Breast Cancer

Breast cancer 1

Breast cancer

Breast cancerClassification and external resources

Mammograms showing a normal breast (left) and a cancerous breast (right).

ICD-10 C50 [1]

ICD-9 174 [2]-175 [3],V10.3 [4]

OMIM 114480 [5]

DiseasesDB 1598 [6]

MedlinePlus 000913 [7]

eMedicine med/2808 [8] med/3287 [9] radio/115 [10] plastic/521 [11]

MeSH D001943 [12]

Breast cancer is a type of cancer originating from breast tissue, most commonly from the inner lining of milk ductsor the lobules that supply the ducts with milk.[13] Cancers originating from ducts are known as ductal carcinomas,while those originating from lobules are known as lobular carcinomas. Breast cancer occurs in humans and othermammals. While the overwhelming majority of human cases occur in women, male breast cancer can also occur.[14]

The size, stage, rate of growth, and other characteristics of a breast cancer determine the kinds of treatment.Treatment may include surgery, drugs (hormonal therapy and chemotherapy), radiation and/or immunotherapy.[15]

Surgical removal of the tumor provides the single largest benefit, with surgery alone curing many cases. To increasethe likelihood of cure, several chemotherapy regimens are commonly given in addition to surgery. Radiation is usedafter breast-conserving surgery and substantially improves local relapse rates and in many circumstances also overallsurvival.[16] Some breast cancers are sensitive to hormones such as estrogen and/or progesterone, which makes itpossible to treat them by blocking the effects of these hormones.Worldwide, breast cancer comprises 22.9% of all cancers (excluding non-melanoma skin cancers) in women.[17] In2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women).[17] Breast cancer is morethan 100 times more common in women than in men, although men tend to have poorer outcomes due to delays indiagnosis.[18][19]

Prognosis and survival rates for breast cancer vary greatly depending on the cancer type, stage, treatment, andgeographical location of the patient. Survival rates in the Western world are high;[18] for example, more than 8 out of10 women (84%) in England diagnosed with breast cancer survive for at least 5 years.[20] In developing countries,however, survival rates are much poorer.

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Signs and symptoms

Early signs of breast cancer

Breast cancer showing an inverted nipple, lumpand skin dimpling.

The first noticeable symptom of breast cancer is typically a lump thatfeels different from the rest of the breast tissue. More than 80% ofbreast cancer cases are discovered when the woman feels a lump.[21]

The earliest breast cancers are detected by a mammogram.[22] Lumpsfound in lymph nodes located in the armpits[21] can also indicate breastcancer.

Indications of breast cancer other than a lump may include thickeningdifferent from the other breast tissue, one breast becoming larger orlower, a nipple changing position or shape or becoming inverted, skinpuckering or dimpling, a rash on or around a nipple, discharge fromnipple/s, constant pain in part of the breast or armpit, and swellingbeneath the armpit or around the collarbone.[23] Pain ("mastodynia") isan unreliable tool in determining the presence or absence of breastcancer, but may be indicative of other breast health issues.[21][22][24]

Inflammatory breast cancer is a particular type of breast cancer whichcan pose a substantial diagnostic challenge. Symptoms may resemble abreast inflammation and may include itching, pain, swelling, nippleinversion, warmth and redness throughout the breast, as well as anorange-peel texture to the skin referred to as peau d'orange;[21] theabsence of a discernible lump delays detection dangerously.

Another reported symptom complex of breast cancer is Paget's diseaseof the breast. This syndrome presents as eczematoid skin changes suchas 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. Approximatelyhalf of women diagnosed with Paget's also have a lump in thebreast.[25]

In rare cases, what initially appears as a fibroadenoma (hard movablelump) could in fact be a phyllodes tumor. Phyllodes tumors are formedwithin the stroma (connective tissue) of the breast and containglandular as well as stromal tissue. Phyllodes tumors are not staged inthe usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline, ormalignant.[26]

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 metastasisinclude bone, liver, lung and brain.[27] Unexplained weight loss can occasionally herald an occult breast cancer, ascan symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, ascan jaundice or neurological symptoms. These symptoms are called non-specific, meaning they could bemanifestations of many other illnesses.[28]

Most symptoms of breast disorders, including most lumps, do not turn out to represent underlying breast cancer.Less than 20% of lumps for example are cancer[29] and benign breast diseases such as mastitis and fibroadenoma ofthe breast are more common causes of breast disorder symptoms. Nevertheless, the appearance of a new symptomshould be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancerat almost any age.[30]

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Risk factorsThe primary risk factors for breast cancer are female sex and older age.[31] Other potential risk factors include: lackof childbearing or breastfeeding,[32] higher hormone levels,[33][34] diet and obesity.

