Antihormonal Therapy for Breast Cancer

Estrogen is a hormone made by your ovaries and other tissue in your body. It serves many critical functions. These include developing your female sex organs in puberty, preparing your breasts and uterus for pregnancy in adulthood, and maintaining your cardiovascular and bone health. Without estrogen, your body cannot sustain pregnancy and is susceptible to heart disease and osteoporosis (thinning of your bones).

Estrogen can also make some cancers grow. Your breasts, uterus, and other female organs are made of cells that are stimulated to grow when exposed to estrogen. These cells have areas on their surface called estrogen receptors.

Estrogen in your blood binds to these receptors and stimulates the cells to grow. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer's growth. Cancers that have estrogen receptors are called estrogen receptor-positive (ER-positive) cancers.

The growth of ER-positive breast cancer cells can be prevented or slowed by reducing their exposure to estrogen. This is the goal of antihormonal therapy for breast cancer. But reducing estrogen levels can also have side effects. This happens because estrogen is necessary for important body functions, such as bone growth and cardiovascular health. Lower estrogen levels lead to thinner bones and heart disease.

Tamoxifen is a drug that has been a main part of antihormonal therapy for early and advanced breast cancer. But several newer antihormonal therapy drugs—called aromatase inhibitor drugs—have proven to be better than tamoxifen for the treatment of ER-positive breast cancer. These drugs have a different side effect profile than tamoxifen.  Also, a new class of drugs called estrogen receptor antagonists work in a similar way as tamoxifen and have been shown to benefit some women with breast cancer.

How does antihormonal therapy work?

Your body makes the active form of estrogen in several steps. First, your ovaries and adrenal glands make an inactive form of estrogen. Next, this inactive form is converted to its active form by an enzyme called aromatase. The active form of estrogen circulates through your body in your blood. Then it comes into contact with your uterus, breasts, and other organs. These organs have estrogen receptors on the surface of their cells. The estrogen binds to those receptors. This binding stimulates activities in the cell that are related to growth.

The goal of antihormonal therapy is to decrease the effect of estrogen on cancer cells. Reducing the effects of estrogen can be done in the following ways:

• By removing your ovaries, the main source of estrogen in your body
• By stopping the conversion of estrogen to its active form, by inhibiting the aromatase enzyme
• By blocking the estrogen receptors so that estrogen cannot bind to cells

Removing your ovaries is a common and effective approach used in many countries. Chemotherapy may also stop your ovaries from making estrogen. Reducing estrogen in your body without removing the ovaries can be done with the use of drugs that stop the ovaries from producing hormones.

Currently, three types (classes) of antihormonal therapy drugs are approved for the treatment of breast cancer. They are:

• Aromatase inhibitors (for postmenopausal women only)
• Selective estrogen receptor modulators (SERMs)
• Estrogen receptor antagonists

These three types of drugs all work by decreasing the amount of estrogen your cells are exposed to. But they do this in different ways.

Aromatase inhibitors - These drugs work by inhibiting the formation of estrogen in your body. Aromatase is the enzyme that starts the process through which hormones in your body are converted to estrogen. Antiaromatase drugs work by inhibiting aromatase. This blocks the conversion of a precursor to estrogen to the active form. Thus, levels of active estrogen in your body fall. Currently, three aromastase inhibitors are approved for the treatment of breast cancer in postmenopausal women: Femara^® (letrozole), Arimidex^® (anastrozole), and Aromasin^® (exemestane).

Selective estrogen receptor modulators (SERM) - SERMs block the estrogen receptors on the surface of cancer cells. Estrogen cannot get into the cells. This removes the growth stimulus to all ER-positive cancer cells. Currently, tamoxifen is the most common SERM used for the antihormonal therapy of breast cancer. But tamoxifen has side effects, including an increased risk of cancer in your uterus, a small risk of blood clots and cataracts.

Estrogen receptor antagonist - Like SERMs, estrogen receptor antagonists work by preventing estrogen from stimulating the growth of ER-positive cells. Faslodex^® (fulvestrant), the first drug in this group, binds to and breaks down estrogen receptors. This means that estrogen can no longer bind to the receptors and stimulate the cell to grow. The U.S. Food and Drug Administration has approved fulvestrant for antihormonal therapy in postmenopausal women with ER-positive breast cancer when previous antihormonal therapies have failed.

What are the side effects of antihormonal therapy?

Antihormonal therapy can have side effects. Tamoxifen can cause a variety of side effects, especially if you take it for a long time. Aromastase inhibitors also have side effects but they can be somewhat different than tamoxifen.

Tamoxifen - Tamoxifen has some side effects similar to symptoms of menopause. These include hot flashes, irregular menstrual periods, and vaginal discharge or bleeding. Not all women get these symptoms. More serious side effects can also occur if you take tamoxifen for a long time.

There are small increases in the risks of blood clots and cataracts (clouding of the lens in your eye). In addition, tamoxifen appears to increase your risk of getting uterine cancer by about two to three times that of the general population. This risk of uterine cancer is similar to that for women taking postmenopausal estrogen replacement therapy.

The majority of uterine cancers can be detected at an early stage, when they are highly curable. So the overall benefit of tamoxifen in women with breast cancer probably outweighs the risk of uterine cancer. All women who have a uterus and take antihormonal therapy should have regular gynecologic examinations.

Aromastase inhibitor drugs - Clinical studies show a slightly increased risk of a low white blood cell count, blood clots, and vaginal bleeding. But these side effects occur less often with antiaromatase drugs than with tamoxifen. But there does appear to be a slight increase in the risk of fractures (broken bones) and joint pain with antiaromatase drugs compared with tamoxifen. No link has been found between antiaromatase drugs and uterine cancer. However, their use has been linked with an increased risk of osteopenia and/or osteoporosis, therefore careful bone mineral density monitoring is recommended. In addition these drugs can cause joint pain which typically improves with the use of anti-inflammatory medications. These symptoms usually improve after 3-6months of treatment with the drug.