Which of the following types of hormones is most commonly administered during hormone replacement therapy?

Some types of breast cancer are affected by hormones, like estrogen and progesterone. The breast cancer cells have receptors (proteins) that attach to estrogen and progesterone, which helps them grow. Treatments that stop these hormones from attaching to these receptors are called hormone or endocrine therapy.

Hormone therapy can reach cancer cells almost anywhere in the body and not just in the breast. It's recommended for women with tumors that are hormone receptor-positive. It does not help women whose tumors don't have hormone receptors (these tumors are called hormone receptor-negative).

When is hormone therapy used for breast cancer?

Hormone therapy is often used after surgery (as adjuvant therapy) to help reduce the risk of the cancer coming back. Sometimes it is started before surgery (as neoadjuvant therapy).

It is usually taken for at least 5 years. Treatment longer than 5 years might be offered to women whose cancers have a higher chance of coming back. A test called the Breast Cancer Index might be used to help decide if a woman will benefit from more than 5 years of hormone therapy.

Hormone therapy can also be used to treat cancer that has come back after treatment or that has spread to other parts of the body.

How does hormone therapy work?

About 2 out of 3 breast cancers are hormone receptor-positive. Their cells have receptors (proteins) for estrogen (ER-positive cancers) and/or progesterone (PR-positive cancers) which help the cancer cells grow and spread.

There are several types of hormone therapy for breast cancer. Most types of hormone therapy either lower estrogen levels in the body or stop estrogen from helping breast cancer cells grow.

Drugs that block estrogen receptors

These drugs work by stopping estrogen from fueling breast cancer cells to grow.

Tamoxifen

Tamoxifen blocks estrogen from connecting to the cancer cells and telling them to grow and divide. While tamoxifen acts like an anti-estrogen in breast cells, it acts like an estrogen in other tissues, like the uterus and the bones. Because of this, it is called a selective estrogen receptor modulator (SERM). It can be used to treat women with breast cancer who have or have not gone through menopause.

Tamoxifen can be used in several ways:

• In women at high risk of breast cancer, tamoxifen can be used to help lower the risk of developing breast cancer.
• For women who have been treated with breast-conserving surgery for ductal carcinoma in situ (DCIS) that is hormone receptor-positive, taking tamoxifen for 5 years lowers the chance of the DCIS coming back in the same breast. It also lowers the chance of getting an invasive breast cancer or another DCIS in both breasts.
• For women with hormone receptor-positive invasive breast cancer treated with surgery, tamoxifen can help lower the chances of the cancer coming back and improve the chances of living longer. It can also lower the risk of a new cancer developing in the other breast. Tamoxifen can be started either after surgery (adjuvant therapy) or before surgery (neoadjuvant therapy). When given after surgery, it is usually taken for 5 to 10 years. This drug is used mainly for women with early-stage breast cancer who have not yet gone through menopause. If you have gone through menopause, aromatase inhibitors (see below) are often used instead.
• For women with hormone-positive breast cancer that has spread to other parts of the body, tamoxifen can often help slow or stop the growth of the cancer, and might even shrink some tumors.

Toremifene (Fareston)

This is another SERM that works in a similar way, but it is used less often and is only approved to treat post-menopausal women with metastatic breast cancer. It is not likely to work if tamoxifen has already been used and has stopped working. These drugs are pills, taken by mouth.

Side effects of tamoxifen and toremifene

The most common side effects of tamoxifen and toremifene are:

• Hot flashes
• Vaginal dryness or discharge
• Changes in the menstrual cycle

When tamoxifen treatment starts, a small number of women with cancer that has spread to the bones might have a tumor flare (thetumor gets bigger for a short time) which can cause bone pain. This usually decreases quickly, but in some rare cases a woman may also develop a high calcium level in the blood that is hard to control. If this happens, the treatment may need to be stopped for a time.

