Dr. Susan Love Research Foundation | Breast Cancer

Raloxifene, a drug currently used to prevent osteoporosis, has been found to work as well as tamoxifen does in reducing breast cancer in high-risk postmenopausal women.

The findings come from the Study of Tamoxifen and Raloxifene (STAR) trial. The clinical trial, which began in 1999, enrolled 19,747 women at high risk for developing breast cancer. Half of the women were randomized to receive the breast cancer drug tamoxifen. The other half received raloxifene (brand name Evista). None of the women, or their doctors, knew which drug they were taking.

All of the women enrolled in the study were postmenopausal, at least 35 years old, and at high risk for developing breast cancer. After the women had taken the drug daily for an average of almost four years, the researchers found that a statistically equivalent number of breast cancers developed in both groups. Among the 9,745 women in the raloxifene group, 167 developed invasive breast cancer, while among the 9,726 women in the tamoxifen group, 163 developed the disease. These numbers indicated that tamoxifen and raloxifene were equally effective at reducing breast cancer and that both cut the risk of developing breast cancer in half.

To determine to what extent tamoxifen and raloxifene decreased breast cancer risk, the researchers compared the number of women who developed breast cancer with the number of women who would have been expected to develop breast cancer if they had not been taking a drug for prevention. For every 1,000 women similar to those enrolled in the STAR trial, about 40 would have been expected to develop breast cancer within five years. This means that in a group of 9,000 women, about 360 would have been expected to develop the disease. Since the STAR trial found that only about half this number of women taking tamoxifen or raloxifene developed breast cancer, the researchers concluded that each drug reduced a woman's risk of developing invasive breast cancer by about 50 percent.

Serious side effects associated with tamoxifen include uterine cancer, blood clots, strokes, and cataracts. Tamoxifen can also cause menopause-like symptoms such as hot flashes and vaginal discharge or bleeding. One of the goals of the STAR trial was to assess the long-term effects of raloxifene. One known serious side effect of raloxifene is blood clots. It can also cause menopause-like symptoms such as hot flashes and vaginal dryness as well as joint pain or leg cramps.

The STAR trial found that raloxifene was less likely than tamoxifen to cause uterine cancer and blood clots. However, this difference was not statistically significant. Tamoxifen is known to double a woman's risk of developing uterine cancer to a rate of about 2 cases per 1,000 women per year. Women who took raloxifene had 36 percent fewer uterine cancers: 36 of 4,732 women in the tamoxifen group developed uterine cancer compared to 23 of the 4,712 women in the raloxifene group. The trial found that the women who took raloxifene had 29 percent fewer blood clots: 141 of 9,726 women in the tamoxifen group developed a blood clot compared with 100 of the 9,745 women in the raloxifene group. Women in both groups experienced an equivalent number of strokes, heart attacks, and bone fractures.

Both tamoxifen and raloxifene, which come as pills, are known as SERMs, or selective estrogen receptor modulators. These drugs, which are only effective in women with hormone-sensitive (estrogen and/or progesterone receptor-positive) tumors, work by blocking estrogen from getting into the breast cells.

Tamoxifen is widely used to treat metastatic breast cancer and to reduce the risk of recurrence in women with early stage disease. In October 1998, it became the first drug approved by the US Food and Drug Administration (FDA) to reduce breast cancer risk in women at high risk for developing the disease. Raloxifene was approved by the FDA for use in the treatment of osteoporosis in 1997 and for osteoporosis prevention in 1999. The STAR trial was initiated after large studies testing the effectiveness of raloxifene in preventing osteoporosis found that women taking the drug developed fewer breast cancers than women taking a placebo.

All STAR participants had an increased risk of breast cancer equivalent to or greater than that of an average 60- to 64-year-old woman. In that age group, 1.66 percent of women—or about 17 of every 1,000 women—would be expected to develop breast cancer within five years. The average risk of breast cancer in the women who chose to enter STAR was about twice as high as this minimum risk. Risk was assessed using the Breast Cancer Risk Assessment Tool. The tool assesses breast cancer risk based on age, family history, reproductive history, number of breast biopsies a woman has had and whether atypical hyperplasia was found, and a woman's age at her first period and at menopause. For the STAR trial, women were also considered high risk if they had previously been diagnosed with lobular carcinoma in situ (LCIS).

Eli Lilly, the pharmaceutical company that makes raloxifene, said it will seek FDA approval to market raloxifene for breast cancer prevention. Women can find more information about future breast cancer prevention clinical trials on the National Surgical Adjuvant Breast and Bowel Project website.

Susan says:

We've known for a long time that tamoxifen increases the risk of uterine cancer and blood clots. Such side effects take on unique significance when a drug is being used to reduce a woman's risk of developing a disease—in this case breast cancer—as opposed to treating a disease a woman already has. That's because not all women at high risk for getting breast cancer will go on to get the disease. And who wants to die of a blood clot because they took a drug to prevent a disease they wouldn't have gotten anyway?

