Diseases

Antioxidants Antioxidants are chemicals that prevent a type of chemical reaction called oxidation. Oxidation is a major source of free radical formation. Antioxidants also mop up the free radicals that are formed. Free radicals are electrically charged chemicals that can attack and damage proteins and DNA, thereby altering genetic information. If enough damage occurs to the DNA segments of a cell that controls cell division and growth, cancer can develop from that single cell. Free radicals can be formed by the normal metabolic activity in the body. However, there is no evidence that dietary intake of antioxidants affects breast cancer risk. Dietary fats Early epidemiological studies suggested that high-fat diets might be associated with increased risks of breast cancer. But this relationship has not been confirmed, and results of studies have been mixed. Furthermore, it is clear that some fats may be protective rather than harmful. There are, however, some theoretical concerns about eating overcooked meats and fats. Diet and lifestyle measures to reduce breast cancer risk Theoretically, there are dietary and lifestyle measures that can decrease free-radical formation and reduce the risk of developing breast and other types of cancer. These measures include

• diets rich in vegetables and fruits;
• diets low in fats, and red and overcooked meats;
• reasonable intake of antioxidants, such as vitamins E and C; and
• regular exercise and weight control.

Evidence that these measures reduce the chances of developing breast cancer is largely based on epidemiological data. Epidemiological evidence is derived from comparing two large populations with similar characteristics that have different diets or levels of exercise. Epidemiological evidence can only be suggestive, not conclusive. In fact, concrete proof that diet and exercise actually reduce the risk of developing breast cancer will be difficult to attain, and there is no evidence that any breast cancer prevention diet exists. When firm scientific data is lacking and is unlikely to be available for the foreseeable future, the doctor has to weigh the risks of his/her recommendations against the potential benefits. Long-term risk and benefit considerations are especially important in advising young, healthy women about preventing a disease that they may or may not develop. In the case of diets low in fat and overcooked meats, diets high in vegetables and fruits, avoiding smoking, and regular exercise, there is enough known benefit and very little known risk, which makes it easy for doctors to recommend them to their patients. Doctors are also comfortable with recommending one multivitamin a day. However, there is no clinical evidence that taking megadoses of vitamins are of any benefit. Megadoses of certain vitamins can have adverse side effects. Exercise There is epidemiological data which show that women who exercise regularly have a lower incidence of breast cancer than women who do not exercise. The reason for such a benefit is unknown, but it may be related to the fact that obese individuals have higher levels of estrogen in the body than people who are not obese. The higher levels of estrogen may increase the risk of breast cancer in obese women.

The American Cancer Society (ACS) recommends a baseline mammogram for all women by age 40 and annual mammograms for women 40 and older for as long as they are in good health. In women with "lumpy breasts" or breast symptoms, and also in women with a high risk of developing breast cancer, sometimes a baseline mammogram at 35 years of age is recommended. This recommendation is somewhat controversial, and there are other viewpoints. However, the U.S. Preventive Services Task Force (USPSTF) recommends against routine mammography screening for women before 50 years of age and suggests that screening end at 74 years of age. The USPSTF recommendations are in opposition to other existing breast cancer screening guidelines from organizations such as the American Cancer Society as described above. The USPSTF guidelines also recommend a screening interval of 2 years and suggest that women 40 to 49 years old who are at high risk for breast cancer consult with their doctor regarding the time to begin regular screening mammography. It is important for women who are concerned about when to begin mammography to discuss the situation with their health-care professional. He or she can help their patient make an informed decision about breast cancer screening that is appropriate for their individual situation. Mammograms and young women There is a special issue regarding mammograms in young women. Since young women have dense glandular breast tissue, routine mammograms have difficulty "seeing through" the dense breast tissue. Therefore mammograms may not be able to detect cancer in the breast because the dense breast tissue around the cancer obscures it. However, this problem can be partly offset by the use of special breast ultrasound, which is now an extremely important additional imaging technique used to supplement mammography in difficult cases. Ultrasound can make visible a lump hidden within dense breast tissue. It may also detect lumps and early breast cancers when mammograms fail to identify a problem. Ultrasound can also help doctors locate specific areas in the breast for biopsy (obtain small samples of tissue to study under a microscope). Sometimes doctors also suggest the use of magnetic resonance imaging (MRI) screening (see below) in younger women with dense breast tissue. Magnetic resonance imaging (MRI) scanning Recent research has shown that MRI scanning may be a useful screening tool for breast cancer in certain high-risk populations. In 2004, a team of Dutch researchers published a study of over 1,900 women at high risk for breast cancer in the New England Journal of Medicine. These women underwent breast cancer screening that included physical exams every 6 months along with yearly mammograms and MRI scans of the breasts. While conventional mammography did detect many cancers at an early stage, some tumors were identified by MRI that were not detected by mammography. Overall, MRI led to the identification of 32 tumors, of which 22 were not seen on the corresponding mammogram. Likewise, some tumors appeared on mammograms that were not visible on the MRI scan. Mammography detected a total of 18 tumors, of which eight were not identified by MRI. The routine use of MRI, however, has many limitations. While it enabled the detection of some tumors in high-risk women, it also detected more noncancerous lesions (false-positives), which lead to many more follow-up examinations and potentially unnecessary surgeries. In fact, MRI led to twice as many unnecessary examinations and three times as many unneeded surgical biopsies of the breast than screening by mammography alone. MRI is also approximately 10 times more costly (average cost $1,000 to $1,500) than mammography. Because of these limitations, experts believe that screening with MRI is impractical for women who do not have an elevated risk of developing breast cancer. However, its benefits appear to outweigh its limitations in certain high-risk populations. The American Cancer Society recommends that women at high risk for breast cancer (greater than 20% lifetime risk) should get an MRI and a mammogram every year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening. Women at high risk for developing breast cancer include those who

