Medicines to Reduce Breast Cancer Risk

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Tamoxifen and raloxifene

Tamoxifen and raloxifene belong to a class of drugs known as selective estrogen response modifiers (or SERMs). This means that they act against the female hormone, estrogen, in some tissues of the body, but act like estrogen in others.

Both drugs are approved for use in the US to lower the risk of breast cancer. They both act against estrogen in the breast, which is why they are useful in reducing the risk of breast cancer. Other SERMs being studied and used in other countries, won’t be discussed in detail here.

Tamoxifen

The main use of tamoxifen is to treat hormone receptor-positive breast cancer (breast cancer with cells that have estrogen and/or progesterone receptors on them). When given after a cancer that is hormone receptor-positive has been completely removed by surgery, tamoxifen lowers the chance that the cancer will come back later and helps patients live longer. It also lowers the chance that a new cancer will develop in the other breast.

Because tamoxifen was able to lower the chance of a new breast cancer occurring in women with breast cancer, doctors tested it to see if it could lower the chance of breast cancer in women who hadn’t had breast cancer but were at risk for it. Studies showed that, in women at high risk for breast cancer, tamoxifen lowered their relative risk up to 50% (one-half). (See below, “What’s relative risk?) This led to tamoxifen being approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women who have an increased risk of breast cancer (and are 35 or older).

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 sometimes called an anti-estrogen. But actually, while it acts as an anti-estrogen in the breast, it acts like estrogen in other tissues, such as the bones and the lining of the uterus (the endometrium).

This drug may be used by women whether or not they have gone through menopause. It’s taken once a day, most often as a pill. Its brand names are Nolvadex® and Soltamox®.

Tamoxifen can rarely cause some serious side effects. Its pro-estrogen effects can lead to cancer of the uterus and problems with serious blood clots, including stroke. (See the section “Weighing risks versus benefits” for more information.)

Raloxifene

Raloxifene (Evista®) is a drug that was first approved by the FDA to prevent and treat osteoporosis (bone thinning) in women past menopause.

Raloxifene helps make bones stronger by acting like estrogen in bone tissue. Like tamoxifen, it also acts as an anti-estrogen in breast tissue. Because it doesn’t act much like estrogen in the uterus, it has a much lower risk of causing cancer of the uterus than tamoxifen. It may also cause fewer problems with serious blood clots.

Because it has less serious side effects, it was tested to see if it, too, could lower breast cancer risk. These studies showed that it works almost as well as tamoxifen, lowering the relative risk of breast cancer by up to about 40% (see “What’s relative risk?”). This led to the approval of raloxifene by the FDA to help reduce breast cancer risk in women who have an increased risk of the disease. It was also found to lower breast cancer risk in women who have osteoporosis but not an increased risk of breast cancer, so it is approved for this group as well.

It is only approved for use in women past menopause because it was only studied in these women. It’s also taken once a day.

How much do these drugs lower the risk of breast cancer?

To understand the effect of these drugs on breast cancer risk, it helps to understand what we mean by relative and absolute risk.

What’s relative risk?

An important note about risk reduction: any medicine that reduces a person’s risk of a certain cancer type by 50% sounds like a no-brainer – cutting your risk by half must be a good thing. But what that means to you depends on what your baseline risk is – what your risk would be without the drug. The 50% number actually refers to relative risk, and to know how much the person’s risk changes (the absolute risk reduction) you must know that person’s baseline risk of that cancer.

For example, if a group of people are considered at high risk of a certain cancer, they may have a 4% risk over the next 5 years -- meaning that of those 100 people, 4 of them are expected to get that cancer. A 50% relative risk reduction means that the risk would be lowered to 2% - or 2 cases in 100 people over the next 5 years. So having the relative risk lowered by 50% would mean the absolute risk went from 4% to 2%. The absolute risk reduction would be 2%. This may be a good thing, but it is not as dramatic as it might first sound when you hear 50%.

Tamoxifen

The Breast Cancer PreventionTrial: Much of what we know about the effect of tamoxifen on breast cancer risk comes from the Breast Cancer Prevention Trial (BCPT). It began in the early 1990s and was sponsored by the National Cancer Institute (NCI).