Rare, but more serious side effects are also possible:

• If a woman has gone through menopause, SERMs can increase her risk of developing endometrial cancer and uterine sarcoma. Tell your doctor right away about any unusual vaginal bleeding (a common symptom of this cancer). Most uterine bleeding is not from cancer, but this symptom always needs quick attention.
• Blood clots are another uncommon, but serious side effect. They usually form in the legs (called deep vein thrombosis or DVT), but sometimes a piece of clot in the leg may break off and end up 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. Rarely, tamoxifen has been associated with strokes in postmenopausal women, so tell your doctor if you have severe headaches, confusion, or trouble speaking or moving.
• Eye problems, such as cataracts, are sometimes seen when taking tamoxifen. It is important to tell your doctor right away if you are having any new trouble with your eyesight.
• Bones can be affected. 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 often strengthens bones to some degree. The benefits of taking these drugs outweigh the risks for almost all women with hormone receptor-positive breast cancer.

Fulvestrant (Faslodex)

Fulvestrant is a drug that attaches to and breaks down estrogen receptors. It is not a SERM. It is known as a selective estrogen receptor degrader (SERD). It acts like an anti-estrogen throughout the body. When given to pre-menopausal women it must be combined with a luteinizing-hormone releasing hormone (LHRH) agonist to turn off the ovaries (see Ovarian suppression below).

Fulvestrant can be given:

• Alone to treat advanced breast cancer that has not been treated with other hormone therapy.
• Alone to treat advanced breast cancer after other hormone drugs (like tamoxifen and often an aromatase inhibitor) have stopped working.
• In combination with a CDK 4/6 inhibitor or PI3K inhibitor to treat metastatic breast cancer as initial hormone therapy or after other hormone treatments have been tried.  

It is given by 2 injections into the buttocks (bottom). For the first month, the 2 shots are given 2 weeks apart. After that, they are given once a month.

Side effects of fulvestrant

Common short-term side effects can include:

• Hot flashes and/or night sweats
• Headache
• Mild nausea
• Bone pain
• Injection site pain

Drugs that lower estrogen levels

Because estrogen stimulates hormone receptor-positive breast cancers to grow, lowering the estrogen level can help slow the cancer’s growth or help prevent it from coming back.

Aromatase inhibitors (AIs)

Aromatase inhibitors (AIs) are drugs that stop most estrogen production in the body. Before menopause, most estrogen is made by the ovaries. But in women whose ovaries aren’t working, either because they have gone through menopause or because of certain treatments, estrogen is still made in body fat by an enzyme called aromatase. AIs work by preventing aromatase from making estrogen.

These drugs are useful for women who have gone through menopause, although they can also be used in pre-menopausal women when they are combined with ovarian suppression (see below).

These AIs are pills taken every day to treat breast cancer:

• Letrozole (Femara)
• Anastrozole (Arimidex)
• Exemestane (Aromasin)

Possible side effects of AIs

The most common side effects of AIs are:

• Hot flashes
• Vaginal dryness
• Bone and joint pain
• Muscle pain

AIs tend to have side effects different from 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 feeling of having arthritis in many different joints at one time. Options for treating this side effect include, stopping the AI and then switching to a different AI, taking a medicine called duloxetine (Cymbalta), or routine exercise with nonsteroidal anti-inflammatory drugs (NSAIDs).  But the muscle and joint pain has led some women to stop treatment. If this happens, most doctors recommend using tamoxifen to complete 5 to 10 years of hormone treatment.

Because AIs drastically lower the estrogen level in women after menopause, they can also cause bone thinning, sometimes leading to osteoporosis and even fractures. If you are taking an AI, your bone density may be tested regularly and you may also be given bisphosphonates (zoledronic acid [Zometa] for example) or denosumab (Xgeva, Prolia), to strengthen your bones.

Ovarian suppression

For pre-menopausal women, removing or shutting down the ovaries (ovarian suppression), which are the main source of estrogen, is effectively making them post-menopausal. This may allow some other hormone therapies, such as AIs, to be used. Ovarian suppression along with tamoxifen or an AI might be recommended for women whose breast cancer is at high risk of coming back.  

