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Breastcancer 

Breast cancer (malignant breast neoplasm) is cancer originatingfrom breast tissue,most commonly from the inner lining of milk ducts orthe lobulesthat supply the ducts with milk.[1] Cancersoriginating from ducts are known as ductalcarcinomas; those originating from lobules are known as lobular carcinomas. Breast cancer is adisease of humans and other mammals; while the overwhelming majority of cases inhumans are women, men can also contract breast cancer.

The size, stage, rate of growth, and othercharacteristics of the tumor determine the kinds of treatment. Treatment mayinclude surgery, drugs (hormonal therapy and chemotherapy), radiation and/or immunotherapy. Surgical removal of the tumor providesthe single largest benefit, with surgery alone being capable of producing acure in many cases. To somewhat increase the likelihood of long-termdisease-free survival, several chemotherapyregimens are commonlygiven in addition to surgery. Most forms of chemotherapy kill cells that aredividing rapidly anywhere in the body, and as a result cause temporary hairloss and digestive disturbances. Radiation may be added to kill any cancercells in the breast that were missed by the surgery, which usually extendssurvival somewhat, although radiation exposure to the heart may cause heartfailure in the future. Somebreast cancers are sensitive to hormones such as estrogen and/or progesterone, which makes it possible totreat them by blocking the effects of these hormones.

Prognosis and survival rate varies greatlydepending on cancer type and staging. With best treatment and dependent onstaging, 5-year relative survival varies from 98% to 23, with an overallsurvival rate of 85%.

Worldwide, breast cancer comprises 22.9% of allcancers (excluding non-melanoma skin cancers) in women. In 2008, breast cancer caused 458,503deaths worldwide (13.7% of cancer deaths in women).[7] Breastcancer is more than 100 times more common in women than breast cancer in men,although males tend to have poorer outcomes due to delays in diagnosis.

Classification

Mainarticle: Breastcancer classification

Breast cancers are classified by several gradingsystems. Each of these influences the prognosis andcan affect treatment response. Description of a breast cancer optimallyincludes all of these factors.

�  Histopathology.Breast cancer is usually classified primarily by its histological appearance. Most breast cancers arederived from the epithelium lining the ducts or lobules, and these cancers areclassified as ductal or lobular carcinoma. Carcinoma in situ is growth of low grade cancerous orprecancerous cells within a particular tissue compartment such as the mammaryduct without invasion of the surrounding tissue. In contrast, invasive carcinoma does not confine itself to the initialtissue compartment.

�  Grade. Grading compares the appearance of the breastcancer cells to the appearance of normal breast tissue. Normal cells in anorgan like the breast become differentiated, meaning that they take on specificshapes and forms that reflect their function as part of that organ. Cancerouscells lose that differentiation. In cancer, the cells that would normally lineup in an orderly way to make up the milk ducts become disorganized. Celldivision becomes uncontrolled. Cell nuclei become less uniform. Pathologistsdescribe cells as well differentiated (low grade), moderately differentiated(intermediate grade), and poorly differentiated (high grade) as the cellsprogressively lose the features seen in normal breast cells. Poorlydifferentiated cancers have a worse prognosis.

�  Stage. Breastcancer staging usingthe TNM system is based on the size of the tumor (T), whether ornot the tumor has spread to the lymph nodes(N) in the armpits, and whether the tumor hasmetastasized (M)(i.e. spread to a more distant part of the body). Larger size, nodal spread,and metastasis have a larger stage number and a worse prognosis.
The main stages are:

�  Stage0 is a pre-cancerous or marker condition, either ductalcarcinoma in situ (DCIS)or lobularcarcinoma in situ (LCIS).

�  Stages1–3 are within the breast or regional lymph nodes.

�  Stage4 is 'metastatic' cancer that has a less favorable prognosis.

�  Receptorstatus. Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones bindto receptors,and this causes changes in the cell. Breast cancer cells may or may not havethree important receptors: estrogen receptor (ER), progesteronereceptor (PR), and HER2/neu.
ER cancer cells depend on estrogen for their growth, so they can be treatedwith drugs to block estrogen effects (e.g.
 tamoxifen), and generally have a betterprognosis.
HER2 breast cancer had a worse prognosis,;
 butHER2 cancer cells respond to drugs such as the monoclonal antibody trastuzumab (in combination with conventionalchemotherapy), and this has improved the prognosis significantly. Cells with none of these receptors arecalled basal-like or triplenegative.