LifestyleSmoking tobacco appears to increase the risk of breast cancer with the greater the amount of smoked and the earlierin life smoking began the higher the risk.[35] In those who are long term smokers the risk is increased 35% to50%.[35] A lack of physical activity has been linked to ~10% of cases.[36]

The association between breast feeding and breast cancer has not been clearly determined with some studies findingsupport for an association and others not.[37] In the 1980s the abortion–breast cancer hypothesis posited that inducedabortion increased the risk of developing breast cancer.[38] This hypothesis has been the subject of extensivescientific inquiry which has concluded that neither miscarriages nor abortions are associated.[39] There may be anassociation between oral contraceptives and the development of premenopausal breast cancer.[40] Whether or not thisassociation is causal is debated and if there is indeed a link the absolute effect is small.[41][42] In those with BRCA1or BRCA2 mutations or a family history modern OCPs do not appear to affect the subsequent risk of breastcancer.[43][44]

There is a relationship between diet and breast cancer including an increased risk with a high fat diet,[45] alcoholintake,[46] and obesity.[47] Dietary iodine deficiency may also play a role.[48]

Other risk factors include radiation,[49] and shift-work.[50] A number of chemicals have also been linked including:polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and organic solvents.[51] Although the radiation frommammography is a low dose, it is estimated that yearly screening from 40 to 80 years of age will cause ~225 cases offatal breast cancer per million women screened.[52]

GeneticsSome genetic susceptibility probably plays a role in most cases.[53] Overall however genetics is believed to be thecause of 5-10% of all cases.[54] In those with zero, one or two affected relatives the risk of breast cancer before theage of 80 is 7.8%, 13.3%, and 21.1% with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6%respectively.[55] In those with a first degree relative with the disease the risk of breast cancer between the age of 40and 50 is double that of the general population.[56]

In less than 5% of cases genetics plays a more significant role.[53] This include those who carry the BRCA1 andBRCA2 gene mutation.[53] These mutations account for up to 90% of the total genetic influence with a risk of breastcancer of 60-80% in those affected.[54] Other significant mutations include: p53 (Li-Fraumeni syndrome), PTEN(Cowden syndrome), and STK11 (Peutz–Jeghers syndrome), CHEK2, ATM, BRIP1, and PALB2.[54] In September2012, researchers reported that there are four genetically distinct types of the breast cancer and that in each type,hallmark genetic changes lead to many cancers.[57]

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Medical conditionsCertain breast changes: atypical hyperplasia and lobular carcinoma in situ found in benign breast conditions such asfibrocystic breast changes are correlated with an increased breast cancer risk.

Pathophysiology

Overview of signal transduction pathwaysinvolved in apoptosis. Mutations leading to loss

of apoptosis can lead to tumorigenesis.

Breast cancer, like other cancers, occurs because of an interactionbetween the environment and a defective gene. Normal cells divide asmany times as needed and stop. They attach to other cells and stay inplace in tissues. Cells become cancerous when mutations destroy theirability to stop dividing, to attach to other cells and to stay where theybelong.

Normal cells will commit cell suicide (apoptosis) when they are nolonger needed. Until then, they are protected from cell suicide byseveral protein clusters and pathways. One of the protective pathwaysis the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway.Sometimes the genes along these protective pathways are mutated in away that turns them permanently "on", rendering the cell incapable ofcommitting suicide when it is no longer needed. This is one of the steps that causes cancer in combination with othermutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide. Insome breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the "on"position, and the cancer cell does not commit suicide.[58]

Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.[59]

Failure of immune surveillance, the removal of malignant cells throughout one's life by the immune system.[60]

Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignantcell growth.[61][62] In breast adipose tissue, overexpression of leptin leads to increased cell proliferation andcancer.[63]

In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian cancer have a first- orsecond-degree relative with one of these diseases. The familial tendency to develop these cancers is called hereditarybreast—ovarian cancer syndrome. The best known of these, the BRCA mutations, confer a lifetime risk of breastcancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. Somemutations associated with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA.These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allowuncontrolled division, lack of attachment, and metastasis to distant organs.[49][64]However there is strong evidence ofresidual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families. This iscaused by unobserved risk factors.[65] This implicates environmental and other causes as triggers for breast cancers.The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA doublestrand breaks (known functions of the encoded protein)[66] These carcinogens cause DNA damage such as DNAcross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.[67][68]

However, mutations in BRCA genes account for only 2 to 3 percent of all breast cancers.[69] About half of hereditarybreast–ovarian cancer syndromes involve unknown genes.

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DiagnosisMost types of breast cancer are easy to diagnose by microscopic analysis of the biopsy. There are however, rarertypes of breast cancer that require specialized lab exams.While screening techniques are useful in determining the possibility of cancer, a further testing is necessary toconfirm whether a lump detected on screening is cancer, as opposed to a benign alternative such as a simple cyst.Very often the results of noninvasive examination, mammography and additional tests that are performed in specialcircumstances such as ultrasound or MR imaging are sufficient to warrant excisional biopsy as the definitivediagnostic and curative method.Both mammography and clinical breast exam, also used for screening, can indicate an approximate likelihood that alump is cancer, and may also detect some other lesions.[70] When the tests are inconclusive Fine Needle Aspirationand Cytology (FNAC) may be used. FNAC may be done in a GP's office using local anaesthetic if required, involvesattempting to extract a small portion of fluid from the lump. Clear fluid makes the lump highly unlikely to becancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, thesethree 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 excisionalbiopsy, where the entire lump is removed.In addition vacuum-assisted breast biopsy (VAB) may help diagnose breast cancer among patients with amammographically detected breast in women.[71]

Excised human breasttissue, showing an

irregular, dense, whitestellate area of cancer 2cm in diameter, within

yellow fatty tissue.

High grade invasiveductal carcinoma, with

minimal tubuleformation, markedpleomorphism, and

prominent mitoses, 40xfield.

Micrograph showinga lymph node invaded

by ductal breastcarcinoma and withextranodal extension

of tumour.

Neuropilin-2expression in normal

breast and breastcarcinoma tissue.

