Endocrine therapy for metastatic breast cancer

INTRODUCTION — Several treatment options are available for women with advanced or metastatic breast cancer. These include chemotherapy, endocrine therapy, and targeted therapy with the monoclonal antibody trastuzumab (Herceptin®).

This topic review will discuss the options for endocrine therapy. General treatment and chemotherapy and trastuzumab for metastatic breast cancer are discussed elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").

Hormones and breast cancer growth — Some breast cancers require the hormone estrogen to grow and spread to other organs while other breast cancers are able to grow and spread without estrogen. Estrogen-dependent breast cancer cells produce a molecule called the estrogen receptor (ER). Approximately 30 to 50 percent of breast cancers in premenopausal women, and 70 to 80 percent of cancers in postmenopausal women make ERs. All women diagnosed with breast cancer should be tested to determine if their cancer expresses ER.

What is endocrine therapy? — Endocrine therapy removes the influence of estrogen on breast cancer cells, preventing the cancer cells from growing and spreading. All endocrine treatment is systemic or body-wide therapy, and is effective against cancer cells regardless of where they are located within the body (eg, the breast, bones, liver, etc). Because endocrine therapy usually has fewer side effects than chemotherapy, it is often recommended as the initial treatment for women with ER-positive metastatic breast cancer.

In general, endocrine therapy can be medical (through the use of drugs) or surgical (usually by removing the ovaries, the main source of estrogen production prior to menopause). In the United States, the majority of women receive medical rather than surgical endocrine therapy for metastatic breast cancer. The choice of therapy often depends upon a woman's menopausal status.

There are two ways of disrupting the effects of estrogen on breast cancer cells: by preventing estrogen production, and by interfering with the ability of estrogen to stimulate the breast cancer cells. Different estrogen deprivation therapies are usually recommended for premenopausal and postmenopausal women. (For more information on the use of endocrine therapy in early stage breast cancer, see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").

Premenopausal endocrine therapy — In premenopausal women, most estrogen is produced by the ovaries. Therefore, removing the ovaries (ovariectomy) or preventing them from producing estrogen through medical therapy (usually requiring monthly injections) is an appropriate method for estrogen deprivation. A summary of endocrine therapies is available in figure 2 .

Postmenopausal endocrine therapy — In contrast, the ovaries of postmenopausal women no longer make estrogen. Two small glands above the kidneys, called the adrenal glands, make precursors for a variety of different hormones, including estrogen. These precursors are then converted to estrogen, mainly in the fat tissues within the body, by an enzyme called aromatase. Aromatase inhibitors are effective treatments for advanced breast cancer. They are most beneficial for postmenopausal women. (See "Selective aromatase inhibitors (SAIs)" below). A summary of endocrine therapies is available in figure 2 .

Importance of hormone receptor expression — Women with ER/PR-positive tumors respond better to endocrine therapy than women with ER/PR-negative tumors (>60 percent response versus 10 percent). However, a trial of endocrine therapy may be warranted in women with ER/PR negative disease because the benefits of endocrine therapy greatly outweigh the risks of chemotherapy. Thus, even if a woman has an ER/PR-negative cancer, she may be offered a trial of endocrine therapy as long as she has slow growing disease, metastasis limited to the bones and/or skin, and limited symptoms related to her cancer.

TAMOXIFEN — Tamoxifen is the first-line endocrine therapy in premenopausal women with advanced breast cancer. Tamoxifen is a standard option for postmenopausal women as well, although more recent data suggest that a different type of endocrine therapy, selective aromatase inhibitors, are better that tamoxifen, as long as a woman's tumor has not become resistant to these drugs. (See "Selective aromatase inhibitors (SAIs)" below).

