Chemoprevention: Drugs that can reduce breast cancer risk

If you're at high risk of breast cancer, preventive medication — chemoprevention — may be an option. Find out about the pros and cons.

Two drugs — tamoxifen (Nolvadex) and raloxifene (Evista) — now have official Food and Drug Administration (FDA) approval to help protect high-risk women from getting breast cancer.

Research is under way to determine if other drugs can do the job as well as or better than tamoxifen and raloxifene. Top on the list of potential breast cancer prevention drugs is a class of medications known as the aromatase inhibitors. Ongoing studies are evaluating the preventive effects of the aromatase inhibitors versus placebo in high-risk postmenopausal women.

How breast cancer chemoprevention works

The drugs used for chemoprevention of breast cancer affect the hormone estrogen, which influences the growth and development of many breast tumors. One type of chemoprevention drug blocks the action of estrogen. The other type reduces the amount of estrogen your body makes.

Protecting breast cells from estrogen: Selective estrogen receptor modulators

Tamoxifen and raloxifene belong to a class of drugs called selective estrogen receptor modulators (SERMs). Throughout the body, these drugs block the function of estrogen by binding to cell proteins — called receptors — that would otherwise bind to estrogen.

In breast cancer, estrogen bound to estrogen receptors promotes tumor growth. SERMs interfere with this process by binding to the receptors in place of estrogen, blocking the hormone's growth-stimulating effect.

SERMs block the effects of estrogen in breast tissue and in bone. But on some of the body's tissues — such as the uterus and blood vessels — SERMs mimic the effect of estrogen. The estrogen effect on those tissues can result in unwanted side effects, including uterine cancer, blood clots, hot flashes and vaginal dryness.

Tamoxifen
Tamoxifen blocks estrogen's ability to stimulate breast tumor growth and has estrogen-like effects on the uterine lining. This SERM is used to treat estrogen receptor positive advanced breast cancer and, for women whose estrogen receptor breast cancer is early stage, to keep the cancer from coming back (recurring) after treatment. Tamoxifen is generally taken for five years.

For chemoprevention, tamoxifen has FDA approval for use in women age 35 and older who have an elevated risk of developing breast cancer within five years. "Elevated risk" is defined as a score of 1.66 percent or greater according to a breast cancer risk assessment (the Gail model), a tool doctors use to estimate breast cancer risk in individual women based on family history and personal history of childbearing, breast biopsy results and other factors.

Data from several clinical prevention trials found that tamoxifen use in women at higher than average risk results in a relative risk reduction of about one-third for noninvasive breast cancer and about one-half for invasive breast cancer.

Although these relative risk estimates seem promising, they don't tell the whole story. In terms of absolute numbers, the risk reduction from taking tamoxifen for five years is about 2 percent. That means that for every 100 women who take tamoxifen, there will be two fewer instances of breast cancer compared with 100 women who don't take tamoxifen. Risk reduction estimates in absolute numbers gives an idea of how many women stand to benefit from taking this medicine. Whether tamoxifen might be right for you depends on your personal risk of developing breast cancer. Ask your doctor for help in understanding risk estimates and how they might apply to you.

In general, chemoprevention with tamoxifen provides the greatest benefit with the fewest side effects if:

You're at high risk of developing breast cancer — because of a personal or family history of breast cancer or precancerous changes such as atypical hyperplasia or lobular carcinoma in situ (LCIS)
You're premenopausal and have a low risk of developing blood clots or uterine cancer
You've had a hysterectomy

Common side effects of tamoxifen include:

Hot flashes
Vaginal discharge
Vaginal dryness
Menstrual irregularities
Nausea

Tamoxifen can also cause rare but potentially life-threatening side effects, including blood clots, endometrial cancer and uterine cancer. The difficult decision on whether to take tamoxifen for breast cancer prevention will depend on your age, risk status, family history, medical history and personal preferences. Taking tamoxifen doesn't guarantee that you'll remain cancer-free. Unless you're at high risk of developing breast cancer, the potential risks of tamoxifen may outweigh the benefits.