F-18 FDGPET/CT:

Metastasis of amamma

carcinoma in theright scapula

ClassificationBreast cancers are classified by several grading systems. Each of these influences the prognosis and can affecttreatment response. Description of a breast cancer optimally includes all of these factors.• Histopathology. Breast cancer is usually classified primarily by its histological appearance. Most breast cancers

are derived from the epithelium lining the ducts or lobules, and these cancers are classified as ductal or lobularcarcinoma. Carcinoma in situ is growth of low grade cancerous or precancerous cells within a particular tissuecompartment such as the mammary duct without invasion of the surrounding tissue. In contrast, invasivecarcinoma does not confine itself to the initial tissue compartment.[72]

• Grade. Grading compares the appearance of the breast cancer cells to the appearance of normal breast tissue.Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes andforms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cellsthat would normally line up in an orderly way to make up the milk ducts become disorganized. Cell divisionbecomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (lowgrade), moderately differentiated (intermediate grade), and poorly differentiated (high grade) as the cellsprogressively lose the features seen in normal breast cells. Poorly differentiated cancers have a worse prognosis.

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• Stage. Breast cancer staging using the TNM system is based on the size of thetumor (T), whether or not the tumorhas spread to the lymph nodes (N) in the armpits, and whether the tumor has metastasized (M) (i.e. spread to amore distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worseprognosis.The main stages are:• Stage 0 is a pre-cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular carcinoma in

situ (LCIS).• Stages 1–3 are within the breast or regional lymph nodes.• Stage 4 is 'metastatic' cancer that has a less favorable prognosis.

• Receptor status. Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus. Chemicalmessengers such as hormones bind to receptors, and this causes changes in the cell. Breast cancer cells may ormay not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2.ER+ cancer cells depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects(e.g. tamoxifen), and generally have a better prognosis. HER2+ breast cancer had a worse prognosis,[73] butHER2+ cancer cells respond to drugs such as the monoclonal antibody trastuzumab (in combination withconventional chemotherapy), and this has improved the prognosis significantly.[74] Cells with none of thesereceptors are called triple negative although they frequently express receptors for other hormones such asandrogen receptor and prolactin receptor.

• DNA assays. DNA testing of various types including DNA microarrays have compared normal cells to breastcancer cells. The specific changes in a particular breast cancer can be used to classify the cancer in several ways,and may assist in choosing the most effective treatment for that DNA type.

PreventionThe World Cancer Research Fund indicated that women can reduce their risk of breast cancer by maintaining ahealthy weight, drinking less alcohol, being physically active and breastfeeding their children.[75] Thesemodifications might prevent 38% of breast cancers in the US, 42% in the UK, 28% in Brazil and 20% in China.[75]

The benefits with moderate exercise such as brisk walking are seen at all age groups including postmenopausalwomen.[75][76]

Prophylactic bilateral mastectomy may be considered in people with BRCA1 and BRCA2 mutations.[77][78] Somecarcinogens are known to take advantage of deficiencies in processes that depend on normal BRCA1 and BRCA2function.

ScreeningBreast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve anearlier diagnosis. The assumption is that early detection will improve outcomes. A number of screening test havebeen employed including: clinical and self breast exams, mammography, genetic screening, ultrasound, andmagnetic resonance imaging.A clinical or self breast exam involves feeling the breast for lumps or other abnormalities. Research findings do notsupport the effectiveness of either type of breast exam, because by the time a lump is large enough to be found it islikely to have been growing for several years and will soon be large enough to be found without an exam.[79]

Mammographic screening for breast cancer uses x-rays to examine the breast for any uncharacteristic masses orlumps.For the average woman, the U.S. Preventive Services Task Force recommends (2009) mammography every two years in women between the ages of 50 and 74.[80] The European Cancer Observatory (2011) recommends mammography every 2 - 3 years between 50 and 69.[81] These task force reports point out that in addition to

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unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but significant increase inbreast cancer induced by radiation.[82] More recently, the Cochrane Collaboration (2011) concluded thatmammograms reduce mortality from breast cancer by 15% or .05% absolute, but also result in unnecessary surgeryand anxiety, resulting in their view that it is not clear whether mammography screening does more good or harm.[83]

The US Cochrane Collaboration now refer readers to The Nordic Cochrane Collection (2012), which reviewsupdated research to state that advances in diagnosis and treatment make mammography screening less effectivetoday. They state screening is “no longer effective.” They conclude that “it therefore no longer seems reasonable toattend” for breast cancer screening at any age, and warn of misleading information on the internet.[84]

Molecular breast imaging is currently under study and may also be an alternative.[85]

ManagementBreast cancer is usually treated with surgery and then possibly with chemotherapy or radiation, or both. Amultidisciplinary approach is preferable.[86] Hormone positive cancers are treated with long term hormone blockingtherapy. Treatments are given with increasing aggressiveness according to the prognosis and risk of recurrence. TheNPI Nottingham Prognostic Index is a useful tool in assessing the prognosis• Stage 1 cancers (and DCIS) have an excellent prognosis and are generally treated with lumpectomy and

sometimes radiation.[87] HER2+ cancers should be treated with the trastuzumab (Herceptin) regime.[88]

Chemotherapy is uncommon for other types of stage 1 cancers.• Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated

with surgery (lumpectomy or mastectomy with or without lymph node removal), chemotherapy (plus trastuzumabfor HER2+ cancers) and sometimes radiation (particularly following large cancers, multiple positive nodes orlumpectomy).

• Stage 4, metastatic cancer, (i.e. spread to distant sites) has poor prognosis and is managed by various combinationof all treatments from surgery, radiation, chemotherapy and targeted therapies. 10 year survival rate is 5% withouttreatment and 10% with optimal treatment.[89]

Surgery

Chest after right breast mastectomy

Surgery involves the physical removal of the tumor, typically alongwith some of the surrounding tissue and frequently sentinel nodebiopsy.

