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Tuesday, December 4, 2007

Breast Cancer

Compiled and Summarized by Anthony
Worldwide, breast cancer is the fifth most common cause of cancer death (after lung cancer, stomach cancer, liver cancer, and colon cancer). In 2005, breast cancer caused 502,000 deaths (7% of cancer deaths; almost 1% of all deaths) worldwide. Among women worldwide, breast cancer is the most common cause of cancer death.

In the United States, breast cancer is the third most common cause of cancer death (after lung cancer and colon cancer). In 2007, breast cancer is expected to cause 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S. Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death. In the U.S., both incidence and death rates for breast cancer have been declining in the last few years. Nevertheless, a U.S. 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.

The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world. Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, though it is less common.

Signs and Symptoms

Early breast cancer can, in some cases, present as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most frequently discovered as an asymptomatic nodule on a mammogram, before any symptoms are present. A lump under the arm or above the collarbone that does not go away may be present.

When breast cancer has invaded the dermal lymphatics - small lymph vessels of the skin, its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer. In inflammatory breast cancer, the breast cancer is blocking lymphatic vessels and this can cause pain, swelling, warmth, and redness throughout the breast, as well as an orange peel texture to the skin referred to as peau d'orange. Although there may have been no previous signs of breast cancer and the cancer might be missed in screening mammograms, Inflammatory Breast Cancer is at least locally advanced at presentation (LABC) and Stage IIIB. Immediate staging tests are required to rule out distant metastes which might already be present making it Stage IV.

Changes in the appearance or shape of the breast can raise suspicions of breast cancer.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer.

Most breast symptoms do not turn out to represent underlying breast cancer. Benign breast diseases such as fibrocystic mastopathy, mastitis, functional mastodynia, and fibroadenoma of the breast are more common causes of breast symptoms. The appearance of a new breast symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

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. More common sites of metastasis include bone, liver, lung, and brain. 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. Pleural effusions are not uncommon with metastatic breast cancer. Obviously, these symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.


Many women who develop breast cancer have no risk factors other than age and sex.

* Gender is the biggest risk because breast cancer occurs mostly in women.

* Age is another critical factor. Breast cancer may occur at any age, though the risk of breast cancer increases with age. The average woman at age 30 years has one chance in 280 of developing breast cancer in the next 10 years. This chance increases to one in 70 for a woman aged 40 years, and to one in 40 at age 50 years. A 60-year-old woman has a one in 30 chance of developing breast cancer in the next 10 years.

* White women are slightly more likely to develop breast cancer than African American women in the U.S.

* A woman with a personal history of cancer in one breast has a three- to fourfold greater risk of developing a new cancer in the other breast or in another part of the same breast. This refers to the risk for developing a new tumor and not a recurrence (return) of the first cancer.

Genetic Causes

Family history has long been known to be a risk factor for breast cancer. Both maternal and paternal relatives are important. The risk is highest if the affected relative developed breast cancer at a young age, had cancer in both breasts, or if she is a close relative. First-degree relatives, (mother, sister, daughter) are most important in estimating risk. Several second-degree relatives (grandmother, aunt) with breast cancer may also increase risk. Breast cancer in a male increases the risk for all his close female relatives. Having relatives with both breast and ovarian cancer also increases a woman's risk of developing breast cancer.

There is great interest in genes linked to breast cancer. About 5-10% of breast cancers are believed to be hereditary, as a result of mutations, or changes, in certain genes that are passed along in families.

* BRCA1 and BRCA2 are abnormal genes that, when inherited, markedly increase the risk of breast cancer to a lifetime risk estimated between 40 and 85%. Women with these abnormal genes also have an increased likelihood of developing ovarian cancer. Women who have the BRCA1 gene tend to develop breast cancer at an early age.

* Testing for these genes is expensive and may not be covered by insurance.

* The issues around testing are complicated, and women who are interested in testing should discuss this with their health-care providers.

Hormonal Causes

Hormonal influences play a role in the development of breast cancer.

* Women who start their periods at an early age (11 or younger) or experience a late menopause (55 or older) have a slightly higher risk of developing breast cancer. Conversely, being older at the time of the first menstrual period and early menopause tend to protect one from breast cancer.

* Having a child before age 30 years may provide some protection, and having no children may increase the risk for developing breast cancer.

