What can be used to reduce the risk of breast cancer?

When drugs are used to reduce the risk of cancer in healthy people, it is called chemoprevention. This is a fairly new and fast-growing area of cancer research.

Many clinical studies have shown that the drugs tamoxifen and raloxifene reduce the risk of breast cancer in women known to have an increased risk. Other studies are looking at newer drugs called aromatase inhibitors to find out if they may help reduce risk. Herbs and dietary supplements are also being studied to find out if they might help reduce risk.

Tamoxifen (also called Nolvadex^® or Soltamox™)

What is tamoxifen?

Tamoxifen is a drug that is taken once a day, most often as a pill. It has been used for more than 25 years to help treat some women with breast cancer.

Tamoxifen works against breast cancer, in part, by interfering with the activity of estrogen. Estrogen is a female hormone that can fuel the growth of breast cancer cells. Tamoxifen blocks estrogen by keeping it from hooking up to receptors (molecules that control the cells' activity) on cells in the breast. For this reason, tamoxifen is often called an anti-estrogen. It is used to treat estrogen receptor-positive breast cancer.

Tamoxifen has been approved by the Food and Drug Administration (FDA) for reducing the risk of breast cancer in women who are 35 or older, and have a higher risk of breast cancer, whether they have gone through menopause or not. (See the section "Weighing risks versus benefits of tamoxifen" for more information.)

Tamoxifen is also approved to treat several types of breast cancer. As a treatment for breast cancer, this drug slows or stops the growth of estrogen receptor-positive cancer cells in the body. (Estrogen receptor-positive breast cancer responds to estrogen, and estrogen receptor-negative breast cancer does not.)

Tamoxifen also helps keep cancer from coming back (recurring) in women who have been treated for breast cancer.

How well does tamoxifen work to reduce the risk of breast cancer?

The Breast Cancer Prevention Trial (BCPT), a large study looking at tamoxifen, was sponsored by the National Cancer Institute (NCI) in the mid 1990s. In this study, more than 13,000 women who were at higher than average risk of breast cancer were assigned to 1 of 2 groups. Each group was to take a pill each day for 5 years. One group took tamoxifen and the other took a placebo (sugar pill), but neither group of women knew which pill they were taking. After watching these women for 7 years, the study found that, compared with the women taking the placebo, those who took tamoxifen had:

• About half the risk of invasive breast cancer. There were 145 cases of breast cancer in the tamoxifen group compared with 250 cases in the placebo group.

• About one-third less risk of non-invasive breast cancer, such as ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). There were 60 cases in the tamoxifen group compared to 93 cases in the placebo group.

During the 7-year follow-up, there was no major difference in the risk of death from breast cancer between the 2 groups. Breast cancer caused 11 deaths in the placebo group and 12 in the tamoxifen group. The total number of deaths (from any cause) was also about the same between the groups.

Another study that looked at tamoxifen for breast cancer risk reduction, the IBIS-I study, was an international clinical trial that began in 1992. It followed more than 7,000 women at increased risk. The study was designed much like the BCPT study described above. After an average of about 8 years, the women taking tamoxifen had about one-third (34%) fewer cases of estrogen receptor-positive breast cancer compared with those taking a placebo.

More recent findings from the IBIS-I study also have shown that the breast cancer risk reduction effect of tamoxifen continued, even after the 5 years the drug was actually taken. In fact, this study has shown that tamoxifen's risk-reducing effects lasted for at least 10 years. In contrast, most of the side effects stop when the drug is stopped.

There are 5 randomized prevention trials comparing tamoxifen with placebo for the reduction of breast cancer risk. The tamoxifen prevention trials showed a 38% reduction in breast-cancer incidence. There was no effect for estrogen receptor-negative breast cancers, but ER-positive cancers were decreased by 48% in the tamoxifen prevention trials. Overall, there was no effect on non-breast-cancer-related deaths; the only cause of death that was increased was blood clots in the lungs (pulmonary embolism). (There were 6 deaths in those taking tamoxifen versus 2 in the placebo group.) The evidence now clearly shows that tamoxifen can reduce the risk of estrogen receptor-positive breast cancer.

Does taking tamoxifen have other benefits?

Tamoxifen reduces the risk of developing breast cancer and can also help prevent osteoporosis, a weakening of the bones that can happen to women after menopause. The BCPT study found that tamoxifen reduced the risk of bone fractures of the hip, wrist, and spine by about one third (32%).

Tamoxifen did not protect against heart attacks in the BCPT study, but it did seem to help in other studies of women who already had breast cancer. More research is needed to resolve these conflicting results.

Are there risks in taking tamoxifen?