• have a BRCA1 or BRCA2 mutation, indicative of a strong inherited risk of breast cancer;
• have a first-degree relative with a BRCA1 or BRCA2 mutation but have not been tested for the mutation;
• received chest radiation -- to treat Hodgkin's disease or other cancers, for example -- between 10 and 30 years of age; or
• have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have first-degree relatives with one of these syndromes.

Women with significant risk factors may want to discuss their screening program with their physician to better determine whether MRI may be useful in their own case. It is important to note that MRI should not be considered a substitute for regular mammography, and mammography is the only screening tool for which a reduction in mortality (death rate) from breast cancer has been proven. Breast self-examination and breast examinations by a doctor Both the American Cancer Society and the USPSTF do not call for regular self-examination of the breasts in their guidelines. The ACS states that breast self-exam is optional, while the USPSTF states that doctors should not teach women to do breast self-examination. The ACS further recommends a clinical breast exam (CBE) by a health-care professional about every 3 years for women in their 20s and 30s and every year for women 40 years of age and over.

In special circumstances, genetic tests can be very helpful both in identifying exceptionally high-risk patients and reducing the level of concern for others. We also now know that the presence of one of these genetic defects does not cause cancer in every patient. Before genetic tests are conducted, individuals being tested must have thorough counseling. A clear understanding of the limitations of the tests and the problems they may pose must precede the testing. The patient must know the meaning of the possible results, whichever way they may turn out, before testing. They should also have settled on a plan for each possible outcome of the test results. Often, the best way to evaluate a potential genetic risk is to test a relative who has already been diagnosed with breast cancer. If the relative's genetic testing (which must cover a large number of possible mutations) proves negative, then there is no need to perform genetic testing on the concerned individual. But the concerned individual should still undergo close monitoring with breast examinations and mammograms. If the test is positive on the relative, then that specific mutation is the only one that needs to be checked in the concerned individual and the other family members.

