Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.
Estrogen can also cause some cancers to grow. The breasts, uterus and other female organs are composed of cells that contain estrogen receptors. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers.
The growth of ER-positive breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of hormonal therapy for breast cancer. However, a reduction in estrogen levels can also result in side effects because estrogen is necessary for important body functions, such as bone growth and cardiovascular health. Lower estrogen levels lead to decreased bone density and heart disease.
Tamoxifen is an anti-estrogen drug that has historically been a mainstay of hormonal therapy. However, several newer hormonal therapy drugs, referred to as aromatase inhibitors, have proven to be superior to tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer and are associated with fewer side effects. Furthermore, a new of drugs called estrogen-receptor antagonists work in a similar way as tamoxifen and have been shown to benefit some patients with breast cancer.
The following is a general overview of the hormonal treatment for breast cancer. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. To determine if a clinical trial is an appropriate option, the potential benefits must be weighed against the potential risks and carefully compared with the benefits and risks of standard treatment. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
How Does Hormonal Therapy Work?
In premenopausal women, the ovaries are the major source of estrogen. After menopause, when ovarian hormone production drops dramatically, some estrogen continues to be produced in tissues outside of the ovaries. In this process, androgens produced by the adrenal glands are converted into estrogen. An enzyme called aromatase is required for this conversion.1
The goal of hormonal therapy is to decrease the effect of estrogen on cancer cells. Reducing the effects of estrogen can be accomplished in the following ways:
- by removing the ovaries, which produce the majority of estrogen in premenopausal women
- by blocking the conversion of androgens to estrogens by inhibiting the aromatase enzyme, or
- by blocking the estrogen receptors so that estrogen cannot bind and stimulate growth-related activity in breast and other cells.
Currently, the types (classes) of anti-estrogen drugs that are approved for the treatment of patients with breast cancer are called:
- Aromatase inhibitors
- Selective estrogen receptor modulators (SERMs)
- Estrogen receptor antagonists
These three classes of drugs work by decreasing estrogen’s effects on the body, but they do so through different mechanisms.
Aromatase inhibitors: Aromatase inhibitors block the conversion of androgens to estrogen, and reduce estrogen levels in postmenopausal women. Currently, three anti-aromatase drugs are approved for the treatment of postmenopausal women with breast cancer: Femara® (letrozole) Arimidex® (anastrozole), and Aromasin® (exemestane).2,3,4 Femara and Arimidex are nonsteroidal aromatase inhibitors that bind reversibly to aromatase. Aromasin is a steroidal aromatase inhibitor that binds permanently to aromatase.
Selective Estrogen Receptor Modulators (SERM): SERMs block estrogen receptors within breast cells, thereby reducing estrogen-stimulated growth. Currently, tamoxifen is the most common SERM used for the hormonal treatment of breast cancer. However, tamoxifen is associated with side effects, including an increased risk of uterine cancer.
Estrogen receptor antagonist: Like SERMs, estrogen receptor antagonists work by preventing estrogen from stimulating the growth of estrogen receptor-positive cells. Faslodex® (fulvestrant), the first estrogen receptor antagonist, binds to and degrades estrogen receptors so that estrogen is no longer able to bind to the receptors and stimulate cellular growth. The Food and Drug Administration (FDA) has approved Faslodex for hormone treatment in postmenopausal women with ER-positive breast cancer that has failed previous hormone therapies.
What Are the Side Effects of Hormonal Therapy?
Tamoxifen: Tamoxifen is associated with some side effects similar to symptoms of menopause, which include hot flashes, irregular menstrual periods and vaginal discharge or bleeding. Not all women will experience these symptoms. More serious side effects can also occur as a result of long-term use of tamoxifen. There is a small increase in the number of blood clots in individuals taking tamoxifen. Individuals taking tamoxifen have a slightly increased risk of developing cataracts. In addition, tamoxifen appears to increase a woman’s risk of developing uterine cancer by about 2-3 times that of the general population.5,6,7,8 This risk of uterine cancer is similar to that for women taking postmenopausal estrogen replacement therapy. Since the majority of uterine cancers can be detected at an early stage when they are highly curable, the overall benefit of anti-estrogen treatment in breast cancer patients probably outweighs the risk of uterine cancer. All women who have a uterus and are receiving anti-estrogen therapy should undergo regular gynecologic examinations.
