OVERVIEW

Information about the prevention of cancer and the science of screening appropriate individuals at high-risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best "treatment" of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable.

Breast cancer is the second leading cause of cancer death in women in the United States, with approximately 200,000 cases diagnosed each year. Progress in the areas of screening and treatment may allow for earlier detection and higher cure rates.

The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person's environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (i.e. the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.

Heredity or Genetic Factors

Family History: Women with a family history of breast cancer have an increased risk of developing breast cancer themselves. In addition, some families are at particularly high risk of cancer due to hereditary cancer syndromes. These families often have multiple family members with cancer, and are more likely to develop cancer at a young age. In the case of breast and ovarian cancers, inherited mutations in two genes - BRCA1 and BRCA2 - have been found to greatly increase the lifetime risk of developing breast and ovarian cancer. Alterations in these genes can be passed down through either the mother's or the father's side of the family.

BRCA1 and BRCA2 alterations are more common in some ethnic groups. A study of BRCA1 estimated that 12 out of 1000 persons of Ashkenazi Jewish descent have a BRCA1 alteration, compared to 2.4 out of 1000 persons in the non-Ashkenazi, non-Hispanic white population. Approximately 2 percent of Ashkenazim (20 out of 1000) have one of three BRCA1 or BRCA2 alterations specific to this population. Less information is available about the frequency of BRCA1 or BRCA2 alterations in other ethnic or racial groups, but a recent study of 200 women with breast cancer found that African-American and white women had a similar likelihood of having a harmful BRCA1 or BRCA2 alteration.

Women with a BRCA1 or BRCA2 alteration are much more likely than other women to develop breast or ovarian cancer. Among women with a BRCA1 or BRCA2 alteration, 36-85 percent will develop breast cancer over the course of their lifetimes, and 16-60 percent will develop ovarian cancer; 2 the broad ranges reflect differences in risk across the different populations and mutations that have been studied. By comparison, among women in the general U.S. population, approximately 13 percent will develop breast cancer and less than 2 percent will develop ovarian cancer.

BRCA1 and BRCA2 alterations are not the only gene alterations responsible for hereditary breast cancer syndromes. Other hereditary cancer syndromes that increase breast cancer risk are Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and Ataxia-Telangiectasia.Mutations in the CHEK2 gene also appear to contribute to some cases of familial breast cancer.

Breast Density: Breast density refers to the extent of glandular and connective tissue in the breast. Breasts with more glandular and connective tissue-and less fat-are denser. Women with higher breast density are at increased risk of developing breast cancer. In addition, dense breasts make it more difficult to detect breast cancer by mammography..

History of Breast Cancer: It is important to realize the women who have been cured of a primary breast cancer are at increased risk for breast cancer on the opposite side and that this risk persists for 20 years or more...

Environmental or Non-Genetic Factors

Reproductive Factors: Several reproductive factors have been associated with an increased incidence of breast cancer. These include an early age at first menstrual cycle, a late age at menopause, and a late age at the birth of the first child.

Postmenopausal Hormones: Results from the Women's Health Initiative suggest that postmenopausal hormone therapy with a combination of estrogen and progestin increases the risk of breast cancer. Furthermore, as use of postmenopausal hormones has declined, breast cancer incidence has also declined; this provides additional support for a link between postmenopausal hormone use and risk of breast cancer.

Alcohol: Moderate alcohol consumption (often defined as two or more drinks per day) has consistently been linked with an increased risk of breast cancer.

Obesity: In premenopausal women, obesity has been linked with a decreased risk of breast cancer, possibly as a result of disrupted menstrual cycles and altered hormone levels. In postmenopausal women, however, obesity has consistently been linked with an increased risk of breast cancer. The link between obesity and postmenopausal breast cancer appears to be strongest among women who have never used postmenopausal hormone therapy, and may be explained by the higher estrogen levels in obese postmenopausal women. A recent study has shown that weight gain in women during adult life increases the risk of postmenopausal breast cancer.

Radiation: Women who have received radiation to the chest for the treatment of Hodgkin's lymphoma or other cancers appear to have an increased risk of breast cancer. A recent international study has also shown that women who have received low or high dose radiation to the chest have an increased risk of developing breast cancer. Therapeutic doses of radiation have long been known to increase the risk of developing breast cancer. However, this study suggests that diagnostic procedures, such as periodic chest X-rays, can also increase the risk of developing breast cancer.

DES: Diethylstilbestrol (DES) is a synthetic estrogen that was used frequently in pregnant women between the 1940s and 1960s. The drug was used to reduce the risk of miscarriages, though later studies indicated that it most likely had no effect on miscarriage risk. In 1971 a study reported that girls born to women who had used DES (DES daughters) had a greatly increased risk of developing a certain type of vaginal cancer. More recent research suggests that DES daughters may also have an increased risk of breast cancer.

