A Deeper Look Into Hormonal Therapies for Metastatic Breast Cancer

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Hormonal therapies are often the first step in treating metastatic breast cancer, at least for those who have tumors which are estrogen receptor positive. 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 your cancer recurred while taking one of these drugs it’s thought that your cancer is likely resistant to the drug.)

Role of Estrogen

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 the cancer. This action of estrogen on cancer cells can be limited in a few different ways; by decreasing the amount of estrogen in the body, or by blocking estrogen receptors so estrogen is unable to stimulate the growth of the cells. In contrast to chemotherapy drugs which directly kill cancer cells directly (simplistically), 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 from the conversion of androgens to estrogen. This conversion is catalyzed by the enzyme aromatase found in fat and muscle. Aromatase inhibitors are medications which block aromatase so that this conversion of androgens to estrogens cannot occur, effectively lowering estrogen levels.

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

It’s also important to note that some estrogen receptor-positive tumors are also HER 2 positive. In tumors that are positive for both of these receptors, anti-estrogen therapy may be used with or without drugs which act on HER 2.

Premenopausal Therapy

If you are premenopausal, your ovaries are still the largest source of estrogen, and hence the fuel, for breast cancer. The goal of treatment in premenopausal women is thus to reduce the ability of estrogen to stimulate the growth of your cancer by either decreasing the amount of estrogen available (ovarian suppression therapy) and interfering with the ability of estrogen to bind with estrogen receptors on breast cancer cells.

Medications such as tamoxifen are referred to as SERMS—selective estrogen receptor modulating agents, 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 may be accomplished by:

  • Using the medication Zoladex (goserelin) – This is a medication given subcutaneously and suppresses the production of estrogen by the body, and is known as a gonadotropic releasing hormone antagonist. The ovaries produce estrogen in response to a hormone known as gonadotropin stimulating hormone secreted by the pituitary gland. Zoladex inhibits the ability of the gonadotropin stimulating hormone to stimulate the ovaries.
  • Oophorectomy – Less commonly, some women choose to have their ovaries removed (through a procedure called an oophorectomy) rather than using Zoladex. This surgery is done less often due to the greater risks associated with surgery, but some women may prefer this method, especially those who have a predisposition to ovarian cancer as well as breast cancer.

    An oophorectomy can often be done as a laparoscopic procedure and is usually a same day surgery. In a laparoscopic oophorectomy a few small incisions are made in the abdomen and the ovaries are removed with the assistance of special instruments.

    Following ovarian suppression therapy, premenopausal women can then be treated with medications as for postmenopausal women discussed below or with tamoxifen.

    Postmenopausal Therapy

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

    Available aromatase inhibitors include:

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

    Aromatase inhibitors may be used  alone, or in combination with a chemotherapy medication. For example, the combination of Femara (letrozole) and Ibrance (palboiclib) and Aromasin (exemastane) with Affinitor (everolimus). There is always a balance when adding in another medication. While the combination may be more effective, there is also an increase in side effects when combining more than one medication.

    It’s helpful to note again that the goal of treatment is often different with metastatic breast cancer than it is with early stage breast cancer. With early stage breast cancer the goal is curative, and the philosophy is to “pull out the big guns” to potentially cure the disease. The philosophy with metastatic breast cancer, in contrast, is often to control the growth of the cancer with the least amount of medication possible, saving other medications for a time when the first medications no longer work.

    Other Hormonal Treatments

    In addition to tamoxifen and aromatase inhibitors, there are a few other hormone-related medications that may be used for metastatic breast cancer. If a breast cancer continues to grow or spread on the above medications it is usually considered resistant to these medications. Metastatic breast cancer almost always becomes resistant to these medications over time. When this happens, options include:

    • Faslodex (fulvestrant)—For postmenopausal women who have progression of their cancer on tamoxifen or an aromatase inhibitor, an option is using the medication Faslodex. Faslodex is currently the only medication approved for breast cancer in a category known as SERD’s—selective estrogen receptor downregulators.

    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 (it is an estrogen receptor antagonist.)  Faslodex may be used alone or in combination with Ibrance (palbociclib), a chemotherapy drug, and given as an injection.

    Infrequently Used Medications

    There are other hormonal therapies which are used infrequently but are sometimes considered as a 3rd line or 4th line treatment. These include:

    • Fareston (toremifene) – Fareston is a medication similar to tamoxifen and also considered an estrogen receptor modulating agent may sometimes be considered for postmenopausal women with estrogen receptor positive breast cancers, particularly for women who lack an enzyme that converts tamoxifen to its active form in the body.
    • Progestins - Megace (megestrol) is a synthetic form of progesterone that is sometimes used for people with estrogen receptor positive breast cancer which has 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 are not commonly used with metastatic breast cancer, but may sometimes be used when other hormone treatments have failed.

    Therapies for Men

    Men with metastatic breast cancer which is hormone receptor positive are usually treated with tamoxifen.

    Side Effects

    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 symptoms include hot flashes and body aches which have been coined “old lady syndrome” though these body aches are often milder than with aromatase inhibitors.

    Serious side effects include an increased risk of blood clots in the legs (venous thromboembolism) which, if untreated, have the potential to break free and travel to the lungs (pulmonary emboli.) Over time, tamoxifen may also cause uterine bleeding and is associated with a small increase in the development of uterine cancer.

    Some women (and men) taking tamoxifen may develop a worsening of their symptoms (for example, increased redness of skin metastases or increased bone pain from bone metastases) within a few days of starting the medication.

    If you develop these symptoms, they will usually resolve within four to six weeks, though sometimes the medication needs to be discontinued. The silver lining if you have this reaction is that a 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, and low platelets and is associated with an increased risk of endometrial cancer. Discuss with your doctor if this option is best for you.

    Aromatase inhibitors (AI’s)

    AI’s can also cause body aches, with around 40 percent of people noting some degree of muscles and joint aching. Bone loss is a side effect, and your oncologist will likely order a bone density to check you for osteoporosis, both at the beginning of treatment, and periodically thereafter. Fractures may occur due to the bone loss, even without bone metastases. AI’s may also increase the risk of heart disease.

    Faslodex

    Faslodex is usually fairly well tolerated, with the most common side effects being hot flashes and elevations of liver function tests.

    Zoladex (goserelin)

    One of the more common side effects of this medication is actually the effect that is desired. The goal of treatment is to suppress the ovaries, in other words, stop the ovaries from releasing estrogen. In doing this it is essentially causes a 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 when first starting the medication, for example, an increase in bone pain in those with bone metastases.

    Oophorectomy

    The primary side effects related to removing the ovaries are, as with medical hormone suppression therapy, the normal symptoms common with menopause such as hot flashes and vaginal dryness. There are also the side effects and risk related to surgery. An oophorectomy can now be done with minimally invasive surgery (a laparscopy) through a few small cuts in the skin, and is usually done as a same day surgical procedure.

    Faslodex (fulvestrant)

    Since this is an anti-estrogen medication, most of the symptoms are similar to those found with menopause, like with tamoxifen and the aromatase inhibitors. Roughly a third of people experience mild nausea, but otherwise this medication is usually well tolerated.

    Sources:

    American Society of Clinical Oncology. Cancer.Net. Hormonal Therapies for Metastatic Breast Cancer. Updated 05/2016. https://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/hormonal-therapy-metastatic-breast-cancer

    Martin, M., Lopez-Tarruella, S., and Y. Gilarranz. Endocrine Therapy for Hormone Treatment-Naïve Advanced Breast CancerBreast. 2016. (Epub ahead of print).

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