Tamoxifen is a member of a class of drugs called the selective estrogen receptor modulators (SERMs). SERMs like tamoxifen are chemically similar to estrogen, but are in fact, very different. Tamoxifen prevents estrogen from binding to the ER, and also interacts with the ER. This interaction can stimulate the cells of different organs in one of two different ways: sometimes in ways that are similar to estrogen stimulation (estrogenic), and other times in a manner that is opposite to the effects of estrogen (that is, antiestrogenic). In the same person, SERMS can be antiestrogenic in some tissues, and estrogenic in others (show figure 1). The following illustrates these concepts: Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, women at high risk of developing breast cancer may decrease their chance of getting breast cancer by taking tamoxifen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Tamoxifen also has antiestrogenic activity in the brain. This can lead to bothersome side effects such as hot flashes, sweating, insomnia that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in bone. This can be beneficial because tamoxifen prevents progression of osteoporosis. Another SERM, raloxifene, is used for the prevention and treatment of osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Tamoxifen is also estrogenic in the liver, leading to an increase in liver production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during the first 18 to 24 months of tamoxifen use, particularly in women who are at high risk for these events (ie, smokers, those with a past history of blood clots). Increased clotting proteins also increases the risk of deep vein thrombosis (blood clots in the major internal veins of the leg) and pulmonary embolus (movement of a blood clot to the lungs). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). The risk of uterine cancers is increased by two- to threefold in women who take tamoxifen. However, the risk of a new uterine cancer is well below 1 percent.

This information must be placed in appropriate context for women who are considering tamoxifen. Women with advanced breast cancer are at high risk of dying of breast cancer in the short term, and the benefits of tamoxifen far outweigh the risks of uterine cancer, blood clots, or other long term effects.

Effectiveness — Between 50 and 60 percent of women whose breast cancers are ER-positive will respond to tamoxifen therapy. In contrast, fewer than 10 percent of women with metastatic ER-negative breast cancers respond to tamoxifen. Chemotherapy or trastuzumab (Herceptin®) therapy are recommended for women with ER-negative disease. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").

Tamoxifen is taken by mouth, at a dose of 20 mg daily. Most breast cancers become resistant to tamoxifen over time. The majority of breast cancers that initially respond remain sensitive to tamoxifen for 12 to 18 months, although some continue to respond for several years. An alternative hormone therapy should be considered if a woman becomes resistant to tamoxifen.

Resistance — The resistance of breast cancer cells to tamoxifen is the greatest limitation of this therapy. However, even among ER-positive breast cancers, some do not respond at all to tamoxifen (called primary resistance); secondary resistance occurs if the tumor initially responds but later become resistant.

Preliminary studies suggest that a protein that is expressed by breast cancer cells called HER2 may help to identify women who are less likely to benefit from tamoxifen therapy (ie, those with primary resistance). However, the results of studies to date have been conflicting, and most doctors offer initial tamoxifen therapy to all premenopausal women with ER-positive breast cancer, regardless of their HER2 status.

Resistance to tamoxifen does not necessarily imply resistance to other endocrine therapies. Treatment options for women who are resistant to tamoxifen include discontinuation of tamoxifen (see "Withdrawal response" below), an alternative endocrine therapy, or systemic chemotherapy.

Premenopausal women with metastatic breast cancer that is resistant to tamoxifen should be treated with surgical removal of the ovaries followed by an SAI (see "Ovariectomy" below).

Flare reaction — Between 3 and 13 percent of women with metastatic disease experience a flare of their breast cancer within two days to three weeks after starting tamoxifen. This "flare" reaction may be characterized by an increase in bone pain, a high blood calcium level, and in women who have tumor deposits within the skin, an increase in the size and/or number of these metastatic skin nodules, or skin redness.

Tumor flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with measures that reduce pain and lower blood levels of calcium. In severe cases, a woman may have to temporarily stop taking tamoxifen until the flare subsides. Many doctors consider a flare reaction to be a sign that hormonal therapy is having a beneficial effect on the breast cancer.

Withdrawal response — Some women who stop tamoxifen when breast cancer begins to progress have an improvement, even if no other treatment is begun. This tamoxifen withdrawal response is most likely to occur in women whose breast cancers initially responded well to tamoxifen. Some women do not require further treatment for up to six months.

Summary — Many women with metastatic breast cancer benefit from tamoxifen, and it is often the first choice for endocrine therapy in premenopausal women. Alternate endocrine therapies may be recommended for women who have a history of blood clots, and for women with risk factors for blood clots.

SELECTIVE AROMATASE INHIBITORS (SAIs) — Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands, and aromatase inhibitors are drugs that reduce estrogen levels by blocking the action of aromatase. Drugs in this class include anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®).