Selective estrogen receptor modulator (SERM) and its effect of estrogen on breast cell growth A selective estrogen receptor modulator (SERM) is a chemical that is designed to act like estrogen in certain tissue such as the bones and not like estrogen in other tissue such as the breast. The use of SERMs takes advantage of the benefits of estrogen while trying to avoid the risks associated with estrogen. Two SERMs, tamoxifen (Nolvadex) and raloxifene (Evista), have been used as preventive treatment. The advantages and disadvantages of each are discussed in more detail below. Tamoxifen Tamoxifen is the first SERM to receive approval by the United States Food and Drug Administration (FDA) in the treatment of breast cancer. Some breast cancer cells are "estrogen sensitive," meaning they possess so-called estrogen receptors and need estrogen to grow and divide. But estrogen has to bind to the receptors of these cancer cells in order to stimulate them. Binding of estrogen to the receptors is analogous to fitting a key into a lock. Tamoxifen blocks the action of estrogen on the cancer cells by occupying the receptors (the locks), thus preventing estrogen (the keys) from fitting into the receptors. Blocking estrogen from the estrogen-sensitive cancer cells stops the growth and multiplication of these cells. Tamoxifen (in higher than usual doses) may also possess other properties that cause the death of breast cancer cells that are not estrogen sensitive. Tamoxifen has been used to treat both advanced and early stage breast cancers. This drug has also proven valuable to women who have had cancer in one breast in reducing the chances of developing cancer in the second breast. Even though tamoxifen behaves like an anti-estrogen agent in breast tissue, it acts like a weak estrogen in the bones. Thus, tamoxifen may have some benefit in preventing osteoporosis fractures in postmenopausal women. Tamoxifen also decreases cysts and lumps in the breasts, especially among younger women. Fewer cysts and lumps make early detection by breast examinations and mammograms easier. This use of the drug would only be in extreme situations and is not an approved use. Primary prevention of breast cancer with tamoxifen The term "primary prevention" means trying to reduce the risks of developing breast cancer in women without a prior history of breast cancer. Tamoxifen not only blocks the action of estrogen on estrogen-sensitive cancer cells, but it also blocks estrogen from acting on cells that are not cancerous. Therefore, by reducing the growth and division of normal breast cells, tamoxifen decreases the population of cells that can develop cancer-causing DNA damage. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1, more than 13,000 women considered at high risk for developing breast cancer were given either tamoxifen or a placebo for 5 years. The women receiving tamoxifen developed 49% fewer breast cancers than women receiving the placebo. A further study, the International Breast Cancer Intervention Study (IBIS-I) in Europe, also confirmed a reduction in the rate of breast cancer development in high-risk women. The United States FDA has approved the use of tamoxifen for primary prevention in women at high risk for developing breast cancer. There is no evidence to suggest that tamoxifen can reduce breast cancer incidence in women considered to have a normal risk for the development of breast cancer. Risks and side effects of tamoxifen The risk of tamoxifen is the development of uterine cancer. Although the overall risk of developing uterine cancer is small (probably less than 1%), in the NSABP-P1 trial, more women on tamoxifen developed uterine cancer than women taking the placebo. Additionally, women over 50 years of age on tamoxifen have a slightly heightened chance of developing blood clots in the veins of the lower extremities. These blood clots can occasionally break off and travel to cause blockage of blood vessels in the lungs (a process called pulmonary embolism). Symptoms of pulmonary embolism include shortness of breath, chest pain, and sometimes shock. Some studies have also reported an increased risk of stroke in patients taking tamoxifen. The other side effects of tamoxifen include weight gain, hot flashes, irregular periods, vaginal dryness or discharge, and a slightly enhanced risk of cataracts. Many of these side effects also depend on the age group being studied. Raloxifene Raloxifene (Evista) is the second SERM to be approved by the FDA. It has been approved for treating and preventing osteoporosis in postmenopausal women. Data suggest that raloxifene, like tamoxifen, can reduce the chance of developing breast cancer in high-risk postmenopausal women. Unlike tamoxifen, raloxifene does not stimulate cells of the uterus and is not believed to increase the risk of uterine cancer. Studies that examined the effects of both tamoxifen and raloxifene (including the STAR trial, which studied over 19,000 postmenopausal women at high risk for developing breast cancer) showed that both drugs lowered the incidence of breast cancer in a similar manner. While both tamoxifen and raloxifene increased a woman's risk of blood clots, the observed increase was smaller with raloxifene. Raloxifene was also associated with a lower risk of uterine cancer and hysterectomy for noncancerous reasons than tamoxifen. However, data suggest that raloxifene is as effective in preventing the development of early, noninvasive cancers as tamoxifen. Data are not available on the effects of raloxifene in premenopausal women, and it is a potential teratogen, meaning that it may cause harm to the developing fetus. Therefore, raloxifene is limited to use by postmenopausal women and not used in women of childbearing age. Aromatase inhibitors Other medications, known collectively as aromatase inhibitors, are also used to block the effects of estrogen. Examples of aromatase inhibitors include anastrozole (Arimidex), and exemestane (Aromasin). Their main activity is to inhibit (block) the action of a particular enzyme (aromatase) that creates estrogen from other normally circulating hormones. Tamoxifen and aromatase inhibitors, therefore, act differently and have different side effects. Aromatase inhibitor medications are an option for postmenopausal women at high risk of developing breast cancer. Surgical measures to prevent breast cancer Preventive or prophylactic mastectomy is the surgical removal of one or both breasts in women who have moderate to high risk of developing breast cancer. Studies have shown that this technique reduces a woman's chance of developing breast cancer by up to 90%. Since small amounts of breast tissue can remain on the chest wall, in the underarm, or even in the abdomen following a mastectomy, it is impossible to completely prevent development of breast cancer by prophylactic mastectomy. Women often choose to have surgical reconstruction of the breasts at the time of surgery. It is very important for a woman considering preventive mastectomy to have a frank discussion with her physician concerning her cancer risk, other available treatments, and the potential complications and implications of the surgery before making a decision. Prophylactic or preventive oophorectomy, or removal of the ovaries, has also been performed in women receiving preventive mastectomies in order to reduce estrogen levels.