�  DNAassays. 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 toclassify the cancer in several ways, and may assist in choosing the mosteffective treatment for that DNA type.

�  Signs andsymptoms

Breastcancer showing an inverted nipple, lump, skin dimpling

The first noticeable symptom ofbreast cancer is typically a lump thatfeels different from the rest of the breast tissue. More than 80% of breastcancer cases are discovered when the woman feels a lump. The earliest breast cancers aredetected by a mammogram.[13] Lumps found in lymph nodes located inthe armpits can also indicatebreast cancer.

Indications of breast cancer other than a lump mayinclude changes in breast size or shape, skin dimpling, nipple inversion, orspontaneous single-nipple discharge. Pain ("mastodynia") is an unreliable tool indetermining the presence or absence of breast cancer, but may be indicative ofother breast healthissues.

Inflammatorybreast cancer is aparticular type of breast cancer which can pose a substantial diagnosticchallenge. Symptoms may resemble a breast inflammation and may include itching,pain, swelling, nipple inversion, warmth and redness throughout the breast, aswell as an orange-peel texture to the skin referred to as peau d'orange; the absence of a discernible lumpdelays detection dangerously.

Another reported symptom complex of breast canceris Paget'sdisease of the breast. This syndrome presentsas eczematoid skinchanges such as redness and mild flaking of the nipple skin. As Paget'sadvances, 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 the breast.

In rare cases, what initially appears as a fibroadenoma (hard movable lump) could in fact be a phyllodes tumor.Phyllodes tumors are formed within the stroma (connective tissue) of the breastand contain glandular as well as stromal tissue. Phyllodes tumors are notstaged in the usual sense; they are classified on the basis of their appearanceunder the microscope as benign, borderline, or malignant.

Occasionally, breast cancer presents as metastatic disease, that is, cancer that hasspread beyond the original organ. Metastaticbreast cancer willcause symptoms that depend on the location of metastasis. Common sites ofmetastasis include bone, liver, lung and brain. Unexplained weight loss canoccasionally herald an occult breast cancer, as can symptoms of fevers orchills. Bone or joint pains can sometimes be manifestations of metastaticbreast cancer, as can jaundice or neurological symptoms. These symptoms arecalled non-specific,meaning they could be manifestations of many other illnesses.

Most symptoms of breast disorders, including mostlumps, do not turn out to represent underlying breast cancer. Benign breastdiseases such as mastitis and fibroadenoma of the breast are more common causesof breast disorder symptoms. Nevertheless, the appearance of a new symptomshould be taken seriously by both patients and their doctors, because of thepossibility of an underlying breast cancer at almost any age.

Risk factors

Mainarticle: Riskfactors of breast cancer

The primary risk factors for breast cancer arefemale sex, age, lack of childbearing or breastfeeding, higher hormone levels, race, economic status and dietaryiodine deficiency.

Most cases of breast cancer cannot be preventedthrough any action on the part of the affected person. The World CancerResearch Fund estimatedthat 38% of breast cancer cases in the US are preventable through reducingalcohol intake, increasing physical activity levels and maintaining a healthyweight. It also estimated that42% of breast cancer cases in the UK could be prevented in this way, as well as28% in Brazil and 20% in China.

Smoking tobacco also increases the risk ofbreast cancer with the greater the amount smoking and the earlier in lifesmoking begins the higher the risk.

In a study of attributable risk and epidemiologicalfactors published in 1995, later age at first birth and not having children accounted for 29.5% of U.S. breastcancer cases, family history of breast cancer accounted for 9.1% and factorscorrelated with higher income contributed 18.9% of cases.[30] Attempts to explain the increasedincidence (but lower mortality) correlated with higher income includeepidemiologic observations such as lower birth rates correlated with higherincome and better education, possible overdiagnosis and overtreatment because of better access to breastcancer screening, and the postulation of as yet unexplained lifestyle anddietary factors correlated with higher income. One such factor may be past hormonereplacement therapy, which was typically more widespread in higherincome groups.

The genes associated with hereditarybreast-ovarian cancer syndromes usuallyincrease the risk slightly or moderately; the exception is women and men whoare carriers of BRCA mutations. These people have a veryhigh lifetime risk for breast and ovarian cancer, depending on the portion ofthe proteins where the mutation occurs. Instead of a 12 percent lifetime riskof breast cancer, women with one of these genes have a risk of approximately 60percent.

