FDA Approves Raloxifene for Breast Cancer Prevention
September 20, 2007 In mid-September, the U.S. Food and Drug Administration approved raloxifene (brand name Evista) as a breast cancer prevention treatment for postmenopausal women at high risk of getting the disease. The only other drug currently approved for use as breast cancer prevention is tamoxifen, which can be used by both premenopausal and postmenopausal women.
Tamoxifen and raloxifene, which come in pill form, are both known as SERMS, or selective estrogen receptor modulators. These drugs block estrogen from getting into breast cells. But although they are anti-estrogenic in the breast, they are estrogenic in others parts of the body, such as the uterus and the bones.
Raloxifene has been used since 1997 for the prevention and treatment of osteoporosis. In 1999, after studies had indicated that raloxifene also appeared to reduce the risk of invasive breast cancer, the National Cancer Institute initiated the STAR Trial (Study of Tamoxifen and Raloxifene) to critically evaluate its risks and benefits for breast cancer prevention.
STAR randomized nearly 20,000 high-risk postmenopausal women into two groups. One group took tamoxifen daily for five years. The other group took raloxifene daily for five years. The researchers then looked at how many women in each group developed breast cancer and what side effects they experienced.
The STAR study results were published in June 2006. The study had found that both tamoxifen and raloxifene reduced a woman's risk of developing invasive breast cancer by about 50 percent. Specifically, 167 of the 9745 women in the raloxifene group developed invasive breast cancer compared with 163 of the 9726 women in the tamoxifen group.
Researchers had hoped that raloxifene would result in fewer side effects than tamoxifen, but that was not the case. STAR found that a woman's risk of developing blood clots, stroke, or uterine cancer appeared to be about the same for both drugs. 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. The STAR trial found that 36 of the 9726 women taking tamoxifen developed uterine cancer and 141 developed blood clots compared with 23 cases of uterine cancer and 100 incidents of blood clots in the 9745 women taking raloxifene. (Although the number was lower in the raloxifene group, the difference was not statistically significant, which means it could have happened by chance.)
The STAR trial also found that women who took tamoxifen were more likely to experience hot flashes, vaginal bleeding, bladder control problems, and leg cramps, but that women taking raloxifene were more likely to experience pain during sexual intercourse and joint pain.
Additionally—and unexpectedly—STAR found that tamoxifen was more effective than raloxifene in reducing the incidence of ductal carcinoma in situ (DCIS), which is a precursor to breast cancer, or lobular carcinoma in situ (LCIS), which is a marker of increased risk. Specifically, the study found that 57 of the women in the tamoxifen group developed DCIS or LCIS compared with 81 in the raloxifene group. Why raloxifene would reduce the risk of invasive breast cancer but not DCIS or LCIS isn't clear.
The FDA's approval of raloxifene for breast cancer prevention was based on the STAR trial findings. The FDA's approval covers the use of raloxifene for breast cancer prevention in postmenopausal women. The drug is not approved for use in premenopausal women because it has not been studied in this population. Raloxifene should not be used by women with current or prior blood clots in the legs, lungs, or eyes. And it should not be taken by women who are currently taking the cholesterol-lowering drug cholestyramine (brand names Locholest and Questran) or estrogens.
Susan says:
Women are considered high risk if their breast cancer risk is equivalent to or greater than that of an average 60- to 64-year old woman. (You can assess your risk using the Breast Cancer Risk Assessment Tool http://www.cancer.gov/bcrisktool/on the National Cancer Institute website.) 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. Using tamoxifen or raloxifene cuts this risk in half.
A 50 percent reduction sounds huge, but it has to be put in perspective. If we had a group of 1000 high-risk women in a room, we’d expect 17 of them to develop breast cancer over a five-year period. If we had another roomful of 1000 high-risk women and gave everyone of them tamoxifen or raloxifene for five years, their risk would be cut in half. This means that 8 women instead of 17 would develop breast cancer. If you think about these numbers in the context of the STAR trial, it means that nearly 20,000 women took raloxifene or tamoxifen every day for five years to prevent about 320 cases of invasive breast cancer.
When the FDA approved tamoxifen for use as breast cancer prevention in high-risk women in 1998, many doctors thought that high-risk women would jump at the opportunity to take it. But they didn’t. Only a minority of the estimated 10 million women in the US who are considered high risk for breast cancer are taking tamoxifen.
If we were better at assessing who is high risk or if tamoxifen was actually able to eliminate a woman’s risk of getting breast cancer, we’d undoubtedly see more women using it for prevention. But that’s not the case. Most high-risk women will not get breast cancer. Furthermore, some of the women who take tamoxifen for prevention will still go on to get breast cancer. So, to put it bluntly, many women decided that they didn’t wants to die of a blood clot because they took a drug to prevent a disease they might not have gotten anyway.
So, where does this leave us? We now have two drugs available for breast cancer prevention. Raloxifene doesn’t decrease the incidence of DCIS or LCIS, which means that it does differ from tamoxifen—but we’re not yet sure how. This also means that although raloxifene has a slightly different side-effect profile, it is not better than tamoxifen.
Whether the fact that there are now two drugs approved for breast cancer prevention will increase women’s interest in these medications remains to be seen. My guess is that women who are taking raloxifene to prevent and treat osteoporosis are probably happy to know that it is also reducing their risk of invasive breast cancer. But I don’t expect that the millions of women who chose to not take tamoxifen because of its side effects will suddenly be interested in raloxifene.
References:
Vogel VG, Costantino JP, et al. Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association. 2006;295, posted online June 5, 2006
http://jama.ama-assn.org/cgi/content/full/295.23.joc60074v1
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