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 of about equal size. 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 about 7 years total, the study compared the women taking the placebo to those who took tamoxifen:

  • Those taking tamoxifen had a lower risk of invasive breast cancer overall. There were 145 cases of breast cancer in the tamoxifen group compared with 250 cases in the placebo group.
  • The risk of breast cancer in the tamoxifen group was cut in half during the first 5 years of the study (while they got the drug), with less improvement in risk during the next 2 years (after the drug was stopped).
  • The lower risk in the tamoxifen group was only seen for estrogen receptor (ER)-positive breast cancers. The rate of ER-negative breast cancer was the same in both groups.
  • The tamoxifen group had a lower risk of non-invasive breast cancer; 38 women had ductal carcinoma in situ (DCIS) in the tamoxifen group and 70 in the placebo group.
  • During the 7-year follow-up, there was no major difference between the groups 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 number of women who died (from any cause) was also about the same in the placebo and tamoxifen groups.

A number of other studies have also looked at tamoxifen for breast cancer risk reduction, including the IBIS-I study, the Royal Marsden study, and the Italian Tamoxifen Prevention study. When data from all 4 of these trials were taken together, they showed that tamoxifen lowered the relative risk of invasive breast cancer by about one-third. Again, tamoxifen has no effect on ER-negative breast cancers, but ER-positive cancers were cut by almost half (decreased by 45%) in these studies compared to groups not taking the drug. (See section “What’s relative risk?”)

The evidence clearly shows that tamoxifen can reduce the risk of ER-positive breast cancer. But the studies did not show any effect on death rates, either from breast cancer or any other cause.

Raloxifene

Studies of raloxifene include the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, the Raloxifene Use for the Heart (RUTH) trial, and the Continuing Outcomes Relevant to Evista (CORE) trial. All of these studies compared raloxifene to placebo (sugar pill) in women past menopause.

Taken together, these 3 studies showed a relative risk of invasive breast cancer of more than half (59%).The studies showed about a 70% relative reduction in the risk of ER-positive breast cancer. (See section “What’s relative risk?”)

The Study of Tamoxifen and Raloxifene (STAR): The largest study to look at the effect of raloxifene on breast cancer risk was the STAR trial. This study compared the effects of tamoxifen and raloxifene on breast cancer risk in more than 19,000 women past menopause who had an 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 breast cancer, although tamoxifen seemed to reduce the risk more.

Looking at all of the selective estrogen response modifier (SERM) studies

A 2013 analysis put together the data from well-controlled studies (combining all of the studies mentioned above with a couple of newer ones), totaling more than 80,000 women. The investigators concluded that SERM drugs lowered breast cancer risk by 38% over a period of 10 years -- the 5 years of taking the drug plus the next 5 years.

Based on the rate of breast cancer in the studies in the analysis, this would translate to about 1 case of invasive breast cancer being prevented for every 53 women taking a SERM drug. If you include non-invasive breast cancers such as DCIS, only about 42 women must take SERMs for 5 years to prevent 1 case of breast cancer (based on a 10 year risk of breast cancer of around 6%).

For a group of women with higher risk, the number that would need to be treated would be much lower. You would need to treat many more women to prevent one breast cancer if the group started out with a lower risk. Note that some of the SERMs used in this large analysis are only available in Europe, but most of the women took tamoxifen and raloxifene.

Studies continue to show that SERMs don’t reduce the risk of ER-negative breast cancers. These cancers are more common in younger women and those with BRCA1 mutations.

Although these drugs haven’t specifically been studied in women with BRCA mutations, it isn’t clear how helpful they are in those women. In the BCPT trial, tamoxifen didn’t seem to help women with BRCA1 genetic mutations, but did seem to help those with BRCA2 mutations.

These studies were not designed to find differences in death rates between the groups taking the SERMs and the placebos, and no differences were observed. So far, women who took SERMs had no survival advantage (did not live longer), although more follow-up is needed.

Are there other benefits to taking these drugs?

Both tamoxifen and raloxifene can help prevent osteoporosis, a weakening of the bones that can happen to women after menopause. In addition to its use as a breast cancer risk reduction measure, raloxifene is approved by the FDA to treat or prevent osteoporosis.


Last Medical Review: 06/04/2013
Last Revised: 07/17/2013