Aromatase inhibitors: Possible side effects of aromatase inhibitors include joint pain and decreased bone density.In a study known as the Intergroup Exemestane Study, postmenopausal women who had received two-to-three years of tamoxifen were assigned either to continue on tamoxifen or to switch to the aromatase inhibitor Aromasin® (exemestane). Women who switched to Aromasin had improved survival, but also experienced a minor loss of bone mineral density in the lumbar spine (2.7% decrease) and the hip (1.4% decrease).9 After almost five years of follow-up, bone fractures had occurred in 7% of women who switched to Aromasin and 5% of women who remained on tamoxifen. Women who are treated with aromatase inhibitors may wish to talk with their doctor about bone health.
How are Hormonal Therapies Used in the Treatment of Early-stage Breast Cancers?
Early stage breast cancers include those with a tumor that measures up to 5cm in diameter and may or may not involve the axillary (underarm) lymph nodes. The use of hormonal therapy appears to benefit all women with hormone receptor-positive early-stage breast cancer. The primary benefit is a reduction in the risk of cancer recurrence.
For premenopausal women, tamoxifen remains the mainstay of hormonal therapy for early-stage breast cancer.10 Tamoxifen is typically used for a period of five years. Suppression of ovarian hormone production, through surgical removal of the ovaries, radiation to the ovaries, or drugs such as leuteinizing hormone releasing hormone (LHRH) agonists, is another approach to hormonal therapy that may be incorporated into the treatment of premenopausal breast cancer patients.
For postmenopausal women, use of an aromatase inhibitor (either alone or sequentially with tamoxifen) appears to produce better outcomes than tamoxifen alone. When considering how best to use aromatase inhibitors in the treatment of postmenopausal breast cancer, researchers have considered several possibilities: aromatase inhibitors could be used for extended hormonal therapy, after a woman has completed tamoxifen treatment;11 women could be switched to aromatase inhibitors after a brief (two to three year) period of tamoxifen therapy;12 or aromatase inhibitors could be used in place of tamoxifen as initial hormone therapy.1314 While it’s still uncertain which of these approaches is best, each of them appears to produce better outcomes than use of tamoxifen alone.
The benefits of hormonal therapy for women with estrogen receptor-positive breast cancer also apply to women with ductal carcinoma in situ (DCIS). Ductal carcinoma in situ (DCIS) is the earliest possible clinical diagnosis of breast cancer and is frequently diagnosed with screening mammography. Patients with this stage of disease rarely suspect that they have breast cancer.Researchers have shown that the addition of tamoxifen to surgery and radiation therapy was more effective for preventing breast cancer recurrence in patients with DCIS than surgery and radiotherapy alone.15 In this study, 1,804 women with DCIS were treated for 5 years with lumpectomy, radiation therapy and either placebo or tamoxifen. Only 8.2% of patients treated with tamoxifen experienced cancer recurrence, compared to 13.4% of patients treated with placebo.
How are Hormonal Therapies Used in the Treatment of Metastatic or Recurrent Breast Cancer?
When breast cancer occurs outside of the breast in the bones, lungs, liver or other organs, it is referred to as metastatic. Patients with breast cancer may also experience a recurrence of cancer after initial treatment with hormonal therapy. Patients with newly diagnosed metastatic breast cancer benefit from initial treatment with hormonal therapy and those with recurrent cancer may benefit from switching to a different hormonal therapy. Hormonal therapy for advanced breast cancer differs depending on whether it is being administered as:
- Initial treatment of metastatic breast cancer
- Hormonal therapy after prior tamoxifen
- Hormonal therapy after prior anti-aromatase drugs
Initial Treatment of Metastatic Breast Cancer
For premenopausal women, initial treatment of metastatic breast cancer may involve tamoxifen along with suppression of the ovaries.16
For postmenopausal women, initial treatment with an aromatase inhibitor appears to result in more anti-cancer response and/or delays in cancer progression than treatment with tamoxifen.