The problem is that we don't know which women who are high risk will go on to get breast cancer. That's why some women are interested in taking a drug to reduce their breast cancer risk. And that's why it's very important that women fully understand the risks and benefits associated with any drug used for breast cancer prevention.

The STAR trial found that a postmenopausal woman at high risk for developing breast cancer could reduce her risk of getting the disease by 50 percent if she took either raloxifene or tamoxifen. This is what this means in real numbers: If you had a group of 1,000 women at high risk for developing invasive breast cancer and followed them for five years, you'd expect about 40 of them to develop breast cancer. If these women took tamoxifen or raloxifene for the five years you were following them, about 20 (rather than 40) would develop breast cancer.

The finding that raloxifene is equivalent to tamoxifen in reducing the risk of invasive breast cancer was not unexpected and it supports what the osteoporosis studies observed. What was unexpected was the finding that raloxifene, unlike tamoxifen, does not prevent ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS), which are the precursors to invasive breast cancer. In the STAR trial, among the 9,726 women in the tamoxifen group, 57 developed LCIS or DCIS, compared to 81 of 9,745 women in the raloxifene group. Why raloxifene would reduce the risk of invasive breast cancer but not LCIS or DCIS isn't clear.

What has caught the media's eye is the finding that the women who took raloxifene were at lower risk of developing blood clots or uterine cancer than the women taking tamoxifen. But lower risk is not the same as no risk. The women who took raloxifene did have an increased risk of uterine cancers and blood clots. It just wasn't as high as the risk that was seen in the women taking tamoxifen. Further—and this is an important issue that the media have tended to overlook—the difference between the number of women in each group who developed side effects was not statistically significant. What does this mean?

It is not enough to judge which drug is better solely by comparing the total number of uterine cancers or blood clots that occurred. In any large study such as this, there is always going to be some difference that is due to chance alone. (If you flip a coin three times, you could get heads three times. That doesn't mean that when you flip a coin you are more likely to get heads. It's just a random occurrence that has happened by chance.) For this reason, researchers use statistical tests that can help to determine the likelihood that a difference between two groups is by chance alone or is in fact a real difference.

In the STAR trial, there was no statistically significant difference between the number of women who developed uterine cancer or blood clots. This means the difference could have just happened by chance, and that there is likely to be no difference in safety between the two drugs. (There was a statistically significant difference between the two groups in the number of women who developed cataracts.)

It is very important that women understand this. The results of this study were presented in a press release and press conference. They have not yet been published in a medical journal. And what they said, the media repeated: "Raloxifene caused less side effects. Raloxifene is the winner!" But it is disingenuous, to say the least, to make that statement given the actual findings of the study. Another problem with the media coverage is that raloxifene has repeatedly been referred to as "the osteoporosis drug." Yes, it has been approved for treating osteoporosis. But tamoxifen is actually just as good as raloxifene is at preventing bone fractures. Further, raloxifene can't prevent all fractures. One large trial found that the drugs were only able to prevent vertebral fractures, and not hip and other fractures.

So, the bottom line is this: We now have two drugs that are about the same. Both reduce breast cancer risk and fractures. And both have side effects. To be sure, it's great that women now have more options. But the results of the STAR study are hardly the breakthrough that the media, the National Cancer Institute, and the pharmaceutical company Eli Lilly, which makes raloxifene, would have you believe.

What should high-risk women do? To date, most high-risk women have been hesitant to take tamoxifen because of its side effects. Whether women will find raloxifene more acceptable remains to be seen. It is not better at reducing the risk of invasive breast cancer risk than tamoxifen, and it doesn't reduce a woman's risk of developing DCIS or LCIS. And while it does have slightly less risk, it's not risk-free. So, to my mind, it doesn't appear that raloxifene will increase the number of women who decide to take a drug to prevent breast cancer. But it does provide a new option for those who are interested in doing so.

What should postmenopausal women with hormone-sensitive breast cancer do? Right now, if you are taking tamoxifen, there is no reason to switch to raloxifene unless you are having side effects. The fact that raloxifene reduces invasive cancer but not DCIS or LCIS means it does differ from tamoxifen, but we're not sure how. This means that we don't have enough information to say that raloxifene should be substituted for tamoxifen. That said, raloxifene has always been and remains a good option for women who can't tolerate an aromatase inhibitor and who want to avoid tamoxifen because they are at high risk for developing blood clots or uterine cancer.

Another group of women who may want to consider raloxifene are those who are taking a bisphosphonate, like alendronate (brand name Fosamax) to prevent osteoporosis. For these women, raloxifene may be an option because it can help reduce breast cancer risk while increasing bone density.