Tamoxifen is a complex drug. Along with its anti-estrogen action, it seems to have some weak estrogen-like properties, too. This is why tamoxifen may increase a woman's chance of some rare but serious health problems such as:

• endometrial cancer (cancer of the lining of the uterus/womb)
• uterine sarcoma (cancer of the connective tissue of the uterus)
• major blood clots (stroke, deep vein thrombosis, pulmonary embolism/lung clot)

Endometrial cancer and uterine sarcoma

Estrogens and agents that act like estrogens are known to raise the risk of endometrial cancer, but only in post-menopausal women. According to the BCPT study, tamoxifen raises the risk of getting endometrial cancer (based on 53 cases in the tamoxifen group versus 17 cases in the placebo group of the study). It also appears to increase the risk of a rare but serious form of cancer known as uterine sarcoma (based on 3 cases in the tamoxifen group versus 1 case in the placebo group).

It is especially important for women who have taken or are taking tamoxifen to talk about these cancer risks with their doctors. These women are strongly encouraged to call their doctors to tell them about any vaginal bleeding or spotting that is not normal. Bleeding, spotting, or discharge could be symptoms of these cancers. Women should also talk to their doctors about the possible benefits, risks, and limitations of testing for early endometrial cancer.

Endometrial cancer usually can be found at an early stage, when treatment works best. The 2 main ways to detect endometrial cancer early are the endometrial biopsy and transvaginal ultrasound. For more information on this, see our document, Endometrial Cancer.

The American Cancer Society (ACS) recommends that women taking tamoxifen learn about their testing options for endometrial cancer so that they can make informed decisions. But at this time we do not recommend routine testing for these women. This is because studies have not shown that routine testing helps find endometrial cancer at a more curable stage. Also, many studies have found that routine testing for endometrial cancer can lead to unnecessary surgery to check out false-positive test results.

Women who have had a hysterectomy (surgery to remove the uterus) are not at risk for endometrial cancer or uterine sarcoma and do not have to worry about these cancers.

Major blood clots

According to the BCPT study, women taking tamoxifen have about twice the chance of developing a blood clot in the lung (called a pulmonary embolism). This finding is based on 28 cases in the tamoxifen group, compared to 13 cases in the placebo group.

Women in the tamoxifen group were also more likely to have a stroke or to have a blood clot in a major vein (called a deep vein thrombosis or DVT). But in this case, the differences were small enough that they may have been due to chance rather than the tamoxifen.

The IBIS-I study also found a higher risk of blood clots (about 2 times higher) in the women who took tamoxifen, especially among those who had recently had major surgery. This risk increased only while the woman was taking tamoxifen; it went away after the tamoxifen was stopped. Women taking tamoxifen who will be having surgery may want to speak with their doctors about this.

Overall, blood clots occur more often in people with high blood pressure or diabetes, smokers, and those who are overweight (obese).

Does tamoxifen have other possible side effects?

Like most medicines, tamoxifen causes side effects in some women. The side effects most often reported by women in the BCPT study were hot flashes and vaginal discharge. There were other side effects, but these were no more common in the women who took tamoxifen than in the women who took placebo.

Some research has shown that women who take tamoxifen have a slightly higher risk for cataracts (a clouding of the lens of the eye). In the BCPT study, women in the tamoxifen group were 21% more likely to develop cataracts than women in the placebo group. They were also more likely to have cataract surgery. But the IBIS-I study did not find an increased risk of cataracts. And as women get older, they are more likely to develop cataracts whether or not they take tamoxifen.

As in the BCPT study, women taking tamoxifen in the IBIS-I study were also more likely to have vaginal discharge and hot flashes. A newer report on the IBIS-I study also found an increased risk of vaginal yeast infections and an increased risk of having brittle nails in women on tamoxifen.

Does taking tamoxifen make a woman start menopause?

Tamoxifen use may start early menopause, and it can cause some of the same kinds of symptoms, such as hot flashes, night sweats, mood swings, and vaginal dryness. In most women who take tamoxifen before menopause, the ovaries work normally and make female hormones (estrogens) in the same or slightly increased amounts.

How long should women take tamoxifen?

When tamoxifen is used to treat breast cancer, it is most often taken for 5 years. In one study, women with early stage breast cancer who took tamoxifen for 10 years got no benefit from taking it longer. They also showed a trend toward having more side effects.

In the BCPT study, women took tamoxifen for 5 years. But the ideal length of time women should take tamoxifen to reduce their risk of breast cancer is not known. Research is being done to try to figure this out.

Based on the best information available at this time, most doctors recommend that women take tamoxifen for 5 years.

Does tamoxifen have the same risks as hormone replacement therapy?

Some women use hormone replacement therapy (HRT), also called post-menopausal hormone therapy (PHT), to reduce hot flashes and other problems that come with menopause and can affect day-to-day living. HRT may also help women maintain bone density and reduce their risk of fractures.

More recent clinical studies have suggested that combined HRT (estrogen plus progestin) raises a woman's chances of heart disease, blood clots, breast cancer, and other serious health problems. Women who are thinking about using HRT after menopause should know about these possible side effects and talk to their doctors about them before making the decision. Those who decide to use HRT should use the lowest dose that works for the shortest possible time.