* Oral contraceptives have not been shown to definitively increase or decrease a woman's lifetime risk of breast cancer.

* A large study conducted by the Women's Health Initiative showed an increased risk of breast cancer in postmenopausal women who were on a combination of estrogen and progesterone for several years. Therefore, women who are considering hormone therapy for menopausal symptoms need to discuss the risk versus the benefit with their health-care providers.

Lifestyle and Dietary Causes

Breast cancer seems to occur more frequently in countries with high dietary intake of fat, and being overweight or obese is a known risk factor for breast cancer, particularly in postmenopausal women.

* This link is thought to be an environmental influence rather than genetic. For example, Japanese women, at low risk for breast cancer while in Japan, increase their risk of developing breast cancer after coming to the United States.

* Several studies comparing groups of women with high- and low-fat diets, however, have failed to show a difference in breast cancer rates.

The use of alcohol is also an established risk factor for the development of breast cancer. The risk increases with the amount of alcohol consumed. Women who consume two to five alcoholic beverages per day have a risk about one and a half times that of nondrinkers for the development of breast cancer. Consumption of one alcoholic drink per day results in a slightly elevated risk.

Studies are also showing that regular exercise may actually reduce a woman's risk of developing breast cancer. Studies have not definitively established how much activity is needed for a significant reduction in risk. One study from the Women's Health Initiative (WHI) showed that as little as one and a quarter to two and a half hours per week of brisk walking reduced a woman's breast cancer risk by 18%.

Benign Breast Disease

* Fibrocystic breast changes are very common. Fibrocystic breasts are lumpy with some thickened tissue and are frequently associated with breast discomfort, especially right before the menstrual period. This condition does not lead to breast cancer.

* However, certain other types of benign breast changes, such as those diagnosed on biopsy as proliferative or hyperplastic, do predispose women to the later development of breast cancer.

Environmental Causes

Radiation treatment increases the likelihood of developing breast cancer but only after a long delay. For example, women who received radiation therapy to the upper body for treatment of Hodgkin disease before 30 years of age have a significantly higher rate of breast cancer than the general population.


An abnormal area on a mammogram, a lump, or other changes in the breast can be caused by cancer or by other, less serious problems. To find out the cause of any of these signs or symptoms, a woman's doctor does a careful physical exam and asks about her personal and family medical history. In addition to checking general signs of health, the doctor may do one or more of the breast exams described below.

* Palpation. The doctor can tell a lot about a lump—its size, its texture, and whether it moves easily—by palpation, carefully feeling the lump and the tissue around it. Benign lumps often feel different from cancerous ones.

* Mammography. X-rays of the breast can give the doctor important information about a breast lump. If an area on the mammogram looks suspicious or is not clear, additional x-rays may be needed.

* Ultrasonography. Using high-frequency sound waves, ultrasonography can often show whether a lump is solid or filled with fluid. This exam may be used along with mammography.

Based on these exams, the doctor may decide that no further tests are needed and no treatment is necessary. In such cases, the doctor may need to check the woman regularly to watch for any changes. Often, however, the doctor must remove fluid or tissue from the breast to make a diagnosis.

Aspiration or needle biopsy. The doctor uses a needle to remove fluid or a small amount of tissue from a breast lump. This procedure may show whether a lump is a fluid-filled cyst (not cancer) or a solid mass (which may or may not be cancer). Using special techniques, tissue can be removed with a needle from an area that is suspicious on a mammogram but cannot be felt.

If tissue is removed in a needle biopsy, it goes to a lab to be checked for cancer cells. Clear fluid removed from a cyst may not need to be checked by a lab.

Surgical biopsy. The surgeon cuts out part or all of a lump or suspicious area. A pathologist examines the tissue under a microscope to check for cancer cells.


In a normal state, cells proliferate in response to external proliferation-promoting signals to fulfill a function such as replacing lost cells or repairing injured tissues. Once the goal has been reached, a set of proliferation-repressing signals is activated. These signals allow the cells to exit the proliferation cycle (cell cycle) by returning to the dormant state (G0), by differentiating, or by dying (apoptosis). Each of these functions is carried out by a complex system of interacting proteins. Constitutive expression by mutation or another genetic change of any component of the proliferation-promoting system may result in uncontrolled proliferation. The constitutively expressed component is called an oncogene.