Femara vs. tamoxifen: A clinical trial has been performed that directly compared Femara and tamoxifen as initial hormonal therapy in postmenopausal patients with ER-positive, metastatic breast cancer. The results of the trial suggest that Femara is superior to tamoxifen. Patients treated with Femara experienced a longer time to cancer progression (9.4 months versus 6 months with tamoxifen).17 Side effects occurred at the same rate in both groups.
Both treatments were generally well tolerated; however, patients treated with Arimidex reported fewer side effects.
Hormonal Therapy for Patients with Advanced Breast Cancer that has Recurred after Prior Tamoxifen
Premenopausal women who have previously received tamoxifen are likely to be treated with ovarian removal or suppression.18
For postmenopausal patients with metastatic breast cancer that has stopped responding to tamoxifen, several phase III clinical trials have indicated that aromatase inhibitors produce better results than another type of hormonal therapy known as megestrol acetate.19 The question of which aromatase inhibitor to use in this setting remains uncertain, however. Femara, Arimidex, and Aromasin are all approved for advanced postmenopausal breast cancer that has stopped responding to tamoxifen.
Femara and Arimidex were compared among postmenopausal women with advanced breast cancer that had progressed following tamoxifen.20Approximately half of the patients had hormone receptor-positive breast cancer and the other half had unknown hormone receptor status. Overall, treatment response was higher in patients treated with Femara (19.1% response rate) than in patients treated with Arimidex (12.3% response rate). Survival was similar in the two treatment groups.
The antiestrogen drug Faslodex has also been approved for the treatment of postmenopausal, estrogen receptor-positive metastatic breast cancer that has progressed following other anti-estrogen therapy. Faslodex has been reported to be at least as effective as the aromatase inhibitor Arimidex in this setting.2122
Hormonal Therapy for Patients with Advanced Breast Cancer that has Recurred after Prior Aromatase Inhibitor Therapy
For patients with metastatic disease that has stopped responding to non-steroidal aromatase inhibitors such as Femara and Arimidex, switching to Aromasin or Faslodex has been shown to provide some benefit.
The effects of Aromasin and Faslodex in women who have stopped responding to treatment with a non-steroidal aromatase inhibitor were assessed in a Phase III clinical trial known as the EFFECT trial.23
The study included nearly 700 postmenopausal women with hormone receptor-positive, advanced breast cancer that worsened or recurred during or shortly after treatment with a non-steroidal aromatase inhibitor. Women were treated with either Aromasin or Faslodex.
- Time to cancer progression was 3.7 months in both treatment groups.
- A reduction in detectable cancer occurred in 6.7% of patients treated with Aromasin and 7.4% of patients treated with Faslodex.
- There were no significant differences between treatment groups in treatment safety or adverse treatment effects.
The researchers concluded that either Aromasin or Faslodex may be used in postmenopausal women with hormone-positive, advanced breast cancer who have received prior treatment with a non-steroidal aromatase inhibitor. There do not appear to be any significant differences between these two agents in this patient population.
Can Hormonal Therapy Reduce the Risk of Developing Breast Cancer?
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).24 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.25
Are There Other Benefits Associated with Hormonal Therapy?
Hormonal treatment may offer additional benefits beyond the treatment of cancer. Although tamoxifen acts against the effects of estrogen in breast tissue, it acts like estrogen in certain other body systems. Tamoxifen may help to lower blood cholesterol and reduce the rate of bone loss (osteoporosis). Two clinical studies have reported that women treated with tamoxifen had a lower risk of cardiac disease than women not treated with tamoxifen.26 In addition, raloxifene (Evista®), another selective estrogen receptor modulator (SERM), is FDA-approved for the prevention and treatment of osteoporosis and appears to reduce the risk of breast cancer.27
Strategies to Improve Hormonal Therapy for Breast Cancer
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in hormonal therapy for breast cancer will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving hormonal therapy for breast cancer include the following:
- Initial Treatment of Metastatic Breast Cancer
- Neoadjuvant Hormonal Therapy
Initial Treatment of Metastatic Breast Cancer
Aromasin® and Faslodex® are approved for treatment of women with metastatic breast cancer that has stopped responding to tamoxifen, but not as initial treatment. However, research indicates that these two drugs may be superior to tamoxifen in the initial treatment of metastatic disease.