Tamoxifen, on the other hand, does not reduce symptoms linked to menopause, and may even make them worse. Like HRT, it appears to raise the risk of blood clots. (The risk of blood clots among post-menopausal women is about the same for women taking tamoxifen as for those women who are taking HRT.) Tamoxifen does reduce breast cancer risk and may help slow or reduce bone loss. In placebo-controlled studies, such as the Breast Cancer Prevention Trial, tamoxifen reduced the risk of bone fractures by almost one-third. Tamoxifen has no clear overall effect on heart disease.

Who should consider taking tamoxifen to reduce their breast cancer risk?

All women thinking about using tamoxifen for breast cancer risk reduction should have a health care professional assess of their risk of developing breast cancer. (There are tools that can be used to figure out breast cancer risk -- see the section, "Breast cancer risk assessment tools.")

The BCPT study looked only at women who were at increased risk for developing breast cancer. These included:

• women 60 years of age and older
• women between the ages of 35 and 59 with risk factors that increased their chances of getting breast cancer within the next 5 years to the same level or higher than that of a 60-year-old woman

The risk for these women was figured out by using the Breast Cancer Assessment Profile. Their risk score was a minimum of 1.7% over the next 5 years. This means that 17 of every 1,000 women with this score were expected to develop breast cancer within 5 years. (See the "Breast cancer risk assessment tools" section for information on how risk scores are figured out.)

Many diseases, including breast cancer, happen more often in older women. We know that breast cancer risk increases as women get older. This means that breast cancer happens more often in women older than 60 years old compared to women in their 40s and 50s. Still, a woman younger than age 60 could have the same risk as a 60-year-old (or even higher) if she has one or more of these factors:

• a BRCA1 or BRCA2 gene mutation
• has already had breast cancer
• any breast biopsy, and especially one that shows either atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS). These conditions are signs of an increased chance of developing invasive breast cancer.
• several close relatives--mother, sister(s), daughter(s) with breast cancer -- especially if they were diagnosed before menopause
• not had any children, or had a first child after age 30
• started menstrual periods before age 12 or went through menopause after age 55

To learn more about your own breast cancer risk and whether you might want to talk to your doctor about taking tamoxifen, see the section, "Breast cancer risk assessment: Should I consider taking tamoxifen?"

Are there women who should NOT take tamoxifen to reduce their breast cancer risk?

Tamoxifen should not be used to reduce breast cancer risk in women who:

• have ever had blood clots or who develop blood clots that need medical treatment
• are taking medicines to thin their blood (warfarin, Coumadin^®, heparin -- drugs that keep blood from clotting)
• have or have had high blood pressure, obesity, or diabetes; or current smokers (tamoxifen increases the risk of blood clots in these women)
• are pregnant or planning to become pregnant
• are breast-feeding
• are younger than 35 years old
• are younger than 60 years old and are not at increased risk
• have not had any breast cancer risk assessment
• are taking hormone replacement therapy, raloxifene, or an aromatase inhibitor

There may be other reasons that a woman should not take tamoxifen, such as cataracts or atypical hyperplasia of the uterus. Women should talk with their doctors about their total health picture in order to make the best possible choices.

Tamoxifen may cause birth defects if it is taken at the time of conception or during pregnancy. Women taking this drug need to use a barrier or another method of birth control that does not involve hormones. If you are pregnant, breast-feeding, or planning to have children tell your doctor before you start tamoxifen. Do not take birth control pills (oral contraceptives) or other birth control that contains hormones while taking this drug without checking with your doctor first.

Should women who have an increased risk of breast cancer take tamoxifen?

Women with an increased risk of breast cancer should think about taking tamoxifen to reduce their risk. As with any medical procedure or treatment, the decision to take tamoxifen is a personal one in which the benefits and risks must be discussed with your doctor.

The balance of these benefits and risks will vary depending on a woman's risk of developing breast cancer, her personal health history, and how she and her doctor weigh the benefits and risks. Even if a woman has an increased risk of breast cancer, tamoxifen may not be right for her. Any woman who is thinking about taking tamoxifen should talk with her doctor about her personal health situation to make the best decision.

Should women who do NOT have an increased risk of breast cancer take tamoxifen?

Tamoxifen has never been studied in healthy women at average risk for breast cancer, but there's no way to know if it would lower their breast cancer risk and if so, by how much. Only higher risk women were allowed to take part in studies to reduce risk because the overall benefit of taking tamoxifen for breast cancer risk reduction is greatest in these women. The FDA approved tamoxifen to be used for breast cancer risk reduction in women who are at high risk and not in average-risk women.

Women at average risk would have the same side effects and risks of the drug, but less benefit because fewer of these women would be likely to develop breast cancer. There is no recommendation to take any breast cancer chemoprevention if you are not thought to be at an increased risk. Women who are not at increased risk may wish to talk with their doctors about their specific situations.