Conversely, the loss by mutation or deletion of a proliferation-repressing gene results in an inability to stop the cell cycle and, thereby, continuous proliferation, possibly leading to cancer. The lost gene is called a tumor suppressor gene. Likewise, constitutive expression of antiapoptotic genes may result in immortalization of the cell, paving the way for further genetic changes and eventually cancer formation. Loss of proapoptotic genes may lead to similar results. Thus, autonomous proliferation and immortality shared by all cancers are the final result of successive genetic changes, which may be different from one cancer to another.

Breast cancer is not an exception in that regard. It is the result of multiple genetic changes that are different from those of other malignancies and that confer to this cancer its characteristic phenotype.

Cell-cycle deregulation in breast cancer

Estrogen and progesterone induce cyclin D1 and c-myc expression. Although both sex hormones provide directionality by shifting the CDKI p21 from CDK2 to CDK4, progesterone promotes maturation by inducing p27, while only estrogen allows multiple cycles. Recent studies have reported common amplification of cyclin D1 (a third of breast cancers), inactivation of p16, and mutation of TP53 in breast cancer.

c-myc overexpression is one of the most common genetic alterations encountered in persons with breast cancer (a third of patients). Depending on the availability of its different partners, it may result in proliferation and chromosomal instability (Myc-Max) or differentiation (Myc-Mad), probably by sequestering Myc and reducing its availability. Amplification of the c-myc gene is associated with a poor prognosis and a high S-phase.

Estrogen receptor (ER)–positive breast cancer cells undergo apoptosis after withdrawal of estrogen, suggesting that this hormone functions not only as a mitogen but also as a survival factor. The antiapoptotic factor Bcl-2 is commonly overexpressed in ER-positive breast cancers.

ER negativity is observed in a third of primary breast cancers and a third of recurrences of ER-positive primaries. The ER gene is usually intact with no identifiable deletions or mutations. Although the exact mechanism of this lack of expression is not known, hypermethylation used normally by the genome to silence certain genes is a possible explanation. Methylation of cytosine-rich areas (called CpG islands) of the ER-gene promoter region has been described in the majority of ER-negative breast cancers and in a small fraction of ER-positive breast cancers. Demethylation of these areas with specific agents (eg, 5-azacytidine) restores ER expression and its function in vitro.

A progesterone receptor (PR) is present in approximately 50% of all ER-positive tumors. Its presence depends on the expression of functional ER, which explains its absence in almost all ER-negative breast cancers. The mitogenic effect of progesterone in breast cancer may depend on the induction of local growth hormone production in the hyperplastic mammary epithelium. However, high doses of progestins have proven inhibitory effects on breast cancer growth mediated by the down-regulation of G1-phase CDKs and cyclin D1 leading to cell differentiation.

Regarding adhesion-dependent cell regulation, the transmembrane glycoproteins, ie, epithelial cadherins (E-cadherins), mediate with their extracellular domain cell-to-cell interactions, thus stabilizing the cell in the epithelial tissue. Their intracellular domain interacts with and controls the transcription factors B-catenins. A mutation or the absence of E-cadherins results in cell detachment, increased motility and invasiveness, and release of B-catenins, which up-regulates c-myc expression.

Expression of E-cadherins is down-regulated in breast cancer. Another family of adhesion molecules, the integrins, is involved in cell-to-matrix interactions. Integrins signal through the Fak-Src pathway, which activates PI3K and AKT, resulting in enhanced survival, proliferation, and motility. The main components of this pathway (Fak, PI3K, and AKT) are inhibited by PTEN (ie, phosphatase on chromosome 10 gene product, mutated in Cowden disease), which results in the suppression of survival and apoptosis.

The epidermal growth factor (EGF) receptor family plays a critical role in mammary tumorigenesis. Other than the EGF receptor itself, 3 other members of this family have been described, including c-erb-B2 (HER2, HER2/neu), c-erb-B3, and c-erb-B4; the latter is called a kinase-dead receptor because it does not carry a kinase function on the cytoplasmic domain of the receptor, which is in contrast to the other members of the family.

These receptors interact with many ligands, including EGF, transforming growth factor (TGF)–alpha, hergulin (or Neu differentiation factor), heparin-binding EGF-like growth factor, beta-cellulin, and epiregulin. Upon binding of a ligand with its cognate receptor, a homodimerization or heterodimerization process occurs, followed by autophosphorylation of the intracellular domain and activation of the intrinsic catalytic domain.

