Hormonal Therapies for Metastatic Breast Cancer

How they work and what the options are

Hormonal therapies are often the first step in treating metastatic breast cancer, at least for those who have tumors that are estrogen receptor-positive. Because estrogen powers the growth of certain cancers, medications that hinder the production of the hormone and its ability to bind to cancer cells can be effective treatments. Examples include tamoxifen and Aromasin (exemestane).

The choice of medications will depend on whether you are premenopausal or postmenopausal, as well as if your cancer recurred while you were using one of these medications. (If that's the case, it’s thought that your cancer is likely resistant to the drug.) In some cases, surgery to remove the ovaries may be recommended instead.

Estrogen and Cancer Growth

For estrogen receptor-positive breast cancers, estrogen works like fuel, binding with estrogen receptors on the surface of cancer cells and stimulating the growth and proliferation of cancer.

This action of estrogen on cancer cells can be limited by decreasing the amount of estrogen in the body or by blocking estrogen receptors so the hormone is unable to have this effect. In contrast to chemotherapy drugs, which kill cancer cells directly, hormonal therapies work by essentially “starving” the cancer cells of estrogen.

Prior to menopause, your ovaries are the biggest producers of estrogen. After menopause, the greatest source of estrogen in the body is the conversion of androgens to estrogen. This is catalyzed by the enzyme aromatase found in fat and muscle. Aromatase inhibitors are medications that block the enzyme so that this conversion cannot occur, effectively lowering estrogen levels.

Some estrogen receptor-positive tumors are also HER2 positive. In these cases, anti-estrogen therapy may be used with or without drugs that act on HER2.

Hormonal therapies are not effective for those who have estrogen receptor- and progesterone receptor-negative tumors.

Premenopausal Therapy

If you are premenopausal, your ovaries are still the largest source of estrogen. Therefore, the goal of treatment in premenopausal women is to reduce the ability of estrogen to stimulate the growth of your cancer by either decreasing the amount of estrogen available and interfering with the ability of estrogen to bind with estrogen receptors on breast cancer cells.

Medications such as tamoxifen are referred to as selective estrogen receptor modulating agents (SERMs), and work by binding to cancer cells so that estrogen present in the body is unable to bind to the cell and signal the cell to grow.

It’s thought that aromatase inhibitors may be more effective than tamoxifen, but these cannot be used in premenopausal women due to the activity of the ovaries. To reduce the estrogen produced by the ovaries, and allow you to use an aromatase inhibitor, your oncologist may recommend ovarian suppression therapy.

Ovarian Suppression Therapy

This may be accomplished with medication or surgery and results in what's called medical menopause.

Zoladex (goserelin)

Zoladex inhibits the ability of the gonadotropin stimulating hormone, a hormone secreted by the pituitary gland that prompts the ovaries to produce estrogen.

Known as a gonadotropin-releasing hormone antagonist, Zoladex is given subcutaneously to suppress the production of estrogen by the body.

Oophorectomy 

Less commonly, some women opt for ovary removal via a procedure called an oophorectomy. This surgery poses greater risks than Zoladex, but it may be preferred in some cases, such as in people with a predisposition to ovarian cancer as well as breast cancer.

After ovarian suppression therapy via either method, premenopausal women can be treated with the same medications as postmenopausal women or with tamoxifen.

Postmenopausal Therapy

After menopause, the largest source of estrogen in the body is the peripheral conversion of androgen to estrogen. Postmenopausal breast cancer may be treated with tamoxifen (to block this converted estrogen from binding with cancer cells), but aromatase inhibitors appear to be more effective with fewer side effects.

Available aromatase inhibitors include:

  • Arimidex (anastrozole)
  • Femara (letrozole)
  • Aromasin (exemestane)

Aromatase inhibitors may be used alone or in combination with chemotherapy medication. For example, the combination of Aromasin (exemestane) and Afinitor (everolimus). There is always a balance when adding another medication. While the combination may be more effective, there is also an increase in side effects.