Standard surgeries include:• Mastectomy: Removal of the whole breast.• Quadrantectomy: Removal of one quarter of the breast.• Lumpectomy: Removal of a small part of the breast.If the patient desires, then breast reconstruction surgery, a type ofcosmetic surgery, may be performed to create an aesthetic appearance.In other cases, women use breast prostheses to simulate a breast under clothing, or choose a flat chest.

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MedicationDrugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy or other types of therapy priorto surgery are called neoadjuvant therapy.There are currently three main groups of medications used for adjuvant breast cancer treatment: hormone blockingtherapy, chemotherapy, and monoclonal antibodies.Hormone blocking therapy

Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogenreceptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormonereceptors). These ER+ cancers can be treated with drugs that either block the receptors, e.g. tamoxifen(Nolvadex), or alternatively block the production of estrogen with an aromatase inhibitor, e.g. anastrozole(Arimidex)[90] or letrozole (Femara). Aromatase inhibitors, however, are only suitable for post-menopausalpatients. This is because the active aromatase in postmenopausal women is different from the prevalent formin premenopausal women, and therefore these agents are ineffective in inhibiting the predominant aromataseof premenopausal women.[91]

ChemotherapyPredominately used for stage 2–4 disease, being particularly beneficial in estrogen receptor-negative (ER-)disease. They are given in combinations, usually for 3–6 months. One of the most common treatments iscyclophosphamide plus doxorubicin (Adriamycin), known as AC. Most chemotherapy medications work bydestroying fast-growing and/or fast-replicating cancer cells either by causing DNA damage upon replication orother mechanisms; these drugs also damage fast-growing normal cells where they cause serious side effects.Damage to the heart muscle is the most dangerous complication of doxorubicin. Sometimes a taxane drug,such as docetaxel, is added, and the regime is then known as CAT; taxane attacks the microtubules in cancercells. Another common treatment, which produces equivalent results, is cyclophosphamide, methotrexate, andfluorouracil (CMF). (Chemotherapy can literally refer to any drug, but it is usually used to refer to traditionalnon-hormone treatments for cancer.)

Monoclonal antibodiesTrastuzumab (Herceptin), a monoclonal antibody to HER2, has improved the 5 year disease free survival ofstage 1–3 HER2+ breast cancers to about 87% (overall survival 95%).[92] Trastuzumab, however, isexpensive, and approximately 2% of patients suffer significant heart damage.[93] Other monoclonal antibodiesare also undergoing clinical trials. Trastuzumab is only effective in patients with the HER2 mutation.

Between 25 and thirty percent of breast cancers have an amplification of the HER2 gene or overexpression of itsprotein product.[94] This receptor is normally stimulated by a growth factor which causes the cell to divide; in theabsence of the growth factor, the cell will normally stop growing. Overexpression of this receptor in breast cancer isassociated with increased disease recurrence and worse prognosis.Aspirin may reduce mortality from breast cancer.[95]

RadiationRadiotherapy is given after surgery to the region of the tumor bed and regional lymph nodes, to destroy microscopic tumor cells that may have escaped surgery. It may also have a beneficial effect on tumor microenvironment.[96][97]

Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal radiotherapy). Conventionally radiotherapy is given after the operation for breast cancer. Radiation can also be given at the time of operation on the breast cancer- intraoperatively. The largest randomised trial to test this approach was the TAR-GIT-A Trial[98] which found that targeted intraoperative radiotherapy was equally effective at 4-years as the usual several weeks' of whole breast external beam radiotherapy.[99] Radiation can reduce the risk of recurrence by 50–66% (1/2 – 2/3 reduction of risk) when delivered in the correct dose[100] and is considered essential when breast

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cancer is treated by removing only the lump (Lumpectomy or Wide local excision).

Prognosis

An example of recurrent breast cancer

A prognosis is a prediction of outcome and the probability ofprogression-free survival (PFS) or disease-free survival (DFS). Thesepredictions are based on experience with breast cancer patients withsimilar classification. A prognosis is an estimate, as patients with thesame classification will survive a different amount of time, andclassifications are not always precise. Survival is usually calculated asan average number of months (or years) that 50% of patients survive,or the percentage of patients that are alive after 1, 5, 15, and 20 years.Prognosis is important for treatment decisions because patients with agood prognosis are usually offered less invasive treatments, such aslumpectomy and radiation or hormone therapy, while patients withpoor prognosis are usually offered more aggressive treatment, such as more extensive mastectomy and one or morechemotherapy drugs.Prognostic factors are reflected in the classification scheme for breast cancer including stage, (i.e., tumor size,location, whether disease has spread to lymph nodes and other parts of the body), grade, recurrence of the disease,and the age and health of the patient. The Nottingham Prognostic Index is a commonly used prognostic tool.The stage of the breast cancer is the most important component of traditional classification methods of breast cancer,because it has a greater effect on the prognosis than the other considerations. Staging takes into consideration size,local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis,the poorer the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin orbeyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones andclose-to-normal cell behaviour (grading). Size is not a factor in staging unless the cancer is invasive. For example,Ductal Carcinoma In Situ (DCIS) involving the entire breast will still be stage zero and consequently an excellentprognosis with a 10yr disease free survival of about 98%.[101]