Transmission of the signal is operated via phosphorylation of adaptor proteins (GRB2-SOS, Shc, IRS-1/2, STAT) docked or recruited to the cytoplasmic domain of the receptor, followed by activation of the RAS-GTP protein, then 1 of 3 pathways to the nucleus (ie, Raf/MEK/ERK-1/2, MEKK1/MEK4/7/JNK, PI3K/AKT/GSK).

Transmission of the signal from adaptor proteins to the nucleus without mediation by RAS is possible through Fak/Src or Rho/Rac/CDC42 pathways. In addition, phospholipase C-gamma is activated by direct interaction with the phosphorylated c-erb-B-2; however, its intracellular pathway is not fully known. The final result is the induction of transcription factors (ie, Myc, NF-kB, ATF, Ets, AP-1, EIK, SRF) that drive the cell cycle by up-regulating cyclins and inhibiting CDKIs and proapoptotic signals.

Once the biological message has been executed, the complex ligand receptor is internalized and destroyed in the lysosomes. The pattern of heterodimerization, the intracellular pathway used, and the rate of internalization and destruction of the receptor depend on the specific ligand bound to the receptor.

Although c-erb-B2 does not have a specific ligand, its role in the signal transmission from the epidermal growth factor receptor is crucial. Cell lines lacking c-erb-B2 are resistant to the tumorigenic effect of EGF, while those with a kinase-deficient or carboxyl terminal–truncated EGF receptor with intact c-erb-B2 can still execute all the functions of the wild type.

The discovery of the role of HER2 in breast cancer was one of the landmarks in breast cancer research in the last 2 decades. HER2 is overexpressed in 20-30% of breast cancers. Tumor cells overexpressing HER2/neu may have up to 2 million copies of the receptor on their surface compared with 20,000-50,000 copies in normal breast epithelial cells. Because of this abundance of HER2/neu, many heterodimers contain HER2/neu, resulting in potent intracellular signaling and malignant growth.

Despite persistent controversy regarding certain aspects of its biology, prognostic value, and methods of evaluation, HER2 overexpression or amplification is generally accepted to be correlated with a high histologic grade, the absence of hormone receptor expression, aneuploidy, a high proliferation index, tumor size, and a poor clinical outcome. Its role as a predictor of response to chemotherapy and hormonal therapy (HT) is not clearly defined.

Certain clinical studies using tamoxifen showed not only a lack of response, but also a detrimental effect in the group of patients overexpressing HER2. Retrospectively reviewed chemotherapy data showed longer disease-free survival and overall survival in HER2 overexpressors who received high doses of doxorubicin-containing chemotherapy compared with HER2-negative patients. Available data concerning the interaction between cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and HER2 overexpression are inconclusive and do not allow the formation of final conclusions. Taxanes seem to have high efficacy in patients overexpressing HER2 (relative risk, 65%) compared with the HER2-negative group (relative risk, 35%).

The IGF family consists of IGF-1, IGF-2, IGF receptor-1, IGF receptor-2, and IGF-binding proteins. The members of this family play an important role in normal mammary development and tumorigenesis. Both IGF-1 and IGF-2 bind to IGF receptor-1, whose strong mutagenic effect is synergistic with estrogen. In breast cancer, IGF receptor-1 and IGF-1 and IGF-2 are overexpressed in epithelial cells and stromal cells, respectively. Paradoxically, this overexpression correlates with a good prognosis, perhaps reflecting simple hormone dependence or association. IGF receptor-2 plays a tumor-suppressing role by down-regulating IGF-2.

The TGF-beta family consists of 3 TGF-beta and 2 interdependent serine-threonine kinase receptors. In normal mammary epithelial cells, TGF-beta blocks the expression of cyclin A, an S-phase–promoting protein and (to a lesser degree) cyclins D and E involved in the G1 phase and induces the expression of the CDKI p15, which results in cell-cycle arrest and, potentially, apoptosis. This explains its role in postlactational mammary gland regression.

Expression of TGF-beta in breast cancer is increased and seems to correlate with disease progression rather than tumor suppression. Mutation of TGF-beta receptors (type I and II) or any of the downstream molecules (Smad4) involved in intracellular signal transduction renders breast cancer cells resistant to its suppressive effects. However, its role in promoting angiogenesis and invasion and in suppressing the immune system becomes advantageous for the cancer cells, which acquire a proliferative advantage by losing sensitivity to TGF-beta and developing a way to escape the host immunosurveillance.