Exercise: Many studies have shown that women who exercise more have a lower risk of developing breast cancer than women with little physical activity. One study involving over 100,000 women reported that long-term physical activity lowers the risk of developing breast cancer by one third. A study from Europe found that physical exercise reduced the risk of postmenopausal breast cancer by 20-80%.

Fresh Fruits and Vegetables: Researchers from France have reported that an increased intake of lignans, found primarily in fresh fruits, vegetables and cereals, decreases the risk of postmenopausal breast cancer. However, not all studies have shown a protective effect of a high intake of fruits and vegetables on reducing the incidence of breast cancer.

Prevention

Cancer is largely a preventable illness. Two-thirds of cancer deaths in the U.S. can be linked to tobacco use, poor diet, obesity, and lack of exercise. All of these factors can be modified. Nevertheless, an awareness of the opportunity to prevent cancer through changes in lifestyle is still under-appreciated.
However, the situation with breast cancer is more complex than with some other cancers and the cause of most cases of breast cancer remain unknown. The risk factors, listed above, do not account for the majority of cases of breast cancer and we must continue to seek these unknown causes.

Diet: Diet is a fertile area for immediate individual and societal intervention to decrease the risk of developing certain cancers. Numerous studies have provided a wealth of often-contradictory information about the detrimental and protective factors of different foods.
There is convincing evidence that excess body fat substantially increases the risk for many types of cancer. While much of the cancer-related nutrition information cautions against a high-fat diet, the real culprit is an excess of calories. Studies indicate that there is little, if any, relationship between body fat and fat composition of the diet. These studies show that excessive caloric intake from both fats and carbohydrates have the same result of excess body fat. The ideal way to avoid excess body fat is to limit caloric intake and/or balance caloric intake with ample exercise.

It is still important, however, to limit fat intake, as evidence still supports a relationship between cancer and polyunsaturated, saturated and animal fats. Specifically, studies show that high consumption of red meat and dairy products can increase the risk of certain cancers. One strategy for positive dietary change is to replace red meat with chicken, fish, nuts and legumes.

High fruit and vegetable consumption has been associated with a reduced risk for developing at least 10 different cancers. This may be a result of potentially protective factors such as carotenoids, folic acid, vitamin C, flavonoids, phytoestrogens and isothiocyanates. These are often referred to as antioxidants.
There is strong evidence that moderate to high alcohol consumption also increases the risk of certain cancers. One reason for this relationship may be that alcohol interferes with the availability of folic acid. Alcohol in combination with tobacco creates an even greater risk of certain types of cancer.

Exercise: Life-long physical activity is an important component of cancer prevention and many studies have shown that increased levels of exercise decrease the risk of developing breast cancer.

Breastfeeding: Long-term breastfeeding may reduce a woman's risk of developing breast cancer by as much as 50%. In a study conducted in China, researchers found a significant association between the duration of lactation and a reduced breast cancer risk. In this study, women who breastfed a child for more than two years had a 54% reduced risk of developing breast cancer, compared with women who breastfed for 6 months or less. In addition, the results indicated that women who had a lifetime duration of lactation anywhere from 73 to 108 months had a significantly lower risk of developing breast cancer. The risk was further decreased for women who breastfed for 109 or more months of their lives. The researchers concluded that prolonged lactation reduces the risk of breast cancer and found that both the duration of lactation per child and the lifetime duration of lactation were important factors.

Prevention for Women at High Risk

Women with a family history of breast cancer and women who carry the BRCA1 and BRCA2 genes are at an increased risk of developing breast cancer and may opt to take more aggressive preventive measures, such as the use of anti-estrogen therapy, prophylactic (preventive) bilateral mastectomy, and/or prophylactic oophorectomy.

Chemoprevention: Drugs that block the effects of estrogen have been shown to reduce the risk of breast cancer in women at high risk of the disease. Two drugs that have been approved for breast cancer risk reduction in certain groups of women are tamoxifen and Evista (raloxifene). Tamoxifen is approved for breast cancer risk reduction in women who are at high risk of the disease (including high-risk premenopausal women). Evista - originally approved for the prevention and treatment of osteoporosis - is approved for breast cancer risk reduction in postmenopausal women with osteoporosis or postmenopausal women at high risk of breast cancer.

