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 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 five 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 Food and Drug Administration (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 is the second SERM to be approved by the FDA. It has been approved for use in preventing osteoporosis in postmenopausal women. 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:
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. Examples of aromatase inhibitors include anastrozole (Arimidex), letrozole (Femara), 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. 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 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.
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 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 five 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 Food and Drug Administration (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 is the second SERM to be approved by the FDA. It has been approved for use in preventing osteoporosis in postmenopausal women. 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:
- 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?
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. Examples of aromatase inhibitors include anastrozole (Arimidex), letrozole (Femara), 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. 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 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.
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