Mammography is an X-ray examination of the breast that has the ability to detect a cancer in the breast when it is quite small, long before it may be felt by breast examination. Approximately 85% to 90% of all breast cancers are detectable by mammography. Early detection by mammography has reduced the mortality rate from breast cancer by 20% to 30% in women over 50 years of age. However, some 10% to 15% of breast cancers are not visible on mammography but can be felt on physical examination of the breast. Therefore, a normal mammogram does not exclude the possibility of breast cancer. Breast examination by a health-care professional by palpation and visual inspection is also important. During a routine physical checkup, a doctor can conduct an examination of the breast.

Breast cancer cells, like all cancers, initially develop because of defects in the genetic material deoxyribonucleic acid (DNA) of a single cell. The human body is composed of trillions of cells. Inside the inner core (nucleus) of each cell is our DNA, located on chromosomes. Every human cell has two sets of 23 chromosomes. Each set is inherited from one parent. DNA exists as long, spiraled strands on these chromosomes. Different segments along the DNA strands contain information for various genes. Genes are blueprints that provide genetic instructions for the growth, development, and behavior of every cell. Most genes carry instructions for the types and the amount of proteins, enzymes, and other substances produced by the cells. Genes also govern the sizes and the shapes of the organs by controlling the rate of division of the cells within these organs. (During cell division, a cell makes a duplicate copy of its chromosomes and then divides into two cells.) Some genes restrict cell division and limit tissue growth. Defects on the DNA strands can lead to gene coding errors, which in turn can cause diseases. When genes that normally restrict cell growth and divisions are absent or defective, the affected cells can divide and multiply without restraint. The cells that divide and multiply without restraint enlarge (forming a tumor) and can also invade adjacent tissues and organs. Sometimes these cells can further break away and migrate to distant parts of the body in a process called metastasis. The ability to multiply without restraint, the tendency to invade other organs, and the ability to metastasize to other parts of the body are the key characteristics of cancers -- characteristics that are due to DNA defects. The cancer-causing DNA defects can be acquired at birth (inherited) or may develop during adult life. The inherited DNA defects are present in every cell of the body. On the other hand, DNA defects that develop during adult life are confined to the descendants (products of cell divisions) of the single affected cell. Generally, inherited DNA defects have a greater tendency to cause cancers and cancers that occur earlier in life than DNA defects that develop during adult life. Research has shown that 5% to 10% of breast cancers are associated with mutations (defects) in two genes known as breast cancer-associated (BRCA) genes, BRCA1 and BRCA2. These genes function to prevent abnormal cell growth that could lead to cancer. Every cell in the body has two BRCA1 or BRCA2 genes, one inherited from each parent. A woman who has received one defective BRCA1 or BRCA2 gene from one parent and a healthy gene from the other is called a carrier of the defective BRCA gene. Even though only one healthy BRCA1 or BRCA2 gene is needed to help prevent cancerous growth of cells, the one remaining healthy BRCA gene is vulnerable to damage during adult life by environmental factors such as toxins, radiation, and other chemicals such as free radicals. Therefore, women bearing a defective BRCA1 or BRCA2 gene are at an increased risk of developing breast and ovarian cancers. Women carrying defective BRCA1 or BRCA2 genes also tend to develop these cancers earlier in life. Other rare genetic mutations are also associated with an increased risk for the development of breast cancer, including mutations of the tumor suppressor gene p53, the PTEN gene, and the ATM (ataxia-telangiectasia mutation) gene. Since inherited DNA defects account for only 5% to 10% of breast cancers, the majority of breast cancers are due to DNA damage that develops during adult life. Environmental factors that can cause DNA damage include free radicals, chemicals, radiation, and certain toxins. But even among individuals without inherited cancer-causing DNA defects, their vulnerability to DNA damage, their ability to repair DNA damage, and their ability to destroy cells with DNA damage, are likely to be genetically inherited. This is probably why the risk of cancer is higher among first-degree relatives of breast cancer patients, even among families that do not carry the defective BRCA1 and BRCA2 tumor-suppressing genes. Some of the errors in the normal control mechanisms allow the accumulation of additional errors in other parts of the system. These errors may lead to gene silencing of critical control genes or the over activity of other growth-stimulating genes by activation of promoter sites adjacent to these otherwise normal genes. Other substances such as estrogen (a female hormone) and certain fatty acids may also increase the risk of breast cancer by stimulating the growth and division of cells of the breast tissue.