Mutated BRCA1 and BRCA2, breast cancer susceptibility genes, are proven risk factors for breast cancer. More than 500 mutations have been described in the BRCA1 gene (band 17q21), and 250 have been described in the BRCA2 gene (band 13q12-13). The mutations occurring at either end of the BRCA1 gene are associated with more aggressive tumors; those occurring at the 5` extremity are associated with breast and ovarian cancers, while those closer to the 3` end are associated with only breast cancer.

The biological function of the BRCA1 gene product is not well known. Accumulated evidence suggests that BRCA1 is a nuclear protein involved in other genes' expression, in cell cycle progression, and in the response to DNA damage. DNA damage results in activation and interaction of BRCA1, BRCA2, RAD51, and TP53 with subsequent expression of p21, which leads to a cell cycle pause until the damage is repaired. The mutation or absence of BRCA1 results in failure to repair the damaged DNA, and the cell cycle continues to accumulate further mutations, eventually leading to tumorigenesis. BRCA2 seems to play a role similar to that of BRCA1 in the cell cycle, other genes' expression, and DNA damage repair.


The most important risk factors for the development of breast cancer are sex, age, and genetics. Because women can do nothing about these risks, regular screening is recommended in order to allow early detection and thus prevent death from breast cancer.

Regular screening includes breast self-examination, clinical breast examination, and mammography.

Breast self-examination (BSE) is cheap and easy. Routine monthly examination may be helpful. Previously considered critical, more recent studies suggest that self breast exam may be less valuable than previously thought, especially for women who are having routine clinical breast examination and/or mammography.

* For women who are menstruating, the best time for examination is immediately after the monthly period.

* For women who are not menstruating or whose periods are extremely irregular, picking a certain date each month seems to work best.

* Instruction in the technique of breast self-examination can be obtained from your health-care provider or from any one of several organizations interested in breast cancer.

Clinical breast examination: The American Cancer Society recommends a breast examination by a trained health-care provider once every three years starting at age 20 years, and then yearly after age 40 years.

Mammograms are recommended every one to two years starting at age 40 years. For women at high risk for the development of breast cancer, mammogram screening may start earlier, generally 10 years prior to the age at which the youngest close relative developed breast cancer.

Obesity after menopause and excessive alcohol intake may increase the risk of breast cancer slightly. Physically active women may have a lower risk. All women are encouraged to maintain normal body weight, especially after menopause and to limit excess alcohol intake. Hormone replacement should be limited in duration if it is medically required.

In women who are genetically at high risk for the development of breast cancer, tamoxifen has been shown to significantly decrease the incidence of the disease. Side effects should be carefully discussed with your health-care provider prior to embarking on therapy. A second drug, raloxifene (Evista), which is now being used for the treatment of osteoporosis, also blocks the effects of estrogen and appears to prevent breast cancer. Initial studies showed that both tamoxifen and raloxifene were able to reduce the risk of invasive breast cancer, but raloxifene did not have this protective effect against noninvasive cancer. Studies are ongoing to further characterize the effectiveness and indications for use of raloxifene as a breast cancer preventive drug.

Occasionally, a woman at very high risk for development of breast cancer will decide to have a preventive or prophylactic mastectomy to avoid developing breast cancer. Additionally, removal of the ovaries has shown to reduce the risk of developing breast cancer in women who have the BRCA1 mutation and who have their ovaries surgically removed before they reach age 40.


The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.

Also see.


The list of complications that have been mentioned in various sources for Breast Cancer includes:

Complications and sequelae of Breast Cancer include:

* Cachexia
* Cerebral metastases
* Lymphangitis carcinomatosa
* Breast lump
* Opsoclonus
* Lung metastases
* Brachial plexus neuropathy
* Back pain
* Liver metastases
* Bone metastases
* Prostate specific antigen levels raised (plasma or serum)
* Bone pain
* CEA raised
* Renal metastases
* Mastalgia
* Pleural effusion
* Lymphadenopathy
* Leucoerythroblastic anemia
* Cutaneous metastasis
* Osteosclerosis
* Nipple discharge


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