Breast cancer risk assessment: Should I consider taking tamoxifen?

The first step in answering this question is to have a health care professional do a breast cancer risk assessment. As is the case with almost all drugs, there are benefits and risks with taking tamoxifen. For women with significant risk of breast cancer, the benefits of chemoprevention often outweigh the risks.

For now, most experts say that a woman's breast cancer risk should be higher than average for her to consider taking tamoxifen. (This is also what the FDA label for tamoxifen says.) A woman who is at higher than average breast cancer risk needs to compare the benefit of possibly reducing her breast cancer risk with the risk of side effects and problems from taking tamoxifen.

Your risk factors need to be identified to find out if you are at higher than average risk for breast cancer. A risk factor is anything that is linked to a higher chance of getting a disease. For example, smoking is a known risk factor for lung and many other cancers. But keep in mind that not all risk factors actually play a part in causing the cancer, and some risk factors cannot be changed.

Age is the major risk factor for breast cancer. The risk goes up as you get older. If you are 60 years old you have a higher risk of having breast cancer than if you are 40. But older women seem to have more of the serious side effects of tamoxifen. In studies, the greatest breast cancer risk reduction with the fewest side effects was seen in younger women who were at higher risk for breast cancer. Such women would include those with atypical ductal hyperplasia or who had a sister or mother with breast cancer. For more, see the section "Weighing risks versus benefits of tamoxifen."

Another risk factor is family history. If your mother, sister, aunt, or grandmother has had breast cancer, or you have a male relative with breast cancer, then you have a higher risk than if you don't have any close relatives with breast cancer. There are other risk factors for breast cancer that are less important, but when they are combined they can influence your risk. Examples of these risk factors are age at first menstruation, age at menopause, and age when your first child was born.

Having a higher risk because of a certain risk factor does not mean that you will develop breast cancer. In fact, most women who have one or more risk factors will never develop breast cancer.

You can get some idea about your risk of breast cancer (and whether tamoxifen might be an option for you) by answering the questions below. These are the same questions that doctors asked women interested in taking part in the BCPT study. The questions deal with age; personal history of breast cancer, LCIS (lobular carcinoma in situ), DCIS (ductal carcinoma in situ), or ADH (atypical ductal hyperplasia); reproductive history; and family history.

QUESTION: How old are you?

If you are younger than 35 years of age: Tamoxifen is not approved for breast cancer risk reduction in women younger than age 35. Women in this age group were not part of the BCPT study because their risk is low to begin with.

If you are 35-55 years of age: Go to the next question.

If you are in your late 50s: When the BCPT study was set up, it was decided that all women 60 and older automatically qualified to take part. This is because breast cancer risk increases with age. The study later showed that tamoxifen appeared to reduce breast cancer risk by about half for women age 60 and older.

Tamoxifen is approved for breast cancer risk reduction in all women over the age of 60, but we don't know how well tamoxifen would work for women in their 50s unless they have other risk factors. But because you are close to the age cutoff, it may be OK for you to take tamoxifen. Talk to your doctor about this, particularly the risks and benefits of taking tamoxifen, along with your personal risks for blood clots and osteoporosis, as well as breast cancer and endometrial cancer.

If you are 60 or older: Most doctors consider an average woman's risk at age 60 to be high enough to take tamoxifen to reduce breast cancer risk, so this is an option for you. When the BCPT study was set up, it was decided that all women 60 and older (regardless of any other risk factor) automatically qualified to take part because breast cancer risk increases with age. Tamoxifen was shown to reduce breast cancer risk by about half for women age 60 and older.

QUESTION: Have you ever had breast cancer, lobular carcinoma in situ or atypical ductal hyperplasia?

If no: Go to the next question.

If yes: If you had breast cancer, including ductal carcinoma in situ (DCIS), did you take tamoxifen as part of your treatment?

If yes: Tamoxifen should only be taken for 5 years, so tamoxifen would not be expected to reduce your risk any further. One of the newer aromatase inhibitors may be an option for you. (We will talk about these later on.) You may want to ask your doctor about this.

If no: The BCPT study did not include women who had breast cancer (or DCIS) in the past. Talk to your doctor about whether taking tamoxifen to reduce your risk is an option for you now.

If you had lobular carcinoma in situ (LCIS) and are 35 or older: Doctors consider the breast cancer risk of women who have had LCIS to be high enough to consider taking tamoxifen, so this may be an option for you. When the BCPT study was set up, it was decided that any woman with LCIS automatically qualified to take part because LCIS is a risk factor for breast cancer.

If you had atypical ductal hyperplasia (ADH) and are 35 or older: ADH by itself may not raise a woman's risk of getting breast cancer to the level where she might consider taking tamoxifen. But women who have had ADH and who also have other risk factors may have a risk that is high enough to consider taking tamoxifen. Talk to your doctor about all of your risk factors and how they affect your risk, so you can make an informed decision about whether or not to take tamoxifen.