The breast cancer grade is assessed by comparison of the breast cancer cells to normal breast cells. The closer tonormal the 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 of1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scaleused). The most widely used grading system is the Nottingham scheme;[102] details are provided in the discussion ofbreast cancer grade.The presence of estrogen and progesterone receptors in the cancer cell is important in guiding treatment. Those whodo not test positive for these specific receptors will not be able to respond to hormone therapy, and this can affecttheir chance of survival depending upon what treatment options remain, the exact type of the cancer, and howadvanced the disease is.In addition to hormone receptors, there are other cell surface proteins that may affect prognosis and treatment. HER2status directs the course of treatment. Patients whose cancer cells are positive for HER2 have more aggressivedisease and may be treated with the 'targeted therapy', trastuzumab (Herceptin), a monoclonal antibody that targetsthis protein and improves the prognosis significantly.Younger women tend to have a poorer prognosis than post-menopausal women due to several factors. Their breastsare 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 factorscontributing to a higher risk of disease recurrence for younger women with breast cancer.[103]

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Psychological aspectsThe emotional impact of cancer diagnosis, symptoms, treatment, and related issues can be severe. Most largerhospitals are associated with cancer support groups which provide a supportive environment to help patients copeand 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 significantimpact on the way a patient copes with a breast cancer diagnosis. Premenopausal women with estrogen-receptorpositive breast cancer must confront the issues of early menopause induced by many of the chemotherapy regimensused to treat their breast cancer, especially those that use hormones to counteract ovarian function.[104]

On the other hand, a small 2007 study conducted by researchers at the College of Public Health of the University ofGeorgia suggested a need for greater attention to promoting functioning and psychological well-being among oldercancer survivors, even when they may not have obvious cancer-related medical complications.[105] The study foundthat older breast cancer survivors showed multiple indications of decrements in their health-related quality of life,and lower psychosocial well-being than a comparison group. Survivors reported no more depressive symptoms oranxious mood than the comparison group, however, they did score lower in measures of positive psychosocialwell-being, and reported more depressed mood and days affected by fatigue. As the incidence of breast cancer inwomen over 50 rises and survival rates increase, breast cancer is increasingly becoming a geriatric issue thatwarrants both further research and the expansion of specialized cancer support services tailored for specific agegroups.[105]

Epidemiology

Age adjustmentAge-standardized death frombreast cancer per 100,000 inhabitants in 2004."WHO Disease and injury country estimates".World Health Organization. 2009. . Retrieved

Nov. 11, 2009.

Worldwide, breast cancer is the most common invasive cancer inwomen. (The most common form of cancer is non-invasivenon-melanoma skin cancer; non-invasive cancers are generally easilycured, cause very few deaths, and are routinely excluded from cancerstatistics.) Breast cancer comprises 22.9% of invasive cancers inwomen[17] and 16% of all female cancers.[107]

In 2008, breast cancer caused 458,503 deaths worldwide (13.7% ofcancer deaths in women and 6.0% of all cancer deaths for men andwomen together).[17] Lung cancer, the second most common cause ofcancer-related death in women, caused 12.8% of cancer deaths inwomen (18.2% of all cancer deaths for men and women together).[17]

The incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatestin the more-developed countries. In the twelve world regions, the annual age-standardized incidence rates per100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22; South-EasternAsia, 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.[108]

The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to themodern lifestyles.[109][110] Breast cancer is strongly related to age with only 5% of all breast cancers occurring inwomen under 40 years old.[111]

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History

Breast cancer surgery in 18th century

Because of its visibility, breast cancer was the form of cancer mostoften described in ancient documents.[112] Because autopsies were rare,cancers of the internal organs were essentially invisible to ancientmedicine. Breast cancer, however, could be felt through the skin, andin its advanced state often developed into fungating lesions: the tumorwould become necrotic (die from the inside, causing the tumor toappear to break up) and ulcerate through the skin, weeping fetid, darkfluid.[112]

The oldest description of cancer was discovered in Egypt and datesback to approximately 1600 BC. The Edwin Smith Papyrus describes 8cases of tumors or ulcers of the breast that were treated bycauterization. The writing says about the disease, "There is notreatment."[113] For centuries, physicians described similar cases intheir practises, with the same conclusion. Ancient medicine, from thetime of the Greeks through the 17th century, was based on humoralism,and thus believed that breast cancer was generally caused byimbalances in the fundamental fluids that controlled the body,especially an excess of black bile.[114] Alternatively, patients often sawit as divine punishment.[115] In the 18th century, a wide variety of medical explanations were proposed, including alack of sexual activity, too much sexual activity, physical injuries to the breast, curdled breast milk, and variousforms of lymphatic blockages, either internal or due to restrictive clothing.[114][116] In the 19th century, the Scottishsurgeon John Rodman said that fear of cancer caused cancer, and that this anxiety, learned by example from themother, accounted for breast cancer's tendency to run in families.[116]

Although breast cancer was known in ancient times, it was uncommon until the 19th century, when improvements insanitation and control of deadly infectious diseases resulted in dramatic increases in lifespan. Previously, mostwomen had died too young to have developed breast cancer.[116] Additionally, early and frequent childbearing andbreastfeeding probably reduced the rate of breast cancer development in those women who did survive to middleage.[116]

