Hormonal Therapy for Breast Cancer
CA Cancer J Clin 2005 55: 195-198.

ESTROGEN AND ESTROGEN RECEPTORS

The hormone estrogen is produced mainly by a woman’s ovaries until menopause (change of life), and then by the adrenal glands and fat tissue. Estrogen causes normal breast tissue to grow, the main reason why women’s breasts are larger than men’s.

When estrogen enters a breast cell, it attaches to estrogen receptors. These are molecules that recognize estrogen and influence the instructions (like growing and dividing) that are sent from the cell’s DNA to the rest of the cell.

In nearly 7 of 10 cases of breast cancer, estrogen promotes the growth of the cancer because the cells contain estrogen receptors. Doctors call these cancers estrogen receptor-positive (often abbreviated as ER-positive). The remaining cases of breast cancers don’t have estrogen receptors and are therefore not influenced by that hormone. These cancers are ER-negative.

OVERVIEW OF HORMONAL THERAPIES

Knowing that estrogen promotes the growth of ER-positive breast cancers, doctors use several methods to block the effect of estrogen or lower estrogen levels. These methods can be divided into two main groups:

* The first group of treatments consists of antiestrogens. These medications have no effect on estrogen levels; instead, they prevent estrogen from causing the cancer cells to grow by binding directly to and blocking the estrogen receptor.
* The second type of treatment lowers the production of estrogen.

These treatments are used in two situations:

* The first is in women who have ER-positive breast cancers that appear to have been completely removed by surgery. However, even if no remaining cancer can be seen or felt by the doctor or found by x-ray tests, it’s still possible that some of the breast cancer cells have spread invisibly to other parts of the body. After a while, these cells might grow and eventually become life threatening.
For this reason, such patients usually have more treatment called adjuvant therapy to kill these stray cells. For women with ER-positive breast cancers, hormonal treatments are used as adjuvant therapy, either alone or together with chemotherapy.
* The second use of hormonal treatments is for women whose cancer remains immediately after surgery (residual cancer), or in whom the cancer comes back months or years after surgery (recurrent cancer).

ANTIESTROGENS

Tamoxifen
The antiestrogen drug used most often is tamoxifen (Nolvadex). It is taken daily in pill form. Taking tamoxifen as adjuvant therapy after surgery, usually for 5 years, reduces the chances of ER-positive breast cancers coming back. Tamoxifen is also used to treat metastatic breast cancer—that is, cancer that has spread. (It can also be used to help prevent the development of breast cancer in a woman at high risk.)

Tamoxifen increases the risk of developing cancer of the lining of the uterus (endometrial cancer). This cancer is usually found at a very early stage and can generally, but not always, be cured by surgery. Tamoxifen can also increase the risk of uterine sarcoma, a rare cancer of the connective tissue of the uterus. If you are taking tamoxifen, tell your doctor right away about any unusual vaginal bleeding (a common symptom of both of these cancers). Most uterine bleeding is not due to cancer, but this symptom always needs prompt evaluation.

Blood clots are another serious side effect of tamoxifen. Other side effects of tamoxifen could include weight gain (although recent studies have not found this), hot flashes, vaginal discharge, and mood swings. Early cataracts may occur rarely. Still, for most women with breast cancer, the benefits of taking tamoxifen far outweigh the risks.

Toremifene
Toremifene (Fareston) is another antiestrogen drug closely related to tamoxifen. It may be an option for postmenopausal women with breast cancer that has metastasized (spread). Like tamoxifen, toremifene is taken daily as pills.

Fulvestrant
Fulvestrant (Faslodex) is a newly approved drug that also acts via the estrogen receptor, but instead of blocking estrogen from attaching to the receptor (as tamoxifen and toremifene do), this drug reduces the number of receptors. It is often effective even if the breast cancer is no longer responding to tamoxifen. It is given by injection once a month. Hot flashes, mild nausea, and fatigue are the major side effects.

Raloxifene
Raloxifene (Evista) is a drug that, like tamoxifen, blocks the effect of estrogen on breast tissue and breast cancer. It was developed to prevent and treat osteoporosis (bone thinning) because it has similar bone strengthening effects to estrogen. But in other ways it is an antiestrogen. It is currently being tested to see if it can reduce a woman’s risk of developing breast cancer. Until more testing is done, raloxifene is not recommended as hormonal therapy for women who have already been diagnosed with breast cancer.