To directly compare Evista to tamoxifen in the prevention of breast cancer in high-risk women, researchers conducted a clinical trial known to as the STAR trial (The NSABP Study of Tamoxifen and Raloxifene [STAR] P-2 Trial). The study found that Evista is as effective as tamoxifen in reducing the risk of invasive breast cancer in high-risk postmenopausal women, but may be less effective in reducing the risk of noninvasive breast cancers such as ductal carcinoma in situ (DCIS). Evista carried a lower risk of blood clots and cataracts than tamoxifen, but is not without side effects. Evista has been found to increase the risk of blood clots and fatal strokes in women with coronary heart disease or at risk for coronary heart disease.

Bilateral Prophylactic Mastectomy (Preventive removal of both breasts): Women who have a family history of breast cancer and women who carry the BRCA1 and BRCA2 genes may reduce their risk of developing breast cancer by 90% by undergoing bilateral prophylactic mastectomy. Prophylactic mastectomy is a drastic measure that may decrease emotional stress regarding the concern over developing breast cancer; however, it may also increase stress related with self-esteem, sexuality and femininity. Women considering this procedure need to weigh the benefits against the consequences, which include the irreversibility of the procedure, the psychological impact and potential problems with implants and reconstructive surgery. While this procedure can greatly decrease the risk of developing cancer, it is not a guarantee that cancer will not develop.

Prophylactic Oophorectomy (Preventive removal of the ovaries): The BRCA1 and BRCA2 genes increase the risk of both breast and ovarian cancer. Since the ovaries produce estrogen, which is linked to the development of both cancers, some women who are at a high risk for developing either cancer will opt to have the ovaries removed. This is an extreme measure and the decision to undergo such a procedure rests in the hands of the patient. Women considering this approach need to weigh the benefits against the consequences, which include sterility and the potential that they could still develop cancer. In addition, removal of both ovaries prior to menopause can introduce the issue of hormone replacement therapy, which carries its own risks.

Screening and Early Detection

For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. The risk factors are different for different types of cancer. An awareness of these risk factors is important because 1) some risk factors can be changed (such as smoking or dietary intake), thus decreasing the risk for developing the associated cancer; and 2) persons who are at high risk for developing a cancer can often undergo regular screening measures that are recommended for that cancer type. Researchers continue to study which characteristics or exposures are associated with an increased risk for various cancers, allowing for the use of more effective prevention, early detection, and treatment strategies.
While all women over the age of 40 should undergo routine screening for breast cancer, women who are at a high risk for developing cancer may want to begin this process at an earlier age and with greater frequency. Increasing surveillance can increase the possibility that cancer could be found at an early stage when treatment is most likely to produce a cure.

Annual Clinical Breast Exam: Regular physical examination plays a vital role in the maintenance of health. An annual gynecological examination is an important screening procedure for many types of cancer and includes a physical examination of the breasts. During this procedure, a physician physically examines the breasts to feel for any lumps or irregularities. The physician can also use this procedure as an opportunity to teach an individual how to perform a breast self exam (BSE). Women are encouraged to perform a BSE every month, because with regular examination they have a greater chance of finding a lump early in its development.
Mammography: It is recommended that women over the age of 40 begin having a yearly mammogram. A mammogram is an x-ray image of the breast that can reveal irregularities and help to detect cancer early when it is most treatable. Mammography at 6-month intervals is advised for younger women at high risk of developing breast cancer since they tend to develop more rapidly growing cancers.

Increasing surveillance in women with a family history of breast cancer might increase the possibility that cancer could be found at an early stage when treatment is most likely to produce a cure. In a multi-center study, researchers compared mammography performance among women with a first-degree family history of breast cancer with performance among women of a similar age and no family history. The results indicated that the positive predictive value of mammography screening is higher among women with a family history of breast cancer than among those without a family history. The number of cancer cases per 1,000 mammography exams was 1.3 to 2 times higher among women with a family history of breast cancer than among those with no such history. Furthermore, they found that the rate of breast cancer detection among women with a family history of breast cancer was similar to the rate found among women who were a decade older and had no such history.

Magnetic Resonance Imaging (MRI): MRI uses radio waves and a magnet to create detailed images of the inside of the body. The American Cancer Society now recommends that women at high risk of breast cancer undergo yearly breast cancer screening with breast MRI in addition to mammography. These recommendations were prompted by several studies of MRI screening of women at high risk of breast cancer. While these studies found that the addition of MRI to mammography increased the frequency of false-positive test results compared to mammography alone, it also produced important improvements in breast cancer detection.

The following groups were defined as candidates for MRI and mammography based on their elevated risk of breast cancer:

- Women with a BRCA1 or BRCA2 mutation
- Women who have a first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
- Women who have a 20-25% or greater risk of breast cancer based on risk assessment tools
- Women who had radiation to the chest between the ages of 10 and 30 years
- Women who have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these syndromes based on a history in a first-degree relative

The American Cancer Society recommends against breast MRI screening in women with a lifetime risk of breast cancer of less than 15 percent. The optimal approach to the screening of women with an intermediate risk of breast cancer (lifetime risk between 15 and 20 percent) remains uncertain, and these women are encouraged to discuss their options with their physician.