Because ancient medicine believed that the cause was systemic, rather than local, and because surgery carried a highmortality rate, the preferred treatments tended to be pharmacological rather than surgical. Herbal and mineralpreparations, especially involving the poison arsenic, were relatively common.Mastectomy for breast cancer was performed at least as early as AD 548, when it was proposed by the courtphysician Aetios of Amida to Theodora.[112] It was not until doctors achieved greater understanding of thecirculatory system in the 17th century that they could link breast cancer's spread to the lymph nodes in the armpit.The French surgeon Jean Louis Petit (1674–1750) and later the Scottish surgeon Benjamin Bell (1749–1806) werethe first to remove the lymph nodes, breast tissue, and underlying chest muscle.[117]

Their successful work was carried on by William Stewart Halsted who started performing radical mastectomies in1882, helped greatly by advances in general surgical technology, such as aseptic technique and anesthesia. TheHalsted radical mastectomy often involved removing both breasts, associated lymph nodes, and the underlying chestmuscles. This often led to long-term pain and disability, but was seen as necessary in order to prevent the cancerfrom recurring.[118] Before the advent of the Halsted radical mastectomy, 20-year survival rates were only 10%;Halsted's surgery raised that rate to 50%.[119] Extending Halsted's work, Jerome Urban promoted superradicalmastectomies, taking even more tissue, until 1963, when the ten-year survival rates proved equal to theless-damaging radical mastectomy.[118]

Breast cancer 12

Radical mastectomies remained the standard of care in America until the 1970s, but in Europe, breast-sparingprocedures, often followed radiation therapy, were generally adopted in the 1950s.[118] One reason for this strikingdifference in approach may be the structure of the medical professions: European surgeons, descended from thebarber surgeon, were held in less esteem than physicians; in America, the surgeon was the king of the medicalprofession.[118] Additionally, there were far more European women surgeons: Less than one percent of Americansurgical oncologists were female, but some European breast cancer wards boasted a medical staff that was halffemale.[118] American health insurance companies also paid surgeons more to perform radical mastectomies thanthey did to perform more intricate breast-sparing surgeries.[118]

Breast cancer staging systems were developed in the 1920s and 1930s.[118]

During the 1970s, a new understanding of metastasis led to perceiving cancer as a systemic illness as well as alocalized one, and more sparing procedures were developed that proved equally effective. Modern chemotherapydeveloped after World War II.[120]

The French surgeon Bernard Peyrilhe (1737–1804) realized the first experimental transmission of cancer byinjecting extracts of breast cancer into an animal.Prominent women who died of breast cancer include Anne of Austria, the mother of Louis XIV of France; MaryWashington, mother of George, and Rachel Carson, the environmentalist.[121]

The first case-controlled study on breast cancer epidemiology was done by Janet Lane-Claypon, who published acomparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestylefor the British Ministry of Health.[122]

In the 1980s and 1990s, thousands of women who had successfully completed standard treatment then demanded andreceived high-dose bone marrow transplants, thinking this would lead to better long-term survival. However, itproved completely ineffective, and 15–20% of women died because of the brutal treatment.[123]

The 1995 reports from the Nurses' Health Study and the 2002 conclusions of the Women's Health Initiative trialconclusively proved that hormone replacement therapy significantly increased the incidence of breast cancer.[123]

Society and cultureBefore the 20th century, breast cancer was feared and discussed in hushed tones, as if it were shameful. As littlecould be safely done with primitive surgical techniques, women tended to suffer silently rather than seeking care.When surgery advanced, and long-term survival rates improved, women began raising awareness of the disease andthe possibility of successful treatment. The "Women's Field Army", run by the American Society for the Control ofCancer (later the American Cancer Society) during the 1930s and 1940s was one of the first organized campaigns. In1952, the first peer-to-peer support group, called "Reach to Recovery", began providing post-mastectomy,in-hospital visits from women who had survived breast cancer.[124]

The breast cancer movement of the 1980s and 1990s developed out of the larger feminist movements and women'shealth movement of the 20th century.[125] This series of political and educational campaigns, partly inspired by thepolitically and socially effective AIDS awareness campaigns, resulted in the widespread acceptance of secondopinions before surgery, less invasive surgical procedures, support groups, and other advances in patient care.[126]

Breast cancer 13

Pink ribbon

The pink ribbon is a symbol to showsupport for breast cancer awareness

A pink ribbon is the most prominent symbol of breast cancer awareness. Pinkribbons, which can be made inexpensively, are sometimes sold as fundraisers,much like poppies on Remembrance Day. They may be worn to honor thosewho have been diagnosed with breast cancer, or to identify products that themanufacturer would like to sell to consumers that are interested in breastcancer—usually white, middle-aged, middle-class and upper-class, educatedwomen.[127]

The pink ribbon is associated with individual generosity, faith in scientificprogress, and a "can-do" attitude. It encourages consumers to focus on theemotionally appealing ultimate vision of a cure for breast cancer, rather thanon the fraught path between current knowledge and any future cures.[128]

Wearing or displaying a pink ribbon has been criticized by the opponents ofthis practice as a kind of slacktivism, because it has no practical positiveeffect and as hypocrisy among those who wear the pink ribbon to show goodwill towards women with breast cancer, but then oppose these women'spractical goals, like patient rights and anti-pollution legislation.[129][130]

Critics say that the feel-good nature of pink ribbons and pink consumptiondistracts society from the lack of progress on preventing and curing breast cancer.[131] It is also criticized forreinforcing gender stereotypes and objectifying women and their breasts.[132] Breast Cancer Action launched the"Think Before You Pink" campaign, and charged that companies have co-opted the pink campaign to promoteproducts that encourage breast cancer, such as high-fat Kentucky Fried Chicken and alcohol.[133]

