Breast cancer (malignant breast neoplasm) is cancers originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas. There are many different types of breast cancer, with different stages (spread), aggressiveness, and genetic makeup; survival varies greatly depending on those factors.[1] Computerized models are available to predict survival.[2] With best treatment and dependent on staging, 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 among women, making it the most common type of non-skin cancer in women and the fifth most common cause of cancer death.[3] In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).[4] Breast cancer is about 100 times more common in women than in men, although males tend to have poorer outcomes due to delays in diagnosis.[5][6][7][8]
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. After surgery, 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).[9] Monoclonal antibodies, such as trastuzumab (Herceptin), 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.[10]
Classification
Main article: Breast cancer classification
Breast cancers can be classified by different schemata. Every aspect influences treatment response and prognosis. Description of a breast cancer would optimally include multiple classification aspects, as well as other findings, such as signs found on physical exam. Classification aspects include stage (TNM), pathology, grade, receptor status, and the presence or absence of genes as determined by DNA testing:
* 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) (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:
Stage 0 is a pre-malignant disease or marker (sometimes called DCIS: Ductal Carcinoma in Situ) .
Stages 1–3 are defined as 'early' cancer and potentially curable.
Stage 4 is defined as 'advanced' and/or 'metastatic' cancer and incurable.
* Histopathology. Breast cancer is usually, but not always, primarily classified by its histological appearance. Most breast cancers are' derived from the epithelium lining the ducts or lobules, and are classified as mammary ductal carcinoma. Carcinoma in situ is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding tissue. In contrast, invasive carcinoma invades the surrounding tissue.[11]
* 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. In cancer grading, tumor cells are generally classified as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade). Poorly differentiated cancers have a worse prognosis.
* Receptor status. Cells have receptors on their surface and in their cytoplasm and nucleus. 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 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 block estrogen effects (e.g. tamoxifen), and generally have a better prognosis.
Generally, HER2+ had a worse prognosis,[12] however HER2+ cancer cells respond to drugs such as the monoclonal antibody, trastuzumab, (in combination with conventional chemotherapy) and this has improved the prognosis significantly.[13]
* 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.
[edit] Signs and symptoms
Breast cancer showing an inverted nipple, lump, skin dimpling
The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a lump.[14] By the time a breast lump is noticeable, it has probably been growing for years. The earliest breast cancers are detected by a mammogram.[15] Lumps found in lymph nodes located in the armpits[14] 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.[14][15][16]
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 peaud'orange.[14]
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.[17]
In rare cases, what initially appears as a fibroadenoma (hard movable lump) could in fact be a phyllodestumor. Phyllodestumors are formed within the stroma (connective tissue) of the breast and contain glandular as well as stromal tissue. Phyllodestumors are not staged in the usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline, or malignant.[18]
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.[19] 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.[20]
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.[21]
[edit] Risk factors
Main article: Risk factors of breast cancer
The primary risk factors that have been identified are sex,[22] age,[23] lack of childbearing or breastfeeding,[24][25] and higher hormone levels[26][27].
In Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective, a 2007 report by American Institute for Cancer Research/ World Cancer Research Fund, it concluded women can reduce their risk by maintaining a healthy weight, drinking less alcohol, being physically active and breastfeeding their children.[28] This was based on an review of 873 separate studies.
In 2009 World Cancer Research Fund announced the results of a further review review that took into account a further 81 studies published subsequently. This did not change the conclusions of the 2007 Report. In 2009, WCRF/ AICR published Policy and Action for Cancer Prevention, a Policy Report that included a preventability study.[29] This estimated that 38% of breast cancer cases in the US are preventable through reducing alcohol intake, increasing physical activity levels and maintaining a healthy weight. It also estimated that 42% of breast cancer cases in the UK could be prevented in this way, as well as 28% in Brazil and 20% in China.
In a study published in 1995, well-established risk factors accounted for 47% of cases while only 5% were attributable to hereditary syndromes.[30] Genetic factors usually increase the risk slightly or moderately; the exception is women and men who are carriers of BRCA mutations. These people have a very high lifetime risk for breast and ovarian cancer, depending on the portion of the proteins where the mutation occurs. Instead of a 12 percent lifetime risk of breast cancer, women with one of these genes has a risk of approximately 60 percent.[31] In more recent years, research has indicated the impact of diet and other behaviors on breast cancer. These additional risk factors include a high-fat diet,[32] alcohol intake,[33][34] obesity,[35] and environmental factors such as tobacco use, radiation,[36] endocrine disruptors and shiftwork.[37] Although the radiation from mammography is a low dose, the cumulative effect can cause cancer.[38] [39]
In addition to the risk factors specified above, demographic and medical risk factors include:
* 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 women of European ancestry than those of African or Asian ancestry.
A National Cancer Institute (NCI) study of 72,000 women found that those who had a normal body mass index at age 20 and gained weight as they aged had nearly double the risk of developing breast cancer after menopause in comparison to women maintained their weight. The average 60 year-old woman's risk of developing breast cancer by age 65 is about 2 percent; her lifetime risk is 13 percent.[40]
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.[41][42][43]
The United Kingdom is the member of International Cancer Genome Consortium that is leading efforts to map breast cancer's complete genome.
Pathophysiology
Breast cancer, like other cancers, occurs because of an interaction between the environment and a defective gene. Normal cells divide as many times as needed and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when mutations destroy their ability to stop dividing, to attach to other cells and to stay where they belong. When cells divide, their DNA is normally copied with many mistakes. Error-correcting proteins fix those mistakes. The mutations known to cause cancer, such as p53, BRCA1 and BRCA2, occur in the error-correcting mechanisms. These mutations are either inherited or acquired after birth. Presumably, they allow the other mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs.[36][44] Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until then, they are protected from cell suicide by several protein clusters and pathways. One of the protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently "on", rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that causes cancer in combination with other mutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide. In some 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.[45]
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.[46]
Failure of immune surveillance, the removal of malignant cells throughout one's life by the immune system.[47]
Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth.[48][49]
People in less-developed countries report lower incidence rates than in developed countries.[citation needed]
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.[50]
[edit] Diagnosis
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While screening techniques (which are further discussed below) 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.
In addition vacuum-assisted breast biopsy (VAB) may help diagnose breast cancer among patients with a mammographically detected breast in women according to a systematic review .[51] In this study, summary estimates for vacuum assisted breast biopsy in diagnosis of breast cancer were as follows sensitivity was 98.1% with 95% CI = 0.972-0.987 and specificity was 100% with 95% CI = 0.997-0.999. However underestimate rates of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were 20.9% with 95% CI =0.177-0.245 and 11.2% with 95% CI = 0.098-0.128 respectively.
Excised human breast tissue, showing an irregular, dense, white stellate area of cancer 2 cm in diameter, within yellow fatty tissue.
Micrograph showing a lymph node invaded by ductal breast carcinoma and with extranodal extension of tumour.
Neuropilin-2 expression in normal breast and breast carcinoma tissue.
Lymph nodes which drain the breast
Screening
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.