Hormone therapy for breast cancer

Hormone therapy is another form of systemic therapy. It is most often used as an adjuvant therapy to help reduce the risk of the cancer coming back after surgery, but it can be used as neoadjuvant treatment, as well. It is also used to treat cancer that has come back after treatment or has spread.

A woman's ovaries are the main source of the hormone estrogen up until menopause. After menopause, smaller amounts are still made in the body's fat tissue, where a hormone made by the adrenal gland is converted into estrogen.

Estrogen promotes the growth of about 2 out of 3 of breast cancers— those having receptors for the hormones estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers). Because of this, several approaches to blocking the effect of estrogen or lowering estrogen levels are used to treat hormone receptor-positive breast cancers. Hormone therapy does not help patients whose tumors are both ER- and PR-negative.

Tamoxifen and toremifene (Fareston^®): These anti-estrogen drugs work by temporarily blocking estrogen receptors on breast cancer cells, preventing estrogen from binding to them. They are taken daily as a pill.

For women with hormone receptor-positive cancers, taking tamoxifen after surgery for 5 years reduces the chances of the cancer coming back by about half and helps patients live longer. A recent study has shown that taking it for 10 years can be even more helpful.

Tamoxifen can also be used to treat metastatic breast cancer, as well as to reduce the risk of developing breast cancer in women at high risk. Toremifene works like tamoxifen, but is not used as often and is only approved for patients with metastatic breast cancer.

The most common side effects of these drugs include fatigue, hot flashes, vaginal dryness or discharge, and mood swings.

Some patients whose cancer has spread to their bones may have a "tumor flare" with pain and swelling in the muscles and bones. This usually subsides quickly, but in some rare cases the patient may also develop a high calcium level in the blood that cannot be controlled. If this occurs, the treatment may need to be stopped for a time.

Rare, but more serious side effects are also possible. These drugs can increase the risk of developing cancers of the uterus (endometrial cancer and uterine sarcoma) in women who have gone through menopause. Tell your doctor right away about any unusual vaginal bleeding (a common symptom of both of these cancers). Most uterine bleeding is not from cancer, but this symptom always needs prompt attention.

Another possible serious side effect is blood clots, which usually form in the legs (called deep venous thrombosis or DVT). Sometimes a piece of clot may break off and end up a blocking an artery in the lungs (pulmonary embolism or PE). Call your doctor or nurse right away if you develop pain, redness, or swelling in your lower leg (calf), shortness of breath, or chest pain because these can be symptoms of a DVT or PE.

Tamoxifen has rarely been associated with strokes in post-menopausal women so tell your doctor if you have severe headaches, confusion, or trouble speaking or moving.

These drugs may also increase the risk of a heart attack, but this is not clear.

Depending on a woman's menopausal status, tamoxifen can have different effects on the bones. In pre-menopausal women, tamoxifen can cause some bone thinning, but in post-menopausal women it is often good for bone strength. The effects of toremifene on bones are less clear.

For almost all women with hormone receptor-positive breast cancer, the benefits of taking these drugs outweigh the risks.

Aromatase inhibitors (AIs): Three drugs that stop estrogen production in post-menopausal women have been approved to treat both early and advanced breast cancer: letrozole (Femara^®), anastrozole (Arimidex^®), and exemestane (Aromasin^®). They work by blocking an enzyme (aromatase) in fat tissue that is responsible for making small amounts of estrogen in post-menopausal women. They cannot stop the ovaries of pre-menopausal women from making estrogen, so they are only effective in women whose ovaries aren’t working (like after menopause). These drugs are taken daily as pills. So far, each of these drugs seems to work as well as the others in treating breast cancer.

Several studies have compared these drugs with tamoxifen as adjuvant hormone therapy in post-menopausal women. Using these drugs, either alone or after tamoxifen, has been shown to better reduce the risk of the cancer coming back later than using tamoxifen alone for 5 years. Schedules that are known to be helpful include:

• Tamoxifen for 2 to 3 years, followed by an aromatase inhibitor (AI) to complete 5 years of treatment
• Tamoxifen for 5 years, followed by an AI for 5 years
• An AI for 5 years

For post-menopausal women whose cancers are hormone receptor–positive, most doctors now recommend using an AI at some point during adjuvant therapy. But it's not yet clear if starting adjuvant therapy with one of these drugs is better than giving tamoxifen and then switching to an AI. We still don't know if giving these drugs for more than 5 years is more helpful than stopping at 5 years. Studies now being done should help answer these questions.

The AIs tend to have fewer serious side effects than tamoxifen—they don't cause uterine cancers and very rarely cause blood clots. They can, however, cause muscle pain and joint stiffness and/or pain. The joint pain may be similar to a new feeling of having arthritis in many different joints at one time. This side effect may improve by switching to a different AI, but it has led some women to stop drug treatment. If this occurs, most doctors recommend using tamoxifen to complete 5 years of hormone treatment.

Because aromatase inhibitors remove all estrogens from women after menopause, they also cause bone thinning, sometimes leading to osteoporosis and even fractures. Many women treated with an aromatase inhibitor are also treated with medicine to strengthen their bones, such as bisphosphonates or denosumab (this is discussed further on).

Ovarian ablation: In pre-menopausal women, removing or shutting down the ovaries, which are the main source of estrogens, effectively makes the woman post-menopausal. This may allow some other hormone therapies to work better. This is most often used to treat metastatic breast cancer.

Permanent ovarian ablation can be done by surgically removing the ovaries. This operation is called an oophorectomy. More often, ovarian ablation is done with drugs called luteinizing hormone-releasing hormone (LHRH) analogs, such as goserelin (Zoladex^®) or leuprolide (Lupron^®). These drugs stop the signal that the body sends to ovaries to make estrogens. They can be used alone or with tamoxifen as hormone therapy in pre-menopausal women. They are also being used along with aromatase inhibitors in studies of pre-menopausal women.

Chemotherapy drugs may also damage the ovaries of pre-menopausal women so they no longer produce estrogen. In some women, ovarian function returns months or years later, but in others, the damage to the ovaries is permanent and leads to menopause. This can sometimes be a helpful (if unintended) consequence of chemotherapy with regard to breast cancer treatment, although it leaves the woman infertile.

All of these methods can cause a woman to have symptoms of menopause, including hot flashes, night sweats, vaginal dryness, and mood swings.

Fulvestrant (Faslodex^®): Fulvestrant is a drug that also acts on the estrogen receptor, but instead of just blocking it, this drug also eliminates it temporarily. 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. It is currently only approved by the FDA for use in post-menopausal women with advanced breast cancer that no longer responds to tamoxifen or toremifene.

Megestrol acetate: Megestrol acetate (Megace^®) is a progesterone-like drug used as a hormone treatment of advanced breast cancer, usually for women whose cancers do not respond to the other hormone treatments. Its major side effect is weight gain, and it is sometimes used in higher doses to reverse weight loss in patients with advanced cancer. This is an older drug that is no longer used very often.

Other ways to control hormones: Androgens (male hormones) may rarely be considered after other hormone treatments for advanced breast cancer have been tried. They are sometimes effective, but they can cause masculine characteristics to develop such as an increase in body hair and a deeper voice.

Another option that may be tried when the cancer is no longer responding to other hormone drugs is giving high doses of estrogen. The main risk is of serious blood clots (like DVTs and PEs). Patients also have trouble with nausea.