Predictive Genetic Testing: The identification of the breast cancer susceptibility genes, BRCA1 and BRCA2, has led to predictive genetic testing for these genes. Since most breast cancers are not the result of known inherited mutations, not all women would benefit from genetic testing. However, women who appear to be at a high risk may benefit from undergoing a test to determine if they do carry the BRCA1 or BRCA2 gene. An accurate genetic test can reveal a genetic mutation, but cannot guarantee that cancer will or will not develop. At this point, genetic tests are used to identify individuals who are at an increased risk of developing cancer, so that these individuals may have the option of taking preventive measures

Fiberoptic Ductoscopy: Fiberoptic ductoscopy (FDS) is a new technique that builds on ductal lavage and allows physicians to directly visualize the inside of a milk duct. During this procedure, a small, flexible tube containing a video camera is inserted into the milk duct, creating a live picture of the inside lining of the duct. This allows the physician to visualize the lining of the milk duct and identify any abnormalities. As in ductal lavage, a salt-water stream washes cells out of the duct for examination under a microscope.
In clinical trials, fiberoptic ductoscopy has proven effective in identifying abnormal cellular masses. This procedure is still being evaluated in clinical trials, but could potentially serve as an additional screening procedure, especially for women who are experiencing nipple discharge.

New or Improved Imaging Devices: Some new developments in breast imaging are aimed at decreasing the number of false positive tests detected by mammography which leads to a large number of unnecessary breast biopsies.

There are intense research programs aimed at improving sonography technology in order to decrease the number of biopsies that are performed for false positive mammograms. One such technique is called ultrasound elasticity imaging which has showed high accuracy in classifying cancerous and benign breast changes. Another promising approach is ultrasound tomography which promises to be more accurate than routine ultrasound.

Digital Mammography: Current data suggests that digital mammography is more accurate than film mammography in certain groups of women. Digital mammography is primarily used to screen young women with dense breasts but some predict this will be a standard technique.

Computer Aided Detection (CAD): CAD involves the use of a computer to evaluate a digital mammographic image. The technology marks areas of the image that appear abnormal and that should be reviewed further by the radiologist. CAD doesn't replace a radiologist's review of a mammogram, but it can supplement it. Some studies, however, have reported that CAD doesn't increase breast cancer detection and may increase false-positive test results.

Digital Thermography: Digital thermography is being used to complement mammography and to distinguish benign from malignant lesions. The procedure uses changes in temperature to identify cancerous tissue, which will react differently to thermal changes than normal breast tissue. The procedure has already proven effective in identifying malignant lesions and preventing unnecessary biopsies.

Tumor Biomarkers: Researchers have begun to explore the role of tumor biomarkers for the early detection of breast cancer. In one study, researchers analyzed nipple aspirate fluids (NAFs) from women with and without breast cancer. The results of the study indicated that the levels of carcinoembryonic antigen (CEA) are significantly higher in nipple fluid from cancerous breasts than tumor-free breasts. However, the CEAs appear to be influenced by some unknown systemic influence, which might diminish the usefulness of the biomarker for early breast cancer detection. At this point, analysis of nipple fluid CEA levels might be used in combination with other methods for the early detection of cancer. Future research will help to define the role of nipple fluid CEA levels in the early detection of breast cancer.

Improvements in Genetics: Although the breast cancer susceptibility genes, BRCA1 and BRCA2, are similar, researchers have found significant differences in the genetic profiles of cancers that result from mutations of these genes. Usually BRCA2 mutations lead to estrogen receptor-positive breast cancer, whereas BRCA1 mutations lead to estrogen receptor-negative breast cancer. These differences indicate inherent differences in the genes.

Researchers from the National Institutes of Health evaluated and compared the genetic profiles from BRCA1 mutations, BRCA2 mutations and sporadic breast cancers. They found that the biological characteristics of the tumors were significantly different depending on which type of genetic mutation caused the tumor. The researchers concluded that an inherited mutation influences the gene-expression profile of the cancer. The results of this study have serious implications for the future treatment of breast cancer because the information could lead to individualized treatment for different types of breast cancer that have historically been treated as the same.

Again, the above-mentioned techniques are new areas of exploration in the screening and early detection of breast cancer. Clinical trials are being utilized to determine the effectiveness of these procedures. While the results look promising and the implications could be exciting, these procedures are not yet the standard. It is imperative that women continue to utilize the existing methods of screening for breast cancer in order to ensure early detection.