Gender and age The most significant risk factors for breast cancer are gender and age. Men can develop breast cancer, but women are 100 times more likely to develop breast cancer than men. The risk of breast cancer also increases with age. Breast cancer is 400 times more common in women who are 50 years old as compared to those who are 20 years old. Family history Another important risk factor is having first-degree relatives (mother, sister, or daughter) with breast cancer or male relatives with prostate cancer. The risk is especially higher if both the mother and sister have had breast cancers, if the cancers in first-degree relatives occurred early in life (before age 50), or if the cancers in these relatives were found in both breasts. Having a male relative with breast cancer and having both relatives with breast and ovarian cancers also increase a woman's risk of developing breast cancer. Families with multiple members with other cancers may have a genetic defect leading to a higher risk of breast cancer. Women who have inherited defective BRCA1, BRCA2, p53, and other DNA repair genes have an increased risk of developing breast cancer, sometimes at early ages, as discussed previously. But even in the absence of one of the known predisposing genetic defects, a strong family history may signify an increased risk because of genetic or environmental factors that are specific to that particular family. For example, increased risk in families could be due to exposure to similar environmental toxins in some cases. Previous breast cancer A woman with a history of breast cancer can develop a recurrence of the same breast cancer years later if the cancer cells had already spread to the lymph nodes or other parts of the body or if cancer cells were not all eliminated during treatment. A woman with previous breast cancer also has a three- to fourfold greater chance of developing another breast cancer in the opposite breast. In women who have been treated for breast cancer with breast conservation therapy (BCT), recurrence of cancer within the treated breast may also occur. Other breast conditions Even though most women with fibrocystic breasts and its related breast symptoms do not have increased risk of developing breast cancer, the lumpy texture and density of the breasts may hamper early cancer detection by breast examination or by mammography. Sometimes, women with fibrocystic breast changes have to undergo breast biopsies (obtaining small tissue samples from the breast for examination under a microscope) to make certain that palpable lumps are not cancerous. Breast biopsies sometimes may reveal abnormal, though not yet cancerous, cell changes (called atypical hyperplasia). Women with atypical hyperplasia of the breast tissue have about a four- to five-fold enhanced likelihood of developing breast cancer. Some other benign cell changes in breast tissue are also associated with a slight increase (one and a half to two times normal) in risk. These are termed hyperplasia of breast tissue without atypia, sclerosing adenosis, fibroadenoma with complex features, and solitary papilloma. The common benign breast tumor known as a fibroadenoma, unless it has unusual features under the microscope, does not confer an increased cancer risk. Breast cancer risks can be additive. For example, women who have first-degree relatives with breast cancer and who also have atypical hyperplasia of the breast tissue have a much higher risk of developing breast cancer than women without these risk factors. Radiation therapy Women with a history of radiation therapy to the chest area as treatment for another cancer (such as Hodgkin's disease or non-Hodgkin's lymphoma) have a significantly increased risk for breast cancer, particularly if the radiation treatment was received at a young age. Hormonal factors Women who started their menstrual periods before age 12, those who have late menopause (after age 55), and those who had their first pregnancy after age 30, or who have never had children have a mildly increased risk of developing breast cancer (less than two times the normal risk). Early onset of menses, late arrival of menopause, and late or no pregnancies are all factors that increase a woman's lifetime level of estrogen exposure. The use of hormone therapy (HT) after menopause, particularly estrogens and progesterone combined, leads to an increase in risk for development of breast cancer in women who are taking HT or who have recently used HT. This risk appears to return to normal if a woman has not used hormone therapy for 5 years or more. Similarly, some studies show birth control pills cause a small increased risk of breast cancer, but this risk also returns to normal after 10 years of nonuse. The decision whether to use hormone therapy or birth control pills involves weighing the risks versus the benefits and should be individualized after consulting one's doctor. Lifestyle factors Dietary factors such as high-fat diets and alcohol consumption have also been implicated as factors that increase the risk for breast cancer. Despite rumors to the contrary, caffeine intake, antiperspirant use, bras, breast implants, miscarriages or abortions, and stress do not appear to increase the risk of breast cancer. It is important to remember that 75% of women who develop breast cancer have no risk factors other than age. Thus, screening and early detection are important to every woman regardless of the presence of risk factors. Alcohol The consumption of alcohol is associated with an increased risk of developing breast cancer, and this risk increases with the amount of alcohol consumed. Compared with nondrinkers, women who consume one alcoholic drink a day have a very small increase in risk. However, those who have two to five drinks daily have about one and a half times the risk of women who drink no alcohol.