TREATMENTS TO REDUCE ESTROGEN LEVELS

Aromatase Inhibitors
Three drugs that stop estrogen production in postmenopausal women have been approved for use in treating breast cancer. These drugs are called letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). All three are given as pills. They work by blocking an enzyme that makes small amounts of estrogen in postmenopausal women. They cannot stop the ovaries of premenopausal women from making estrogen. For this reason, they are only effective in postmenopausal women.

Many doctors prefer aromatase inhibitors to tamoxifen as the first hormonal treatment for postmenopausal women whose breast cancer has come back, if the cancer is hormone receptor- positive.

These drugs have been compared with tamoxifen as adjuvant hormone therapy. They have fewer side effects than tamoxifen because they don’t cause endometrial cancer and very rarely cause blood clots. They can, however, cause osteoporosis and bone fractures because they remove all estrogens from a postmenopausal woman. This side effect is still being studied.

They are at least as effective as tamoxifen in preventing breast cancer from coming back in postmenopausal women. Based on recent studies, many doctors recommend aromatase inhibitors as the first choice for breast cancer adjuvant hormonal therapy, except in women who have some medical reason to avoid these drugs (for example, women who already have severe osteoporosis).

Ovarian Ablation
Removing estrogens from premenopausal women is another effective way of treating ER-positive breast cancer. This can be done surgically by removing the ovaries. It also can be done with drugs called luteinizing hormone-releasing hormone (LHRH) analogs. The usual LHRH analogs are goserelin or leuprolide; both are given as injections, usually every month. These drugs stop the ovaries from making estrogens and are effective as adjuvant therapies. Chemotherapy drugs may also damage the ovaries so they no longer produce estrogen. However, chemotherapy does not stop the ovaries from making estrogen in all women. And even when it does, this effect is sometimes temporary.

OTHER HORMONAL THERAPIES FOR BREAST CANCER

Megestrol Acetate
Megestrol acetate (Megace) is another drug used for hormone treatment of advanced breast cancer, usually for women whose cancer does not respond to the other hormone treatments. It is given as pills. The major side effect is weight gain, and it is sometimes used to reverse weight loss in patients with advanced cancer.

Androgens
Androgens (male hormones) may be considered after other hormone treatments for advanced breast cancer have been tried. Androgens cause masculine characteristics to occur, for example, more body hair and a deeper voice. They are sometimes effective, but are not used as often as they were in the past.

WHICH HORMONAL TREATMENT IS BEST FOR YOU?

There is no single answer to this question, because there is no single hormonal treatment that is best for all women with ER-positive breast cancer. The choice of hormonal treatment will depend on whether you are pre- or postmenopausal, whether you have any other health problems, and whether you have taken other hormonal treatments before. Much still remains to be learned about these medications and the best ways to combine them, and recommendations may change over the next few years as results of studies in progress are reported.

For about three decades, tamoxifen was the first choice for adjuvant hormonal treatment and for women with residual or recurrent or ER-positive breast cancer. Recent studies have found that aromatase inhibitors are at least as good and seem to be a little better than tamoxifen as the first treatment in both of these situations.

Recent studies have also found that for postmenopausal women who have already started adjuvant hormonal treatment with tamoxifen, the usual 5-year course of that drug may not be the best choice. Newer options include completing 5 years of tamoxifen and then taking an aromatase inhibitor for a few more years (how long this additional treatment should be used is still uncertain). Another option is to take tamoxifen for a few years and then switch to an aromatase inhibitor, with the combined length of treatment remaining at 5 years. It appears that taking tamoxifen and an aromatase inhibitor at the same time is no better than one drug at a time.

For breast cancer that returns after treatment with tamoxifen, an aromatase inhibitor or fulvestrant is often effective in shrinking the new tumors. If the first treatment was an aromatase inhibitor, tamoxifen can be recommended if the cancer returns.

Tamoxifen remains the first choice for hormonal treatment of premenopausal women. The combination of an LHRH analog with an aromatase inhibitor is currently being studied in clinical trials (the LHRH analog prevents the ovaries from producing estrogen, and the aromatase inhibitor prevents other tissues from producing even small amounts of estrogen). However, this combination is still not recommended for routine use until results of these clinical trials are known.