SAIs cause hot flashes and increase the risk of osteoporosis (thinning of the bones) and subsequent bone fractures. In contrast to tamoxifen, they do not appear to increase the risk of blood clots or endometrial cancer.

SAIs are recommended only for postmenopausal women (those without functioning ovaries). They should not be used in menstruating women for two reasons: They are not strong enough to block the higher estrogen levels that are produced in the ovaries Women with functioning ovaries who receive SAIs can have increased blood levels of male hormones, leading to side effects such as excessive hair growth and a deeper voice. They may also induce ovarian cysts.

As compared to tamoxifen, anastrozole, letrozole, and exemestane are associated with superior response rates, time to progression, and overall survival when they are used as a first line treatment in postmenopausal women with metastatic breast cancer [1]. As a result, these medications have become the treatment of choice for postmenopausal women with hormone-responsive breast cancer if there is a relapse while receiving adjuvant tamoxifen, if adjuvant endocrine treatments have not been used, or if there is a relapse more than one year after discontinuing adjuvant tamoxifen or an SAI. If a woman has relapsed during or within 12 months after receiving an SAI in the adjuvant setting, fulvestrant or a SERM, such as tamoxifen or toremifene, is an appropriate first-line treatment (see "Pure antiestrogens" below and see "Other SERMS" below).

Anastrozole — Anastrozole is taken by mouth, at a dose of 1 mg once daily. The possible side effects of anastrozole are mild, and include postmenopausal symptoms (since it reduces estrogen levels), and rarely gastrointestinal complaints.

Trials of first-line therapy in postmenopausal women with newly diagnosed metastatic breast cancer have shown that anastrozole is at least as active as tamoxifen, with fewer thromboembolic events and less vaginal bleeding.

Letrozole — Letrozole was directly compared to tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Compared to tamoxifen, letrozole was associated with a significantly higher overall response rate, longer time to progression, and longer time until chemotherapy was required.

Exemestane — Like the others, exemestane is at least as good as tamoxifen for first-line therapy. Unlike the others, exemestane may also be effective in women who have never responded to tamoxifen and in women who have had a poor response to anastrozole and letrozole. In one study of women whose breast cancers had failed to respond to multiple endocrine therapies, exemestane led to a response in 13 percent of women, and the cancer was stabilized in an additional 17 percent of women [2].

PURE ANTIESTROGENS — Like tamoxifen, pure antiestrogens such as fulvestrant (Faslodex®) block the stimulatory influence of estrogen on breast cancer cells. However, unlike tamoxifen, they do not mimic the effects of estrogen in other tissues.

Fulvestrant is administered as a monthly intramuscular (IM) injection, and it is effective in women whose cancers have progressed on tamoxifen. Two separate studies have compared fulvestrant to the selective aromatase inhibitor anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer. In both, fulvestrant was at least as good as anastrozole. One of the most important advantages of this drug is that it is given by injection rather than taken in pill form; this is important for patients whose insurance does not cover prescriptions but does cover office visits and hospital treatment.

OTHER SERMS — Newer SERMs such as toremifene (Fareston®) are currently being studied in women with metastatic breast cancer. As initial hormone therapy, toremifene has similar activity and side effects as tamoxifen, and is a reasonable alternative to tamoxifen for initial treatment of advanced breast cancer. However, toremifene is not effective for women who have failed tamoxifen and should not be used in this setting.

Raloxifene is not an acceptable alternative to tamoxifen because there are no data that it is is effective in metastatic breast cancer.

ESTROGEN DEPRIVATION THERAPY

Premenopausal women

Ovariectomy — Ovariectomy refers to surgical removal of the ovaries. Since the ovaries are not the main source of estrogen production in postmenopausal women, this therapy is only recommended for premenopausal women.

About one-third of women with metastatic breast cancer will have a response to ovariectomy. However, tamoxifen is as effective as ovariectomy, and is usually recommended first (see "Tamoxifen" above). If a breast cancer becomes resistant to tamoxifen, ovariectomy may then be considered.