Breast cancer cultureBreast cancer culture, or pink ribbon culture, is the set of activities, attitudes, and values that surround and shapebreast cancer in public. The dominant values are selflessness, cheerfulness, unity, and optimism. Appearing to havesuffered bravely is the passport into the culture.The woman with breast cancer is given a cultural template that constrains her emotional and social responses into asocially acceptable discourse: She is to use the emotional trauma of being diagnosed with breast cancer and thesuffering of extended treatment to transform herself into a stronger, happier and more sensitive person who isgrateful for the opportunity to become a better person. Breast cancer thereby becomes a rite of passage rather than adisease.[134] To fit into this mold, the woman with breast cancer needs to normalize and feminize her appearance,and minimize the disruption that her health issues cause anyone else. Anger, sadness and negativity must besilenced.[134]

As with most cultural models, people who conform to the model are given social status, in this case as cancersurvivors. Women who reject the model are shunned, punished and shamed.[134]

The culture is criticized for treating adult women like little girls, as evidenced by "baby" toys such as pink teddybears given to adult women.[134]

The primary purposes or goals of breast cancer culture are to maintain breast cancer's dominance as the preëminentwomen's health issue, to promote the appearance that society is "doing something" effective about breast cancer, andto sustain and expand the social, political, and financial power of breast cancer activists.[135]

Breast cancer 14

OveremphasisCompared to other diseases or other cancers, breast cancer receives a disproportionate share of resources andattention. In 2001 MP Ian Gibson, chairman of the House of Commons of the United Kingdom all party group oncancer stated "The treatment has been skewed by the lobbying, there is no doubt about that. Breast cancer sufferersget better treatment in terms of bed spaces, facilities and doctors and nurses."[136] Breast cancer also receivessignificantly more media coverage than other, equally prevalent cancers, with a study by Prostate Coalition showing2.6 breast cancer stories for each one covering cancer of the prostate.[137] Ultimately there is a concern thatfavouring sufferers of breast cancer with disproportionate funding and research on their behalf may well be costinglives elsewhere.[136] Partly because of its relatively high prevalence and long-term survival rates, research is biasedtowards breast cancer. Some subjects, such as cancer-related fatigue, have been studied in little except women withbreast cancer.One result of breast cancer's high visibility is that statistical results can sometimes be misinterpreted, such as theclaim that one in eight women will be diagnosed with breast cancer during their lives—a claim that depends on theunrealistic assumption that no woman will die of any other disease before the age of 95.[138] This obscures thereality, which is that about ten times as many women will die from heart disease or stroke than from breastcancer.[139]

The emphasis on breast cancer screening may be harming women by subjecting them to unnecessary radiation,biopsies, and surgery. One-third of diagnosed breast cancers might recede on their own.[140] Screeningmammography efficiently finds non-life-threatening, asymptomatic breast cancers and pre-cancers, even whileoverlooking serious cancers. According to H. Gilbert Welch of the Dartmouth Institute for Health Policy andClinical Practice, research on screening mammography has taken the "brain-dead approach that says the best test isthe one that finds the most cancers" rather than the one that finds dangerous cancers.[140]

In pregnancyCancers found during or shortly after pregnancy appear at approximately the same rate as other cancers in women ofa similar age. As a result, breast cancer is one of the more common cancers found during pregnancy, although it isstill rare, because only about 1 in 1,000 pregnant women experience any sort of cancer.[141]

Diagnosing a new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed tobe a normal discomfort associated with pregnancy.[141] As a result, cancer is typically discovered at a somewhat laterstage than average in many pregnant or recently pregnant women. Some imaging procedures, such as MRIs(magnetic resonance imaging), CT scans, ultrasounds, and mammograms with fetal shielding are considered safeduring pregnancy; some others, such as PET scans are not.[141]

Treatment is generally the same as for non-pregnant women.[141] However, radiation is normally avoided duringpregnancy, especially if the fetal dose might exceed 100 cGy. In some cases, some or all treatments are postponeduntil after birth if the cancer is diagnosed late in the pregnancy. Early deliveries to speed the start of treatment arenot uncommon. Surgery is generally considered safe during pregnancy, but some other treatments, especially certainchemotherapy drugs given during the first trimester, increase the risk of birth defects and pregnancy loss(spontaneous abortions and stillbirths).[141] Elective abortions are not required and do not improve the likelihood ofthe mother surviving or being cured.[141]

Radiation treatments may interfere with the mother's ability to breastfeed her baby because it reduces the ability ofthat breast to produce milk and increases the risk of mastitis. Also, when chemotherapy is being given after birth,many of the drugs pass through breast milk to the baby, which could harm the baby.[141]

Breast cancer 15

ResearchA considerable part of the current knowledge on breast carcinomas is based on in vivo and in vitro studies performedwith breast cancer cell (BCC) lines. These provide an unlimited source of homogenous self-replicating material, freeof contaminating stromal cells, and often easily cultured in simple standard media. The first line described, BT-20,was established in 1958. Since then, and despite sustained work in this area, the number of permanent lines obtainedhas been strikingly low (about 100). Indeed, attempts to culture BCC from primary tumors have been largelyunsuccessful. This poor efficiency was often due to technical difficulties associated with the extraction of viabletumor cells from their surrounding stroma. Most of the available BCC lines issued from metastatic tumors, mainlyfrom pleural effusions. Effusions provided generally large numbers of dissociated, viable tumor cells with little or nocontamination by fibroblasts and other tumor stroma cells. Many of the currently used BCC lines were established inthe late 1970s. A very few of them, namely MCF-7, T-47D, and MDA-MB-231, account for more than two-thirds ofall abstracts reporting studies on mentioned BCC lines, as concluded from a Medline-based survey.Treatments are constantly 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 scientificmeetings such as that of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposium,[142]

and the St. Gallen Oncology Conference in St. Gallen, Switzerland.[143] These studies are reviewed by professionalsocieties and other organizations, and formulated into guidelines for specific treatment groups and risk category.List of cell linesMainly based on Lacroix and Leclercq (2004).[144] For more data on the nature of TP53 mutations in breast cancercell lines, see Lacroix et al. (2006).[145]

This is an incomplete list, which may never be able to satisfy particular standards for completeness. You canhelp by with reliably sourced entries.