In more recent years, research has indicated theimpact of diet and other behaviors on breast cancer. These additional riskfactors include a high-fat diet, alcoholintake, obesity, and environmental factors such astobacco use, radiation, endocrine disruptors and shiftwork. Although the radiation frommammography is a low dose, the cumulative effect can cause cancer.

In addition to the risk factors specified above,demographic and medical risk factors include:

�  Personalhistory of breast cancer: A woman who had breast cancer in one breast has anincreased risk of getting a second breast cancer.

�  Familyhistory: A woman's risk of breast cancer is higher if her mother, sister, ordaughter had breast cancer, the risk becomes significant if at least two closerelatives had breast or ovarian cancer. The risk is higher if her family membergot breast cancer before age 40. An Australian study found that having otherrelatives with breast cancer (in either her mother's or father's family) mayalso increase a woman's risk of breast cancer and other forms of cancer, includingbrain and lung cancers.

�  Certainbreast changes: Atypical hyperplasia and lobularcarcinoma in situ foundin benign breast conditions such as fibrocysticbreast changes arecorrelated with an increased breast cancer risk.

Those with a normal body mass index at age 20 whogained weight as they aged had nearly double the risk of developing breastcancer after menopause in comparison to women who maintained their weight. Theaverage 60-year-old woman's risk of developing breast cancer by age 65 is about2 percent; her lifetime risk is 13 percent.

Prevention

Exercise may decrease breast cancer risk. Also avoiding alcohol and obesity.Prophylactic bilateral mastectomy may be considered in patients withBRCA1 and BRCA2 mutations. A 2007report concluded that women can somewhat reduce their risk by maintaining ahealthy weight, drinking less alcohol, being physically active andbreastfeeding their children.

Pathophysiology

Mainarticle: Carcinogenesis

 

Overviewof signal transduction pathways involved in apoptosis. Mutations leading to loss ofapoptosis can lead to tumorigenesis.

Breast cancer, like other cancers, occurs because of an interactionbetween the environment and a defective gene. Normal cells divide as many timesas 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 mutationsknown to cause cancer, such as p53, BRCA1 and BRCA2,occur in the error-correcting mechanisms. These mutations are either inheritedor acquired after birth. Presumably, they allow the other mutations, whichallow uncontrolled division, lack of attachment, and metastasis to distantorgans.[35][45] Normal cells will commit cell suicide(apoptosis) when they are no longer needed.Until then, they are protected from cell suicide by several protein clustersand pathways. One of the protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway. Sometimes the genes alongthese protective pathways are mutated in a way that turns them permanently"on", rendering the cell incapable of committing suicide when it isno longer needed. This is one of the steps that causes cancer in combinationwith other mutations. Normally, the PTEN protein turns off the PI3K/AKT pathwaywhen the cell is ready for cell suicide. In some breast cancers, the gene forthe PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the"on" position, and the cancer cell does not commit suicide.

Mutations that can lead to breast cancer have beenexperimentally 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.

In the United States, 10 to 20 percent of patientswith breast cancer and patients with ovarian cancer have a first- orsecond-degree relative with one of these diseases. Mutations in either of twomajor susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) andbreast cancer susceptibility gene 2 (BRCA2), confer a lifetime risk of breastcancer of between 60 and 85 percent and a lifetime risk of ovarian cancer ofbetween 15 and 40 percent. However, mutations in these genes account for only 2to 3 percent of all breast cancers.

Diagnosis

While screening techniques (which are furtherdiscussed below) are useful in determining the possibility of cancer, a furthertesting is necessary to confirm 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 special circumstancessuch as ultrasound or MR imaging are sufficient to warrantexcisional biopsy as the definitive diagnostic andcurative method.

Both mammography and clinical breast exam, alsoused for screening, can indicate an approximate likelihood that a lump iscancer, and may also detect some other lesions. When the tests are inconclusive FineNeedle Aspiration and Cytology (FNAC) may be used. FNAC may be done in a GP'soffice using local anaesthetic if required, involves attempting to extract asmall portion of fluid from the lump. Clear fluid makes the lump highlyunlikely to be cancerous, but bloody fluid may be sent off for inspection undera microscope for cancerous cells. Together, these three tools can be used todiagnose breast cancer with a good degree of accuracy.

Other options for biopsy include core biopsy, where a section of the breastlump is removed, and an excisional biopsy, where the entire lump is removed.

In addition vacuum-assistedbreast biopsy (VAB)may help diagnose breast cancer among patients with a mammographically detectedbreast in women.

 

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