QUESTION: Do you have family members who have had breast cancer?

If no: Go to the next question.

If yes and you are age 35 or older: When the BCPT study was set up, it was decided that any woman age 35 and older with at least 3 close relatives who have had breast cancer automatically qualified because a strong family history is a risk factor for breast cancer. A close relative was defined as a mother, sister, or daughter for the purposes of that study.

If you have grandmothers, aunts, and/or first cousins who are all related (for example, all on one side of the family and related by blood rather than marriage) and who were diagnosed with breast cancer before age 50 and/or ovarian cancer at any age, or male relatives with breast cancer, you may want to talk to your doctor about your risk and whether or not you should take tamoxifen.

If you have been told you are "positive for the breast cancer gene" or that you have a mutation (change) in one of the breast cancer genes (BRCA1 or BRCA2): The breast cancer risk of women who have had a genetic test result that shows a mutation (change) in the BRCA1 or BRCA2 gene is high enough to take tamoxifen to reduce breast cancer risk. If you are age 35 or older this may be an option for you if you do not choose to have both breasts removed to prevent cancer (bilateral prophylactic mastectomy).

As part of the follow-up to the BCPT study, the researchers looked at how well tamoxifen worked on women in the study with BRCA1 or BRCA2 mutations. They found that tamoxifen seemed to reduce breast cancer risk among BRCA2 carriers by about 60%. But it did not change breast cancer risk among women with BRCA1 mutations. Still, the number of women in both groups was small, and the true impact of tamoxifen among women with these mutations is not well understood.

QUESTION: Do you have other breast cancer risk factors, such as:

• starting menstrual periods before age 12
• having no children, or having your first child after age 30
• going through menopause after age 55

If no: Based on what is known today, most women under age 55 who do not have breast cancer in the family, have never had breast cancer themselves, or who don't have other risk factors are not at high enough risk to take tamoxifen.

If yes: A few women under age 55 who have not had breast cancer themselves and do not have it in their families may have a combination of risk factors that would put them in a higher risk category. If you think this might be true for you, then talk to your doctor about your risk of getting breast cancer.

Breast cancer risk assessment tools

Researchers have built some statistical models to help predict a woman's risk of getting breast cancer.

The Risk Disk is a tool designed for health professionals based on the questions above. It is a tool that doctors and nurses can use to help women make informed decisions about taking tamoxifen. It gives a risk score by calculating a woman's risk of getting breast cancer in the next 5 years and over her lifetime.

The tool does have some limits, though. For instance, some doctors say it does not count family history enough. It's also important to note that this tool was created for health professionals, so it may use terms and explanations that patients may not understand. Ask your doctor about using this tool to give you a better idea about your risks and whether you should consider taking tamoxifen.

Other risk tools based largely on risk factors linked to family history, such as the BRCAPRO, and Claus models, are used only by professional genetics counselors to estimate breast cancer risk.

None of these tools is perfect. Each has its strengths and weaknesses, and a woman's risk may vary depending on the tool used. Many tools have not been tested on minority women, so they may not work the same for everyone. These tools can give you a rough estimate of risk, but they can't predict for sure if you will develop breast cancer.

Weighing risks versus benefits of tamoxifen

Based largely on the results of the BCPT study, the Food and Drug Administration (FDA) approved tamoxifen to reduce the risk of breast cancer in women whose risk of developing the disease was at least 1.67% within the next 5 years based on the Gail score (calculated from the Gail risk tool). This included all women over the age of 60, as well as those between 35 and 59 with factors that increased their risk to this level, whether or not they had gone through menopause.

Because of the possibility of serious side effects, not everyone who meets the FDA requirements for taking tamoxifen would necessarily have an overall benefit from it. Since the BCPT study, researchers have tried to look at more than just a woman's risk of developing breast cancer when trying to decide whether she might benefit. For example, older women are at higher risk of breast cancer than are younger women, which could mean tamoxifen might be more likely to reduce this particular risk. But older women are also more likely to have a stroke or blood clot, which could mean tamoxifen might be riskier for them.

All pre-menopausal women with a risk of developing breast cancer that is greater than 1.7% in 5 years are likely to have an overall benefit from taking tamoxifen to reduce their risk. Most post-menopausal women (especially those who are not obese and who have had hysterectomy) also have an overall benefit from taking tamoxifen.

Recent studies estimate that about 3 out of 20 (15%) women over the age of 35 would be eligible to take tamoxifen to reduce their risk of breast cancer, according to the FDA criteria. But only about 1 in 3 of these eligible women would have benefits that clearly outweighed the risk. Generally speaking, younger women at high risk appear to have a better benefit-to-risk ratio from tamoxifen than do older women. As with any drug, it's important to remember that each woman is unique, and the possible benefits and risks for her depend on many factors.