Cell line Primary tumor Origin ofcells

Estrogenreceptors

Progesteronereceptors

ERBB2amplification

MutatedTP53

Tumorigenic inmice

Reference

600MPE Invasive ductalcarcinoma

+ - - [146]

AU565 Adenocarcinoma - - + - [146]

BT-20 Invasive ductalcarcinoma

Primary No No No Yes Yes [147]

BT-474 Invasive ductalcarcinoma

Primary Yes Yes Yes Yes Yes [148]

BT-483 Invasive ductalcarcinoma

+ + - [146]

BT-549 Invasive ductalcarcinoma

- - + [146]

Evsa-T Invasive ductalcarcinoma,mucin-producing,signet-ring type

Metastasis(ascites)

No Yes ? Yes ? [149]

Hs578T Carcinosarcoma Primary No No No Yes No [150]

MCF-7 Invasive ductalcarcinoma

Metastasis(pleuraleffusion)

Yes Yes No No(wild-type)

Yes (with estrogensupplementation)

[151]

Breast cancer 16

MDA-MB-231 Invasive ductalcarcinoma

Metastasis(pleuraleffusion)

No No No Yes Yes [152]

SkBr3 Invasive ductalcarcinoma

Metastasis(pleuraleffusion)

No No Yes Yes No [153]

T-47D Invasive ductalcarcinoma

Metastasis(pleuraleffusion)

Yes Yes No Yes Yes (with estrogensupplementation)

[154]

In other animals• Mammary tumor for breast cancer in other animals

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External links• Breast cancer (http:/ / www. dmoz. org/ / Health/ Conditions_and_Diseases/ Cancer/ Breast/ / ) at the Open

Directory Project

Article Sources and Contributors 22

Article Sources and ContributorsBreast cancer  Source: http://en.wikipedia.org/w/index.php?oldid=516441760  Contributors: -Midorihana-, 107339pp, 12 Noon, 1966batfan, 2T, 2help, 2over0, 32cllou, 4trtrtyuyuyygh, 5 albertsquare, 67starstrukk, 7, A. 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Image Sources, Licenses and ContributorsFile:Mammo breast cancer.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mammo_breast_cancer.jpg  License: Public Domain  Contributors: Hehkuviini, Morning2kFile:En Breast cancer illustrations.gif  Source: http://en.wikipedia.org/w/index.php?title=File:En_Breast_cancer_illustrations.gif  License: Public Domain  Contributors: Morning2kFile:Breast cancer.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Breast_cancer.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Hic et nuncFile:Signal transduction pathways.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Signal_transduction_pathways.svg  License: GNU Free Documentation License  Contributors:cybertoryImage:Breast cancer.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Breast_cancer.JPG  License: Public Domain  Contributors: John HaymanImage:Invasive Ductal Carcinoma 40x.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Invasive_Ductal_Carcinoma_40x.jpg  License: Creative Commons Attribution-Sharealike 3.0 Contributors: Difu WuImage:Breast carcinoma in a lymph node.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Breast_carcinoma_in_a_lymph_node.jpg  License: Creative CommonsAttribution-Sharealike 3.0  Contributors: NephronImage:Neuropilin-2 (Nrp2) expression in normal breast and breast carcinoma tissue.jpg  Source:http://en.wikipedia.org/w/index.php?title=File:Neuropilin-2_(Nrp2)_expression_in_normal_breast_and_breast_carcinoma_tissue.jpg  License: Creative Commons Attribution 2.0  Contributors:Hironao Yasuoka1 , Rieko Kodama1 , Masahiko Tsujimoto2 , Katsuhide Yoshidome3 , Hiroki Akamatsu3 , Masaaki Nakahara3 , Michiya Inagaki1 , Tokio Sanke1 and Yasushi Nakamura1Image:Mamma-CA.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mamma-CA.jpg  License: Creative Commons Attribution 3.0  Contributors: Hg6996File:Mastectomie 02.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mastectomie_02.jpg  License: Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors:AcrocynusFile:RecurrentbreastCA1.gif  Source: http://en.wikipedia.org/w/index.php?title=File:RecurrentbreastCA1.gif  License: Creative Commons Attribution-Sharealike 3.0  Contributors: JamesHeilman, MD

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File:Breast cancer world map - Death - WHO2004.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Breast_cancer_world_map_-_Death_-_WHO2004.svg  License: CreativeCommons Attribution-Sharealike 2.5  Contributors: Lokal_ProfilFile:Louis-Jacques Goussier Enzyklopädie Diderot Pl XXIX.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Louis-Jacques_Goussier_Enzyklopädie_Diderot_Pl_XXIX.jpg License: Public Domain  Contributors: Louis-Jacques GoussierFile:Pink ribbon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Pink_ribbon.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: MesserWoland

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