Gonadotropin releasing hormone agonists — Gonadotropin releasing hormone agonists (GnRH) agonists prevent the ovaries from functioning. All of the GnRH agonists (eg, goserelin (Zoladex®) and leuprolide (Lupron®)) must be injected to be effective. As occurs with tamoxifen therapy, some women may experience a transient flare of breast cancer symptoms when they first begin taking GnRH agonists.

Therapy with GnRH agonists is as effective as ovariectomy for premenopausal women with metastatic breast cancer that is ER or PR positive. However, women treated with a GnRH agonist are more likely to have hot flashes and a flare of breast cancer symptoms.

GnRH agonists have also been combined with tamoxifen in premenopausal women. Combined therapy with tamoxifen and ovarian ablation/suppression is sometimes favored over either approach alone for premenopausal women because it results in higher response rates, a longer time to progression, and possibly has a small beneficial impact on overall survival.

Once a premenopausal woman has disease progression with tamoxifen and ovarian ablation/suppression, she has become postmenopausal and SAIs are an appropriate alternative.

Postmenopausal women — As noted above, estrogen deprivation therapies are usually recommended for women whose breast cancers have become resistant to tamoxifen, rather than as initial endocrine therapy. While premenopausal women may be offered ovariectomy or a GnRH agonist, the available options for postmenopausal women who have failed tamoxifen include SAIs, pure antiestrogens, and if endocrine therapy is still appropriate, sex steroid hormones such as progestins, androgens, and/or estrogen.

Progestins — Progestins can be fairly effective for the treatment of metastatic breast cancer, although it is not clear how they work. Drugs in this class include oral megestrol acetate (Megace®); medroxyprogesterone acetate (Depo-Provera®) is an injectable form of treatment given every 12 weeks, though it has no advantages over megestrol acetate. These are effective hormone therapies, and are typically used third line, after failure of estrogen deprivation therapy and tamoxifen.

Progestins like megestrol can be associated with significant side effects, including weight gain, fluid retention, and vaginal bleeding. Progestins also increase the risk of blood clots, and are not recommended for women who have previously had blood clots or women who have risk factors for blood clots (eg, smokers).

Estrogen — Before current endocrine therapies were available, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen; this approach is ineffective before the menopause. It is not known how high dose estrogen therapy works.

Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to high dose estrogens. It is usually given as 15 mg estradiol twice daily. Side effects including breast tenderness, vaginal discharge, nausea/vomiting, and more seriously, heart failure and blood clots. As with progestins, estrogens are not recommended for women with a blood clotting disorder or women who have risk factors for blood clots (eg, smokers).

Androgens — Androgens (eg, testosterone, fluoxymesterone [Halotestin®], and testolactone) are male hormones; some are useful in the treatment of advanced breast cancer. About 20 percent of such women will respond to androgens such as fluoxymesterone. These drugs are rarely used because of their associated side effects, which include deepening of the voice, growth of dark hair on the body, fluid retention, and jaundice (yellowing of the skin caused by altered liver function).

Danazol, a weaker androgen, has a response rate of 20 percent. The possible side effects of danazol include swelling and hot flashes. In general, androgen therapy is not as effective as progestin therapy or high-dose estrogen.

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation

(www.komen.org)
The Hormone Foundation

(www.hormone.org/public/other.cfm, available in English, Spanish, and Portuguese)


[1-10]


Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mauri, D, Pavlidis, N, Polyzos, NP, Ioannidis, JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 2006; 98:1285.
2. Jones, S, Vogel, C, Arkhipov, A, et al. Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group. J Clin Oncol 1999; 17:3418.
3. Bonneterre, J, Thurlimann, B, Robertson, JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000; 18:3748.
4. Nabholtz, JM, Buzdar, A, Pollak, M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758.
5. Mouridsen, H, Gershanovich, M, Sun, Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596.
6. Rose, C, Vtoraya, O, Pluzanska, A, et al. Letrozole vs anastrozole: second line treatment in postmenopausal women with advanced breast cancer (abstract). Proc Am Soc Clin Oncol 2002; 21:34a.
7. Noberasco, C, Bajetta, E, Zilembo, N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52:454.
8. Kaufmann, M, Bajetta, E, Dirix, LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000; 18:1399.
9. Taylor, CW, Green, S, Dalton, WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998; 16:994.
10. Klijn, JG, Blamey, RW, Boccardo, F, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19:343.