The final word on tamoxifen to reduce breast cancer risk

Scientists are working very hard to develop information about competing risks, such as how a woman's risk of heart disease should affect her decisions about breast cancer risk reduction. As new information comes in, recommendations about who should and who should not take tamoxifen may change. Also keep in mind that your risk changes over time -- with age, with a new diagnosis of breast cancer in your family, or if you have a breast biopsy.

Some experts think that more research is needed to learn more about the benefits and risks of tamoxifen for breast cancer risk reduction. The BCPT study showed the risk of getting breast cancer was reduced by almost half, but after 7 years of research, this did not translate into any effect on deaths from breast cancer. Other, smaller studies have not found as strong a benefit for tamoxifen. More research is needed to answer the many questions about using tamoxifen to reduce the risk of breast cancer.

Raloxifene (Evista^®)

What is raloxifene?

Raloxifene is a drug that is like tamoxifen in many ways. It is a pill that is taken each day. Like tamoxifen, it stops breast cells from being affected by estrogen. Both drugs can also help prevent osteoporosis, or weakening of the bones, that can happen in women after they reach menopause.

Raloxifene is approved by the FDA to help reduce breast cancer risk in women past menopause who are at high risk for breast cancer. Raloxifene is also approved to help prevent and treat osteoporosis in women past menopause, even those who do not have a higher risk of breast cancer.

What are the possible benefits of taking raloxifene?

Information about raloxifene is limited compared with that on tamoxifen. It has been studied for a shorter time and in fewer women.

One large study looked at more than 7,000 women with osteoporosis after menopause. Half took raloxifene and half took placebo (a sugar pill) in a study called the Multiple Outcomes of Raloxifene Evaluation, or MORE trial. Although the study was designed to look at osteoporosis, results suggested that raloxifene might also reduce breast cancer risk. After 8 years there were fewer breast cancer cases in the women taking the drug than in those taking the placebo (40 cases in the raloxifene group versus 58 cases in the placebo group).

Raloxifene was also found to make bones stronger and reduce the risk of certain types of bone fractures.

A larger study, known as the STAR (Study of Tamoxifen and Raloxifene) trial, included more than 19,000 women past menopause who were at increased risk of breast cancer. Half were assigned to take tamoxifen and half were assigned to take raloxifene each day for 5 years.

Both drugs reduced the risk of invasive breast cancer about the same -- there were 163 breast cancers in the tamoxifen group and 168 cases in the raloxifene group. And newer data also shows that raloxifene reduced the risk of non-invasive cancers (DCIS and LCIS) the same way tamoxifen did.

Another study, called the Raloxifene Use for the Heart (RUTH) trial, was designed to look at the effect of this drug on the heart and on invasive breast cancer. The RUTH trial looked at 10,101 women past menopause with coronary heart disease who took either raloxifene or placebo daily for 5 years. It found that raloxifene did not have a major effect on the risk of coronary events (death from heart problems, non-fatal heart attacks, or hospitalization for other heart problems), and it reduced the risk of invasive breast cancer. But the women who took raloxifene had higher rates of stroke and blood clots, much like those seen with tamoxifen.

Both raloxifene and tamoxifen have been found to reduce the risk of bone fractures by about one-quarter to one-third.

What are the possible risks of taking raloxifene?

While raloxifene can cause side effects, there may be less risk of certain serious side effects than with tamoxifen.

Major blood clots

As with tamoxifen, blood clots in the legs or lungs are a risk with raloxifene. In the MORE and RUTH trials, the number of blood clots in the lungs or legs in women taking raloxifene was slightly higher than in those getting the placebo.

But in the STAR trial, the women taking raloxifene had 30% fewer blood clots than those taking tamoxifen (100 cases vs. 141 cases). So while raloxifene may raise this risk slightly, it doesn't raise it as much as tamoxifen.

In most, but not all studies to date, tamoxifen is linked to higher risk of stroke. In the STAR trial the risk of stroke was much the same in the raloxifene and tamoxifen groups. But the risk of stroke was not increased in the RUTH trial when women taking raloxifene were compared to women taking placebo. More study is needed in this area.

Uterine cancers

In the MORE trial, the women taking raloxifene were not more likely to get endometrial cancer, a serious side effect of tamoxifen. But very few endometrial cancers were seen in either the women taking the drug or those taking the placebo, and not all of the women were examined for this type of cancer.

About half of the women in the STAR trial still had a uterus and were at possible risk for uterine cancer. Among these women, there were 36% fewer cases of uterine cancer in those taking raloxifene compared with those taking tamoxifen (23 cases versus 36 cases). But the number of cases was so small that the researchers thought the difference may be due to chance rather than the drugs. It is not clear if raloxifene increases the risk of uterine cancer overall, but if it does, the increase may be less than that seen with tamoxifen.