Aromasin: Research indicates that Aromasin appears to be superior to tamoxifen as initial hormonal therapy for metastatic breast cancer. Among 122 patients with hormone-positive breast cancer who were initially treated with either Aromasin or tamoxifen, patients treated with Aromasin had nearly 3 times more anti-cancer responses than those treated with tamoxifen (41% versus 17%).28
Faslodex: Faslodex appears to be effective as initial (first-line) hormonal therapy for women with advanced breast cancer that is estrogen- and progesterone-receptor positive. Research indicates that Faslodex produced more anti-cancer responses than tamoxifen (44% versus 30%, respectively) and also extended the time to cancer progression by roughly three months.29
Neoadjuvant Hormonal Therapy
Neoadjuvant therapy is treatment administered before surgery. The purpose of neoadjuvant therapy is to shrink the cancer prior to surgery, thereby increasing the likelihood that a patient will be able to undergo breast-conserving surgery (removal of the cancer and a small amount of normal tissue) instead of mastectomy (removal of the entire breast). Administration of anti-aromatase agents prior to surgery is being evaluated to determine whether this approach may benefit women with breast cancer. Research with Arimidex and Femara suggest that both appear to be superior to tamoxifen as neoadjuvant therapy.
Neoadjuvant Arimidex: Arimidex administered prior to surgery has been shown to improve the chances of undergoing breast-conserving surgery. In a clinical trial, either Arimidex alone, tamoxifen alone, or Arimidex plus tamoxifen was administered before surgery to 330 postmenopausal women with ER-positive, early stage breast cancer. Prior to receiving neoadjuvant therapy, approximately 123 of the patients were known to be ineligible for breast-conserving therapy. After neoadjuvant therapy, over 90% of these patients had their cancer shrink enough that they became eligible for breast-conserving therapy. Treatment with Arimidex appears to provide the best chance for receiving breast-conserving therapy compared to tamoxifen or the combination of Arimidex and tamoxifen.Of patients who were initially considered ineligible for breast-conserving therapy, 45% of the patients who received Arimidex where subsequently considered eligible after neoadjuvant therapy, compared to 26% who received the combination Arimidex plus tamoxifen and 22.2% who received tamoxifen.30
Neoadjuvant Femara: Results from a study comparing Femara to tamoxifen as neoadjuvant treatment indicate that Femara provided more benefit. More of the women who received Femara had an anti-cancer response and were able to undergo breast-conserving surgery than those who were treated with tamoxifen. For patients with ER-negative cancer, the response to therapy was low in both groups.31
1 Lake DE, Hudis C. Aromatase Inhibitors in Breast Cancer: An Update. Cancer Control. 2002;9:490-498.
2 Food and Drug Administration. FDA Oncology Tools Approval Summary for Femara® for Treatment of advanced breast cancer in postmenopausal women. Available at http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=169. Accessed March 29, 2002.
3 Food and Drug Administration. FDA Oncology Tools Approval Summary for Arimidex® for Treatment of advanced breast cancer in postmenopausal women with disease progression following Nolvadex® therapy. Available at http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=156. Accessed March 29, 2002.
4 Food and Drug Administration. FDA Oncology Tools Approval Summary for Aromasin® for Treatment of advance breast cancer in postmenopausal women whose disease has progressed following Nolvadex® therapy. Available at http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=170 Accessed March 29, 2002.
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9 Coleman R, Banks L, Girgis S, et al. Skeletal effects of exemestane on bone mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncology. 2007;8:119-27.
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28 Paridaens L, Dirix C, Lohrisch L, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annals of Oncology 2003;14:1391-1398.
29 John F, Robertson A, Howell P, et al. Faslodex versus Nolvadex for the first-line treatment of advanced breast cancer (ABC) in postmenopausal women. Annals of Oncology 2002;13:46 (Abstract #164).
30 Smith I, Dowsett M on behalf of the IMPACT Trialists. Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial. Proceedings from the 2003 San Antonio Breast Cancer Symposium. December 2003. Abstract #1.
31 Ellis MJ, Coop A, Singh B, et al. Femara® Is More Effective Neoadjuvant Endocrine Therapy Than Nolvadex® for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial. Journal of Clinical Oncology 2001;18:3808-3816.