Breast Cancer

Description

Alternative Names

Hormone Therapy

Hormone therapy works by blocking estrogen that causes cell-proliferation. They are used for adjuvant therapy and for advanced cancers in patients with hormone receptor positive tumors. Over the past few years, many new anti-estrogen agents have become available. Generally they do one or more of the following:

• Block the hormone receptor itself.
• Suppress estrogen production.
• Destroy the ovaries (which produce estrogen).

Tamoxifen and Selective Estrogen Receptor Modulators (SERMs)

Tamoxifen (Nolvadex) has been the standard hormonal agent used for breast cancer. It is the prototype for a growing class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Other SERMs being studied for breast cancer include toremifene (which is very similar to tamoxifen), idoxifene, and droloxifene.

Candidates. Tamoxifen is used for any cancer stage in women of all ages who have hormone receptor-positive cancers. In addition, it is being used protect against cancer in high-risk women.

Tamoxifen as Adjuvant Therapy. When used as adjuvant therapy for early stage hormone receptor positive breast cancer, tamoxifen is for a total of five years as tolerated. Evidence now shows that taking it for five years significantly improves survival rates and reduces recurrence. Taking it longer appears to confer no additional advantages. Patients whose tumors are convincingly hormone receptor-negative do not benefit. Comparisons between tamoxifen and other SERMs used for adjuvant therapy are underway.

Side Effects. Hormone therapy with SERMs has fewer side effects than chemotherapy, but can still cause hot flashes, vaginal bleeding and discharge, and visual disturbances.

Of concern is an increased risk for blood clots, which can, in rare cases, be life-threatening. Tamoxifen, and possibly toremifene pose a long-term increased risk for uterine (endometrial), cancer, though not enough to offset the benefits from breast cancer prevention. Any woman on tamoxifen with vaginal bleeding should see her physician immediately to rule out uterine cancer. Although early evidence indicates that some of the newer SERMs may not increase the risk for uterine cancer. Long-term studies are needed.

Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.

Aromatase Inhibitors

Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. These agents are showing great promise for breast cancer and do not have the potentially severe complications of tamoxifen: blood clots and uterine cancer. Aromatase inhibitors are classified as either nonsteroidal or steroidal agents. (A steroid in this case does not refer to the drugs known as corticosteroids. The term here refers to one of a family of hormones that include male and female reproductive hormones and which have a specific chemical structure.)

• Nonsteroidal Aromatase Inhibitors. Anastrozole (Arimidex) and letrozole (Femara) are now important treatments for advanced breast cancer patients with hormone-receptor positive tumors. Anastrozole has also now been approved for early breast cancer treatment in postmenopausal women. Both agents are proving to be at least as effective as tamoxifen and have fewer side effects, including vaginal bleeding and blood clots. A five-year study published in 2002 comparing anastrozole to tamoxifen also reported lower risks for uterine cancer with anastrozole. (Tamoxifen was more bone-protective, however.) Another newer nonsteroidal agent, vorozole (Rivisor) is under investigation. The use of aromatase inhibitors in the adjuvant setting for treatment of early stage, hormone receptor positive breast cancer is under investigation.
• Steroidal Aromatase Inhibitors. The steroidal aromatase inhibitors include exemestane (Aromasin) and formestane (Lentaron). Exemestane is the only oral aromatase inhibitor to date. In one 2000 study, exemestane was more effective than tamoxifen in sustained response. It is now used in metastatic breast cancer for postmenopausal women who do not respond to tamoxifen, but it may have wider benefits. Formestane is given by injection and is also effective, although is still under investigation in the U.S. One study suggested it might be particularly beneficial for elderly breast cancer patients.

One study suggested that using a nonsteroidal and steroidal aromatase inhibitor sequentially (e.g., formestane followed by anastrozole at the time of treatment failure) may extend the time to disease progression more than therapy with one agent.

Selective Estrogen Receptor Downregulators (SERDs)

Selective estrogen receptor downregulators (SERDs) block estrogen in all tissues in the body. Fulvestrant (Faslodex) is one such agent, which is proving to be at least as effective as anastrozole in delaying time to disease progression in women with advanced breast cancer. Side effects are generally gastrointestinal problems and hot flashes.

Progestins

Progestins, particularly megestrol (Megace), have been used as second- or third-line treatment of advanced breast cancer when tamoxifen fails. Some of the aromatase inhibitors, however, are proving to be more effective and some have fewer side effects, such as weight gain.

Ovarian Ablation

Ovarian ablation literally shuts down estrogen production from the ovaries. This can be accomplished chemically with medications or it can be done by destroying the ovaries with surgery or radiation. Note: osteoporosis is one serious side effect of this approach, but a number of therapies are available that can help prevent bone loss.

Chemical Ovarian Ablation. Drug treatment (nonchemotherapy agents) used to completely block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary agents used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, which results in the cessation of ovulation and estrogen production. Studies are now suggesting that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who take standard chemotherapy and they experience fewer serious side effects. A major analysis of four trials using LHRH agonists plus tamoxifen also suggested that this combination should be the standard for patients with advanced breast cancers that are hormone-receptor positive, although this is an area of controversy. (Chemotherapy is still more effective in women with estrogen-negative tumors.)

Ovariectomy. Ovariectomy, the removal of the ovaries, has modestly improved breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility and can have a major negative emotional impact on many younger patients.