While you may be eager to be as aggressive as you can about your treatment, as is usually recommended for early-stage breast cancer (when the goal is a cure), metastatic breast cancer treatment is aimed at controlling the growth of the cancer with the least amount of medication possible. Other medications are saved for when the first one no longer works.

Other Hormonal Treatments

If a breast cancer continues to grow or spread while you're on the above medications, it's usually considered resistant to them—and this almost always happens in cases of metastatic breast cancer over time.

When it does, a few other hormone-related medications may be used, the most common of which is a drug called Faslodex (fulvestrant).

Faslodex an option for postmenopausal women whose cancer progresses on tamoxifen or an aromatase inhibitor. Faslodex is currently the only approved breast-cancer medication in a category known as selective estrogen receptor downregulators (SERDs).

This medication is referred to as a “pure antiestrogen” and blocks the effect of estrogen on estrogen receptor-positive breast cancer cells, but in a different way than tamoxifen. Faslodex may be used alone or in combination with the chemotherapy drug Ibrance (palbociclib). It's given as an injection.

Less-Used Medications

Hormonal therapies that are used less often but may be considered as a third- or fourth-line treatment include:

  • Fareston (toremifene): Similar to tamoxifen, Fareston is an estrogen receptor-modulating agent. It may sometimes be considered for postmenopausal women with estrogen receptor-positive breast cancers, particularly for those who lack an enzyme that converts tamoxifen to its active form in the body.
  • Progestins: Megace (megestrol) is a synthetic form of progesterone that's sometimes used for people with estrogen receptor-positive breast cancer that's become resistant to tamoxifen. It was used more frequently in the past before newer drugs became available.
  • Sex steroid hormones: Hormones such as estrogen and androgens may sometimes be used when other hormone treatments have failed.

Men with metastatic breast cancer that's hormone receptor-positive are usually treated with tamoxifen.

Side Effects

Negative side effects are something to consider with any medication. Be sure you discuss the possibility hormone therapy side effects with your doctor while deciding on treatments, and report any serious ones after you start your regimen.

Tamoxifen

Tamoxifen has different functions, both mimicking the effect of estrogen in some parts of the body and counteracting it in others.

The most common tamoxifen side effects include:

  • Hot flashes
  • Body aches

The combination of these symptoms is similar to menopause. However, these body aches are often milder than those that result from aromatase inhibitors.

Serious side effects include an increased risk of:

  • Blood clots in the legs (venous thromboembolism) that can, if untreated, break free and travel to the lungs (pulmonary emboli)
  • Uterine bleeding (typically after extended use)
  • Development of uterine cancer (typically after extended use)

Your symptoms may get worse on this drug, with, for example, skin metastases becoming redder or bone metastases becoming more painful. This typically happens within a few days of starting the medication and resolves in four to six weeks.

If it doesn't resolve, you may need to go off the drug. The silver lining is that this kind of flare reaction is considered a sign that the medication is working and will be effective. Zoladex may also cause a similar flare reaction.

Note that Tamoxifen may cause:

  • Abnormal liver function tests
  • Anemia
  • Low platelets
  • Increased risk of endometrial cancer

Aromatase inhibitors (AIs)

AIs can cause:

  • Body aches, which affect about 40 percent of people
  • Bone loss, which may cause fractures even without bone metastases; your doctor may order bone-density tests before and after treatment.
  • Increase your risk of heart disease

Faslodex (fulvestrant)

Since this is an anti-estrogen medication, most of the symptoms are similar to those found with menopause, such as with tamoxifen and the aromatase inhibitors.

Roughly a third of people experience mild nausea, but otherwise, this medication is usually well tolerated.

Zoladex (goserelin)

This drug essentially causes medically-induced menopause and, thus, the normal symptoms of menopause such as hot flashes and vaginal dryness are common.

As with tamoxifen, some people may have a flare reaction (temporary increase in cancer symptoms) when first starting the medication.

Oophorectomy

The primary side effects related to removing the ovaries are, as with medical hormone suppression therapy, the normal symptoms common with menopause. You should also consider the side effects of and risks related to surgery in general.

An oophorectomy can now be done laparoscopically, with just a few small cuts in the skin. It's usually done as an outpatient procedure.

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