for Women's Health Research indicated that breast cancer remains the most feared disease, even though heart disease is a much more common cause of death among women. Many doctors say that women exaggerate their risk of breast cancer.

Racial disparities

Several studies have found that black women in the U.S. are more likely to die from breast cancer even though white women are more likely to be diagnosed with the disease. Even after diagnosis, black women are less likely to get treatment compared to white women. Scholars have advanced several theories for the disparities, including inadequate access to screening, reduced availability of the most advanced surgical and medical techniques, or some biological characteristic of the disease in the African American population. Some studies suggest that the racial disparity in breast cancer outcomes may reflect cultural biases more than biological disease differences. Research is currently ongoing to define the contribution of both biological and cultural factors.
UK

45,000 cases diagnosed and 12,500 deaths per annum. 60% of cases are treated with Tamoxifen, of these the drug becomes ineffective in 35%.
Developing countries

As developing countries grow and adopt Western culture they also accumulate more disease that has arisen from Western culture and its habits (fat/alcohol intake, smoking, exposure to oral contraceptives, the changing patterns of childbearing and breastfeeding, low parity). For instance, as South America has developed so has the amount of breast cancer. “Breast cancer in less developed countries, such as those in South America, is a major public health issue. It is a leading cause of cancer-related deaths in women in countries such as Argentina, Uruguay, and Brazil. The expected numbers of new cases and deaths due to breast cancer in South America for the year 2001 are approximately 70,000 and 30,000, respectively.” However, because of a lack of funding and resources, treatment is not always available to those suffering with breast cancer.
History

Breast cancer may be one of the oldest known forms of cancerous tumors in humans. The oldest description of cancer was discovered in Egypt and dates back to approximately 1600 BC. The Edwin Smith Papyrus describes 8 cases of tumors or ulcers of the breast that were treated by cauterization.The writing says about the disease, "There is no treatment." For centuries, physicians described similar cases in their practises, with the same conclusion. It was not until doctors achieved greater understanding of the circulatory system in the 17th century that they could establish a link between breast cancer and the lymph nodes in the armpit. The French surgeon Jean Louis Petit (1674–1750) and later the Scottish surgeon Benjamin Bell (1749–1806) were the first to remove the lymph nodes, breast tissue, and underlying chest muscle. Their successful work was carried on by William Stewart Halsted who started performing mastectomies in 1882. The Halsted radical mastectomy often involved removing both breasts, associated lymph nodes, and the underlying chest muscles. This often led to long-term pain and disability, but was seen as necessary in order to prevent the cancer from recurring. Radical mastectomies remained the standard until the 1970s, when a new understanding of metastasis led to perceiving cancer as a systemic illness as well as a localized one, and more sparing procedures were developed that proved equally effective.

Prominent women who died of breast cancer include Empress Theodora, wife of Justinian; Anne of Austria, mother of Louis XIV of France; Mary Washington, mother of George, and Rachel Carson, the environmentalist.

The first case-controlled study on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.
Society and culture
Pink ribbon.svg

In the fall of 1991, Susan G. Komen for the Cure handed out pink ribbons to participants in its New York City race for breast cancer survivors.[75]

The widespread acceptance of second opinions before surgery, less invasive surgical procedures, support groups, and other advances in patient care have stemmed, in part, from the breast cancer advocacy movement.[76]

In the month of October, the National Breast Cancer Awareness Month is recognized by survivors, family and friends of survivors and/or victims of the disease. A pink ribbon is worn to recognize the struggle that sufferers face when battling with the cancer.

Pink for October is an initiative started by Matthew Oliphant, which asks that any sites willing to help make people aware of breast cancer, change their template or layout to include the color pink, so that when visitors view the site, they see that the majority of the site is pink. Then after reading a short amount of information about breast cancer, or being redirected to another site, they are aware of the disease itself.

The patron saint of breast cancer is Agatha of Sicily.

The pink and blue ribbon was designed in 1996 by Nancy Nick, President and Founder of the John W. Nick Foundation to bring awareness that "Men Get Breast Cancer Too!"
In 2009 Out of the Shadow of Pink, A Man's Pink and the Brandon Greening Foundation for Breast Cancer in Men joined together to globally establish the third week of October as Male Breast Cancer Awareness Week