The RUTH trial found that raloxifene had no effect on the risk of any cancer other than breast cancer.

Other side effects

In clinical trials, other effects reported in some women taking raloxifene included:

• hot flashes
• vaginal dryness or irritation
• leg cramps
• flu-like symptoms
• swelling in the hands or feet

These side effects are usually mild and get better over time.

Overall, when compared with tamoxifen, raloxifene has not been found to have a strong effect on the risk of heart attacks or strokes in any of the major studies done to date. Raloxifene also seems to be less likely than tamoxifen to increase the risk of cataracts.

Is raloxifene available for reducing breast cancer risk?

Raloxifene is approved by the FDA to reduce breast cancer risk in women past menopause who are at high risk of breast cancer or who have osteoporosis. It is also approved to treat osteoporosis in women with average breast cancer risk.

Raloxifene to reduce breast cancer risk: A few differences

Raloxifene seems to reduce the risk of invasive breast cancer as well as tamoxifen. It poses less risk than tamoxifen in terms of some side effects, such as uterine cancers and blood clots. Raloxifene is only used in women who have gone through menopause. (Tamoxifen can be used by women before or after menopause.) Women need to talk to their doctors and weigh the possible benefits and risks before deciding whether or not raloxifene is right for them.

Aromatase inhibitors

What are aromatase inhibitors?

Aromatase inhibitors are newer drugs that are sometimes used to treat breast cancer or help keep breast cancer from coming back after surgery. The drugs in this class include:

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

Aromatase inhibitors work a little differently than tamoxifen and raloxifene. Instead of blocking the estrogen receptors, they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow. These drugs are only used in women who have already gone through menopause.

What are the benefits and risks of taking aromatase inhibitors?

Studies have shown that aromatase inhibitors are better than tamoxifen for treating advanced breast cancer. For keeping breast cancer from coming back after surgery, several studies have found that aromatase inhibitors (used instead of or after tamoxifen) are slightly better than tamoxifen alone.

Some short-term effects of aromatase inhibitors are much like those caused by tamoxifen, including hot flashes and vaginal dryness. Muscle and joint pain and headaches may happen more often.

Aromatase inhibitors seem much less likely to cause serious blood clots than tamoxifen. Unlike tamoxifen and raloxifene, aromatase inhibitors are more likely to speed up osteoporosis (bone thinning) and cause more broken bones. Based on the few studies done so far, they do not seem to raise the risk of endometrial cancer or uterine sarcoma, like tamoxifen does.

Because these drugs have been available for a shorter period of time, much less is known about other possible long-term effects they may have, such as on the risk of heart disease. Future research will help define these effects.

Are aromatase inhibitors approved for use in reducing breast cancer risk?

At this time, no. Aromatase inhibitors are not approved to be used to reduce breast cancer risk. They are used either to treat advanced breast cancer or given after surgery (instead of or after tamoxifen) to help prevent breast cancer from coming back (recurring). The FDA has not approved any of these drugs to reduce the risk of developing breast cancer.

But studies are now being done to see if aromatase inhibitors can reduce breast cancer risk. The British IBIS-II study is comparing anastrozole to placebo for 5 years in 6,000 post-menopausal women who are at increased risk of breast cancer. Results are expected in 2012. The MAP3 study is comparing exemestane to placebo in a similar group of about 4,500 women at increased risk. Results should be available in late 2010. Smaller studies are also being done with letrozole.

Aromatase inhibitors to reduce breast cancer risk: More research is needed

Like raloxifene, aromatase inhibitors may some day prove to be as good as or even better than tamoxifen in reducing breast cancer risk, but more study results will be needed to show this. Much less is known about the possible long-term effects of these drugs. Even if they are shown to reduce risk, each woman and her doctor will still need to weigh the possible benefits and risks when deciding if one of them is right for her.

Other compounds being studied

Some other medicines, such as bexarotene, lovastatin, and deslorelin, are in early stage clinical trials for breast cancer chemoprevention. It is not yet clear how well they may work to reduce breast cancer.

A few dietary supplements are also being studied to look at their possible role in reducing breast cancer risk. These include grapeseed extract, folate, omega-3 fatty acids, and vitamins B6 and B12.

Other clinical trials are looking at breast cancer reduction as an unintended effect of drugs used for other reasons. (This is how raloxifene, used for osteoporosis, was found to be useful in breast cancer.) Drugs currently being researched include aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), and statins (drugs used to lower cholesterol).

This type of research takes many years. It will probably be some time before meaningful results on any of these compounds are available.

What does all of this mean for you?

Chemoprevention with either tamoxifen or raloxifene offers a way to reduce (but not eliminate) the risk of developing invasive breast cancer in women who are at increased risk for the disease.