There are several ways to remove or shut down the ovaries to treat breast cancer:

• Oophorectomy: Surgery to remove the ovaries. This is permanent and is also called ovarian ablation.
• Luteinizing hormone-releasing hormone (LHRH) agonists: These drugs are used more often than oophorectomy. They stop the signal that the body sends to the ovaries to make estrogen, which causes temporary menopause. Common LHRH drugs include goserelin (Zoladex) and leuprolide (Lupron). They can be used alone or with other hormone drugs (tamoxifen, aromatase inhibitors, fulvestrant) as hormone therapy in pre-menopausal women.
• Chemotherapy drugs: Some chemo drugs can damage the ovaries of pre-menopausal women so they no longer make estrogen. Ovarian function can return months or years later in some women, but in others the damage to the ovaries is permanent and leads to menopause.

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

Hormone therapy after surgery for breast cancer

 After surgery, hormone therapy can be given to reduce the risk of the cancer coming back. Taking an AI, either alone or after tamoxifen, has been shown to work better than taking just tamoxifen for 5 years.

These hormone therapy schedules are known to be helpful for women who are post-menopausal when diagnosed:

• Tamoxifen for 2 to 3 years, followed by an AI for 2 to 3 years (5 years total of treatment)
• Tamoxifen for 2 to 3 years, followed by an AI for 5 years (7 to 8 years of treatment)
• Tamoxifen for 4½ to 6 years, followed by an AI for 5 years (9½ to 11 years of treatment)
• Tamoxifen for 5 to 10 years
• An AI for 5 to 10 years
• An AI for 2 to 3 years, followed by tamoxifen for 2 to 3 years (5 years total of treatment)
• For women who are unable to take an AI, tamoxifen for 5 to 10 years is an option

For most post-menopausal women whose cancers are hormone receptor-positive, most doctors recommend taking an AI at some point during adjuvant (after surgery) therapy. Standard treatment is to take these drugs for about 5 years, or to take in sequence with tamoxifen for 5 to 10 years. For women at a higher risk of recurrence, hormone treatment for longer than 5 years may be recommended. Tamoxifen is an option for some women who cannot take an AI. Taking tamoxifen for 10 years is considered more effective than taking it for 5 years, but you and your doctor will decide the best schedule of treatment for you.

These therapy schedules are known to be helpful forwomen who are pre-menopausal when diagnosed :

• Tamoxifen (with or without ovarian suppression) for 5 to 10 years.
• Tamoxifen (with or without ovarian suppression) for 5 years followed by an AI for 5 years if you have gone through menopause.
• AI plus some sort of ovarian suppression (see above) for 5 to 10 years.

If you have early-stage breast cancer and had not gone through menopause when you were first diagnosed, your doctor might recommend taking tamoxifen first, and then taking an AI later if you go through menopause during treatment. Another option is ovarian suppression by getting a drug called a luteinizing hormone-releasing hormone (LHRH) agonist, which turns off the ovaries, along with an AI. Pre-menopausal women should not take an AI alone for breast cancer treatment because it is unsafe and can increase hormone levels.

If cancer comes back or has spread

AIs, tamoxifen, and fulvestrant can be used to treat more advanced hormone-positive breast cancers, especially in post-menopausal women. They are often continued for as long as they are helpful. Pre-menopausal women might be offered tamoxifen alone or an AI in combination with an LHRH agonist for advanced disease.

Less common types of hormone therapy

Some other types of hormone therapy that were used more often in the past, but are rarely given now include:

• Megestrol acetate (Megace), a progesterone-like drug
• Androgens (male hormones), like testosterone
• Estradiol (a form of estrogen)

These might be options if other forms of hormone therapy are no longer working, but they can often cause side effects.

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Treating Breast Cancer

• Surgery for Breast Cancer
• Radiation for Breast Cancer
• Chemotherapy for Breast Cancer
• Hormone Therapy for Breast Cancer
• Targeted Drug Therapy for Breast Cancer
• Immunotherapy for Breast Cancer
• Treatment of Breast Cancer by Stage
• Treatment of Triple-negative Breast Cancer
• Treatment of Inflammatory Breast Cancer
• Treating Breast Cancer During Pregnancy