Raloxifene
Raloxifene, another SERM, is approved by the FDA for reducing the risk of invasive breast cancer in postmenopausal women at high risk of the disease, as well as in postmenopausal women with osteoporosis. Before being approved for breast cancer chemoprevention, raloxifene had FDA approval for treatment of postmenopausal osteoporosis. Like tamoxifen, raloxifene binds to estrogen receptors and blocks estrogen's effects in the breast and other tissues. Unlike tamoxifen, raloxifene doesn't exert estrogen-like effects on the uterus.

In large clinical trials, raloxifene was as effective as tamoxifen in preventing estrogen receptor positive breast cancer in high-risk postmenopausal women who did not have a personal history of breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial, a large National Cancer Institute-sponsored study comparing tamoxifen with raloxifene in high-risk postmenopausal women, found that each drug reduced the relative breast cancer risk by about half. Here again, though, in absolute terms, the reduction in risk was about two in 100. Women taking raloxifene experienced 29 percent fewer blood clots and 36 percent fewer uterine cancers than did women in the tamoxifen group.

Both drugs may cause hot flashes, bladder problems, vaginal discharge, vaginal dryness or vaginal irritation — side effects that can reduce quality of life. In this area, too, tamoxifen and raloxifene seem to differ. The women who took tamoxifen in the STAR trial reported better sexual function, but they also had more hot flashes, bladder problems, leg cramps and gynecologic problems such as vaginal dryness. Women taking raloxifene, on the other hand, experienced more frequent bone and muscle problems, pain during intercourse and weight gain.

Also, women who have had a history of blood clots or cardiac risk factors or a prior history of coronary heart disease or are at risk of stroke should not take raloxifene. In these situations, it's important that women evaluate the risk-benefit balance with their physicians.

Many women who could take tamoxifen or raloxifene because of their high risk of breast cancer choose not to take either drug. The decision to take these medications needs to be individualized. To some women, the reduction in breast cancer risk doesn't outweigh the increase in risk of blood clots and uterine cancer with tamoxifen, or the troublesome side effects of both drugs. Talk with your doctor to weigh the pros and cons in light of your own personal circumstances.

Aromatase inhibitors

Aromatase inhibitors reduce estrogen levels in a woman's body by preventing an enzyme called aromatase from converting other hormones to estrogen. By reducing the amount of estrogen in your body, you deprive breast cancer cells of the fuel they need to grow and thrive. Aromatase inhibitors are only effective in postmenopausal women.

Three aromatase inhibitors are currently used to treat breast cancer in postmenopausal women: anastrozole (Arimidex), exemestane (Aromasin) and letrozole (Femara).

In a study of women who had estrogen receptor positive breast cancer and received standard treatment — surgery plus radiation therapy or chemotherapy — study participants were randomly assigned to take either tamoxifen or anastrozole in an attempt to prevent a recurrence of breast cancer. Study results show anastrozole was slightly better than tamoxifen in reducing the risk of recurrence. The risk of developing a new cancer in the other breast was also lower among women who took anastrozole than in those who took tamoxifen.

These promising results have led researchers to embark on a number of studies to evaluate the effectiveness of aromatase inhibitors in preventing breast cancer in high-risk postmenopausal women who haven't been diagnosed with breast cancer.

Aromatase inhibitors appear to be at least as effective as and possibly better than tamoxifen, with fewer side effects. Serious adverse effects, such as blood clots and uterine cancer, are less common with aromatase inhibitors. However, aromatase inhibitors may be more likely to contribute to bone fractures and the bone-thinning disease osteoporosis.

Nonsteroidal anti-inflammatory drugs

Several studies have looked into the effects of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer risk. NSAIDs include many common over-the-counter painkillers, such as ibuprofen (Advil, Motrin, others) and naproxen sodium (Aleve).

Study results are mixed. Some research has found that women who had breast cancer and who regularly take aspirin or other NSAIDs have a slightly decreased risk of breast cancer recurrence. But other studies haven't shown a significant association between breast cancer risk and NSAIDs.

It remains unknown whether aspirin and other NSAIDs help protect against breast cancer and if so, exactly how they work to do so. Researchers speculate that the medications work by blocking the activity of cyclooxygenase (COX) enzymes, which may reduce estrogen levels and prevent tumors from forming. However, some NSAIDs, such as celecoxib (Celebrex) and naproxen sodium (Aleve), may increase the risk of heart attack and stroke. It's wise to discuss your individual risk profile with your doctor to determine whether the potential benefits of taking an NSAID outweigh the risks for you.