Introduction to breast cancer prevention
For so many women, there is no more dreaded disease than breast cancer. Breast cancer elicits fears related to loss of body image and sexuality, surgery, and death. As is the case for most cancers, the exact cause of breast cancer is not clearly known.
Furthermore, there is currently no cure for advanced disease, and there is no definitive way of preventing it.
Our knowledge of how breast cancer develops is expanding rapidly. As a result, new medications are being developed to reduce the risk of breast cancer among women at high risk of contracting this disease. For the majority of women, lifestyle changes, a healthy diet, cautious use of selected antioxidants, exercise, and weight reduction can also help reduce the chance of developing breast cancer.
To date, the most important strategy in improving survival is still breast cancer screening and early detection.
The risk is even higher for women with previous breast cancer, those who have first-degree relatives with breast cancer, those with multiple family members with cancer, and those who have inherited "cancer genes."
What are the biological causes of breast cancer?
Breast cancer, like all cancers, initially develops 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.
Human DNA is thought to contain approximately 50,000 to 100,000 genes. 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.
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%-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 CHEK-2 gene, and the ATM (ataxia-telangiectasia mutation) gene.
Since inherited DNA defects account for only 5%-10% of breast cancers, the majority of breast cancers are due to DNA damages that develop 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 overactivity 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.
What are the risk factors for developing breast cancer?
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. Breast cancer is 400 times more common in women who are 50 years old as compared to those who are 20 years old.
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 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.
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.
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.
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 fivefold 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.
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.
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.
Studies have confirmed that long-term use (several years or more) of hormone therapy (HT) after menopause, particularly estrogens and progesterone combined, leads to an increase in risk for development of breast cancer.
This risk appears to return to normal if a woman has not used hormone therapy for five 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. Cigarette smoking, caffeine intake, antiperspirant use, 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.
What are breast cancer prevention treatments?
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 and Raloxifene, have been used as preventive treatment. The advantages and disadvantages of each are discussed in more detail below.
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.
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.
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.
Data suggest that raloxifene, like tamoxifen, can reduce the chance of developing breast cancer in high-risk 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, some data suggested that raloxifene might not be 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.
Controversies or other concerns about the use of tamoxifen or raloxifene as a primary prevention for patients at high risk
The data from studies of raloxifene and tamoxifen are encouraging. But there are still unresolved issues such as:
- Do women treated with tamoxifen or raloxifene for primary prevention have a higher long-term survival rate than women who received the placebo do?
- Does tamoxifen or raloxifene really prevent breast cancer, or do they only suppress the growth of existing breast cancer, thus delaying detection?
- If tamoxifen is offered to healthy, young women, what are the long-term side effects? Does breast-cancer reduction translate into better long-term survival and quality of life?
- How many years should patients be kept on the medication?
Select groups of high-risk women for whom a preventive medication such as tamoxifen or raloxifene should considered for use as primary prevention.
A specific model has been developed to assist doctors in predicting breast cancer risks for their patients. This model was used in the NSABP tamoxifen trial and is available to help evaluate patients considering this question.
Some doctors would consider recommending tamoxifen to perimenopausal (the years around menopause) or raloxifene to postmenopausal patients with several first-degree relatives who have had breast cancer if the patient has had biopsies with abnormal, but not yet cancerous cell changes (atypical hyperplasia) or a type of localized breast cancer (lobular carcinoma in situ). This recommendation would be even stronger if the patient has had a hysterectomy.
Studies are also ongoing to determine whether tamoxifen or raloxifene are effective in preventing breast cancer in women with inherited BRCA1 or BRCA2 genes.
Aromatase inhibitors
Other medications, known collectively as aromatase inhibitors, are also used to block the effects of estrogen. 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. Studies are under way to compare their use as breast-cancer preventive drugs together and in sequence.
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 chose 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.
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Last Editorial Review:20/1/2010
