Wouldn’t it be wonderful if women at increased risk for breast cancer could just take a pill every day for a few years to lower their chance of developing the disease? Actually, there is not one such drug, but two: tamoxifen and raloxifene. Both are selective estrogen-receptor modulators, or SERMs.
A consensus statement from a worldwide group of breast cancer experts, published in Lancet Oncology in 2011, called tamoxifen the current “preventive agent of choice” for most women at high risk. And in 2013 the U.S. Preventive Services Task Force reaffirmed its recommendation that certain women at high risk be prescribed tamoxifen or raloxifene. This was based on a systematic research review done at its request, which found that both drugs can significantly reduce breast cancer risk in high-risk women. A woman’s risk is determined by several factors including her family history, age, and whether she has had a breast biopsy (see box, "Assessing Breast Cancer Risk").
The decision about taking tamoxifen or raloxifene is not quite so simple, however. The drugs have significant risks (tamoxifen more so), and there are still many unknowns.
Time for tamoxifen?
Tamoxifen was approved by the Food and Drug Administration (FDA) in 1977 to treat breast cancer and, subsequently, to prevent recurrences. In 1998 it was also approved to reduce the risk of breast cancer in high-risk women who are 35 and older, regardless of their menopause status. The drug helps prevent the cancer by blocking estrogen activity in breast tissue. The standard recommendation is to take it for five years, as noted in guidelines from the American Society of Clinical Oncology, which were updated in 2013.
Several studies have looked at tamoxifen’s potential for preventing breast cancer. Notably, the Breast Cancer Prevention Trial included more than 13,000 women at increased risk, who took the drug or a placebo for five years. The tamoxifen group had significantly fewer breast cancers than the placebo group, with the benefits seen only for estrogen-receptor-positive cancers (which represent 70 to 80 percent of cases). Tamoxifen use was also associated with a lower incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), which can progress to cancer. The results were so dramatic that the trial was stopped early so that women in the placebo group could also begin taking tamoxifen.
Overall, studies have shown that a five-year course of tamoxifen reduces the risk of breast cancer in high-risk women by 30 to 50 percent, with the benefit lasting at least 10 years. In two small studies, the benefits appeared to be even greater in the years after ending treatment. Another study concluded that the use of tamoxifen for prevention is cost-effective in post-menopausal women under 55.
That’s all good news. On the downside are tamoxifen’s serious side effects. Though it has anti-estrogenic effects in the breast, it has pro-estrogenic effects in other body tissues, notably the uterus, thereby increasing the risk of uterine cancer. It also raises the risk of blood clots in the legs (deep venous thrombosis) and lungs (pulmonary embolism), strokes and cataracts. The risks, which decrease after stopping the drug, are greater in older women, especially those with a history of blood clots or cataracts. Women on tamoxifen who have had a hysterectomy, of course, cannot get uterine cancer, though they can experience the other problems. Other less serious but still troublesome side effects include early menopause, hot flashes, vaginal discharge and mental fogginess (“chemo brain”).
Ready for raloxifene?
Raloxifene (Evista) has been used to prevent and treat osteoporosis in postmenopausal women since the late 1990s. Subsequently, it was discovered that the drug also lowers breast cancer risk. In 2007 the FDA approved it for breast cancer prevention—but, in contrast to tamoxifen, only for use after menopause, simply because it has been studied only in postmenopausal women. Similar to tamoxifen in its antiestrogenic effects in breast tissue, raloxifene appears to be somewhat less beneficial overall—though also less risky. In a clinical trial of 19,000 women, called STAR, it was 76 percent as effective as tamoxifen in preventing invasive breast cancer but was much less likely to cause uterine cancer, blood clots, and cataracts.
Hot flashes and other menopause-related symptoms seem to be lower with raloxifene as well, though users have reported a higher frequency of other side effects, such as musculoskeletal problems (like joint and muscle aches or leg cramps), weight gain, and pain during sexual intercourse. Like tamoxifen, the standard recommendation is to take the drug for five years. One paper noted a significant reduction in breast cancer risk after four years.
SERMS: more concerns and caveats
- The optimal dose, timing and duration of treatment with either medication are still unknown. Some research suggests that taking tamoxifen for 10 years is better for women who have breast cancer, but it’s not known if longer is also better for prevention. Studies have looked only at five years for prevention, which is why that is that standard recommendation.
- Benefits may vary, depending on genetic differences and possibly even dietary factors. The drugs have been tested mostly in white women.
- The drugs do not reduce the risk of estrogen-receptor-negative breast cancer, and their effectiveness in women with a genetic predisposition (notably BRCA gene mutations) is not clear. Moreover, so far prevention studies have not found that the drugs reduce deaths from breast cancer, but the follow-up periods may have been too short to show this.
- Both drugs (particularly raloxifene) have the added benefit of building bones in postmenopausal women—but some research suggests that tamoxifen may reduce bone mass in premenopausal women.
What to do if you're at higher breast cancer risk
If you’re at increased risk for breast cancer, talk to your doctor about whether you’re a good candidate for tamoxifen or raloxifene. You may want to see a breast cancer specialist. You and your doctor should weigh the benefits and risks carefully.
The drugs have been underutilized because, as some studies have shown, many doctors have been reluctant to prescribe them. And some women have been reluctant to take them because they may fear the risks more than they appreciate the benefits. It is hoped that the latest Task Force recommendations will encourage more doctors to discuss use of these drugs with their patients. But more research is still needed to better identify which women would have the most benefit and the least harm.
Neither drug should be taken by women who have a history of blood clots or stroke, including mini-strokes (TIAs); are on blood thinners; are pregnant (or planning to become pregnant) or breastfeeding; have uncontrolled hypertension; or are on hormonal birth control or hormone therapy (which would generally be contraindicated in high-risk women anyway). Smokers should not take the drugs, since smoking further increases the risk of blood clots.
Because tamoxifen’s risks increase in older women, this drug is perhaps best prescribed before a woman goes into menopause or not long after. Looking for ways to minimize side effects, some researchers are investigating the use of lower doses or transdermal administration. In contrast, raloxifene should be taken only after menopause.
Other drugs, including aromatase inhibitors (approved for breast cancer treatment) are also being investigated for their preventive potential. Based on preliminary research, some of these may one day prove to be as good as, if not better than, tamoxifen and raloxifene in their risk/benefit profiles.
Several online tools assess breast cancer risk. A good one is the Breast Cancer Risk Assessment Tool from the National Cancer Institute, which calculates a woman’s risk of developing breast cancer over the next five years, as well as lifetime risk.