All chemoprevention has possible side effects. And these drugs may not be right for all women who have an increased risk for breast cancer. If you are thinking about taking one of them, make sure you have a clear understanding of your breast cancer risk (using a quantitative risk assessment tool), as well as the potential benefits and side effects of these medicines. Your doctor can help you gather information and make the decision about whether or not chemoprevention is the right choice for you.

Additional resources

More information from your American Cancer Society

The following information may also be helpful to you. These materials may be ordered from our toll-free number or found on our Web site.

• American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention (also available in Spanish)

• Breast Cancer (also available in Spanish)

• Breast Cancer Dictionary (also available in Spanish)

• Breast Cancer: Early Detection (also available in Spanish)

• Genetic Testing: What You Need to Know

• Non-cancerous Breast Conditions (also available in Spanish)

• More information on any of the drugs discussed here is available, too.

National organizations and Web sites*

Along with the American Cancer Society, other sources of information and support include:

Facing Our Risk of Cancer Empowered (FORCE)
Toll-free number: 1-866-824 RISK (1-866-824-7475)
Web site: www.facingourrisk.org
Offers breast and ovarian cancer risk assessment information, resources to figure out risk, and support for women at increased risk

Hereditary Cancer Center (HCC)
Toll-free number: 1-800-648-8133
Web site: medicine.creighton.edu/hcc
Educational information, counseling, and genetic testing referrals are offered to families at high risk for a variety of cancers

National Cancer Institute (NCI)
Toll-free number: 1-800-422-6237 (1-800-4-CANCER)
Web site: www.cancer.gov
Offers general cancer information and a tool to help you find professionals who provide cancer genetics services, such as cancer risk assessment, genetic counseling, and more. The direct link is www.cancer.gov/search/geneticsservices. Breast cancer prevention info is available at www.cancer.gov/cancertopics/prevention-genetics-causes/breast

National Women's Health Information Center (NWHIC)
Toll-free number: 1-800-994-9662
Web site: www.womenshealth.gov
Offers information on many women's health issues, as well as referrals to other appropriate organizations

Prevent Cancer Foundation (PCF)
Toll-free number: 1-800-227-2732
Web site: www.preventcancer.org
Provides easy-to-understand information about cancer and how you can lower your cancer risk

Susan G. Komen for the Cure
Toll-free number: 1-877-GO KOMEN (1-877-465-6636)
Web site: www.komen.org
Offers a wide variety of information on breast health and breast cancer

*Inclusion on this list does not imply endorsement by the American Cancer Society.

No matter who you are, we can help. Contact us anytime, day or night, for information and support. Call us at 1-800-227-2345 or visit www.cancer.org.

References

Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287:847-857.

Barrett-Connor E, Mosca L, Collins P, et al, for the Raloxifene Use for The Heart (RUTH) trial investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137.

Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001;65:125-134.

Chemoprevention: Drugs that can reduce breast cancer risk. MayoClinic.com website. Available at: http://www.mayoclinic.com/health/breast-cancer/WO00092. Accessed July 10, 2008.

Cuzick J. Aromatase inhibitors for breast cancer prevention. J Clin Oncol. 2005;23:1636-1643.

Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296–300.

Cuzick J, Forbes J, Edwards R, et al, IBIS Investigators. First results from the International Breast cancer Intervention Study (IBIS-I): A randomized prevention trial. Lancet. 2002;360:817-824.

Cuzick J, Forbes JF, Sestak I, et al. Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer--96-Month Follow-up of the Randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-282.

Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-1662.

Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388.

Freedman AN, Graubard BI, Rao SR, et al. Estimates of the number of U.S. women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003;95:526-532.

Gail MH, Constantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829-1846.

Grady D, Cauley JA, Geiger MJ, et al; Raloxifene Use for The Heart Trial Investigators. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100:854-61.

King MC, Wieand S, Hale K, et al. National Surgical Adjuvant Breast and Bowel Project. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251-2256.

Kinsinger LS, Harris R, Woolf SH, et al. Chemoprevention of breast cancer: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:59-67.

Land SR, Wickerham DL, Costantino JP, et al. Patient-Reported Symptoms and Quality of Life During Treatment with Tamoxifen or Raloxifene for Breast Cancer Prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2742-2751.

Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751-1761.

Powles TJ, Ashley S, Tidy A, et al. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007;99:283-290.

Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet. 1998;352:98-101.

U.S. Preventive Services Task Force. Chemoprevention of breast cancer: Recommendations and rationale. Ann Intern Med. 2002;137:56-58.

Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction. J Clin Oncol. 2009;27:3235-3258.

Veronesi U, Maisonneuve P, Rotmensz N, et al, Italian Tamoxifen Study Group. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007;99:727-737.

Veronesi U, Maisonneuve P, Sacchini V, et al. Tamoxifen for breast cancer among hysterectomised women. Lancet. 2002;359:1122-1124.

Vogel VG, Costantino JP, Wickerham DL, et al. Effect of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741.

Last Medical Review: 09/15/2009
Last Revised: 09/15/2009