The various types of cancers behave differently, with distinct rates of growth and patterns of spreading (metastasis) to other areas of the body. Some cancers are "favorable" and treatable, while others are highly aggressive. Compared to other cancers, breast cancer is on the more treatable end of the spectrum if diagnosed early. It is considered a "favorable" cancer because it can be detected early by breast examination or by mammography. Pancreatic cancer, for example, is on the lethal end of the spectrum of cancers. Pancreatic cancer is often difficult to detect until it is very far advanced. Studies have clearly shown that the smaller the size of the breast cancer when detected, the better the chance of a surgical cure and long-term survival. The likelihood of a cure is also higher if the cancer is removed before it has spread to lymph nodes and other organs such as the lungs, liver, bones, and brain. Currently, mammography and breast examinations serve as the foundation for screening for breast cancer. It is extremely important for a woman to have regular breast examinations as well as mammograms to detect early breast cancer.

Estrogen is a female hormone that is produced by the ovaries. During the reproductive years, a woman's body is exposed to high levels of estrogen. After menopause, the production of estrogen by the ovaries decreases. Estrogen is sometimes prescribed to treat some of the problems often associated with menopause, such as hot flashes, night sweats, sleeplessness, and vaginal dryness. Estrogen has the additional benefit of prevention of bone thinning (osteoporosis). However, results from a large clinical trial of postmenopausal women receiving hormone therapy (HT) released in 2002 showed that the overall risks of estrogen plus progestin therapy outweighed the benefits of hormone therapy. Combined hormone therapy with estrogen and progestin was shown to increase the risk of heart disease, stroke, and blood clots. High levels of estrogen over long periods also increase the risk of developing breast and uterine cancer. Estrogen stimulates the cells of the breast and the uterine lining to grow and divide. Breast cells that are actively dividing are believed to have a greater chance of DNA damage as well as a higher number of cells that already have DNA damage. A higher number of cells with DNA damage elevate the risk of cancer development. Women who have an early onset of their menstrual period (or menses) and late menopause are more likely to develop breast cancer than women with late menses onset and early menopause. This difference is believed to be attributable to the longer period of estrogen exposure in the first group.

With modern mammography equipment, the amount of radiation exposure is extremely small. Although there is no level of radiation without some theoretical risk, there is no evidence of increased breast cancer risks from mammography performed in the recommended manner. Furthermore, the benefits of early detection far outweigh these theoretical concerns.