Women at Increased Risk for Breast Cancer Should Be Offered Medications to Reduce Risk, Draft Recommendations Advise 

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When we have good data, we can make better health-care choices.

—Heidi D. Nelson, MD, MPH

Clinicians should engage in shared decision-making with women who are at increased risk of breast cancer about using medications, such as tamoxifen and raloxifene (Evista), to reduce risk, and should offer prescriptions to women considered at low risk for adverse effects from these medications, advises a draft recommendation statement from the U.S. Preventive Services Task Force (USPSTF).1 The statement also reaffirms the USPSTF’s 2002 recommendation against the routine use of tamoxifen or raloxifene to reduce breast cancer risk in women at low or average risk.

The USPSTF updated draft recommendation statement is consistent with positions of other organizations, including ASCO, which has recommended offering tamoxifen to women at increased risk for breast cancer, or raloxifene to postmenopausal women at increased risk. (While tamoxifen has been approved by the U.S. Food and Drug Administration [FDA] for reducing breast cancer risk in women of any age, raloxifene is approved for postmenopausal women only.) The public comment period for the draft recommendation closed on May 13, and the final statement is expected to take several months.

The draft recommendation statement is based on updated evidence on the risks and benefits of these medications from seven randomized, controlled trials—four comparing tamoxifen and placebo, two comparing raloxifene and placebo, and one comparing tamoxifen and raloxifene, the Study of Tamoxifen and Raloxifene (STAR). The review and meta-analysis of these trials, published in the Annals of Internal Medicine,2 concluded that both medications reduced the incidence of invasive breast cancer and fractures and increased the risk of thromboembolic events. Tamoxifen was more effective than raloxifene in reducing breast cancer risk, but also increased the risk of endometrial cancer and cataracts.

Confidence in Results

Heidi D. Nelson, MD, MPH, the lead author of the review that was conducted at the Pacific Northwest Evidence-based Practice Center at Oregon Health & Science University, noted that the studies were done well, “We have confidence in the results of the trials and that they can support the recommendations.” Dr. Nelson is Research Professor of Medical Informatics and Clinical Epidemiology and Medicine at Oregon Health & Science University and Medical Director of Cancer Prevention and Screening at Providence Health & Services in Portland.

In an interview with The ASCO Post, Dr. Nelson noted that it was unusual to have numerous, large, high-quality prevention trials. “When we have good data, we can make better health-care choices. It is important to critically evaluate the evidence before making practice recommendations,” Dr. Nelson said.

“The placebo-controlled primary prevention trials indicate that tamoxifen and raloxifene reduce the incidence of invasive breast cancer by 7 to 9 cases per 1,000 women over a 5-year period, primarily by reducing estrogen receptor–positive breast cancer. New results from STAR show that tamoxifen has a greater effect than raloxifene by reducing breast cancer [even further],” according to the evidence review. The head-to-head trial of tamoxifen and raloxifene “resolved some of the gray areas,” Dr. Nelson said, and helped “refine a more detailed description of the differences between the medications.”

The evidence review found that raloxifene reduced the risk of vertebral fractures by 7 cases per 1,000 women, while tamoxifen reduced the risk of nonvertebral fractures by 3 cases per 1,000 women. Both medications increased the risk of thromboembolic events, although tamoxifen increased the risk of such events by 4 more per 1,000 than did raloxifene. Tamoxifen, but not raloxifene, increased the risk of endometrial cancer and cataracts. Older women had more endometrial cancer and thromboembolic events than did women younger than 50.

The most commonly reported side effects were vasomotor symptoms, vaginal discharge, itching, and dryness for tamoxifen and vasomotor symptoms and leg cramps for raloxifene. The head-to-head trial, however, found that tamoxifen users had more gynecologic problems, vasomotor symptoms, leg cramps, and bladder control symptoms, and that raloxifene users had more musculoskeletal problems, dyspareunia, and weight gain.

‘The Tricky Part’

While the evidence review provided robust estimates of the benefits and harms of tamoxifen and raloxifene, “the tricky part is finding the right candidate,” Dr. Nelson said. Finding the ideal candidate would mean determining on an individual basis who is at highest risk of invasive breast cancer and most likely to benefit from a risk-reduction medication, but is at low risk of adverse effects from the medication.

The task force draft recommendation statement calls for the development of models to more precisely predict which women will not only have a high probability of developing breast cancer, but also have a low probability of thromboembolic and other medication-related events. Such models, however, do not currently exist. Current risk-stratification models are largely based on the National Cancer Institute’s Breast Cancer Risk Assessment Tool (Gail model).

“The original Gail model included age, age at menarche, age of first birth, family history of breast cancer in first-degree relatives, number of previous breast biopsies, and history of atypical hyperplasia,” according to the evidence review. Although the Gail model has been used to define high risk in many breast cancer trials, “on a woman-to-woman basis, it is not a good predictor,” Dr. Nelson said.

Subsequent models include one or more of the Gail model variables in addition to factors such as race, previous false-positive mammograms or benign breast disease, body mass index or height, estrogen and progestin use, history of breastfeeding, menopause status or age, smoking, alcohol use, physical activity, education, mammographic breast density, and diet. Reviewing 19 studies that have evaluated 13 different risk-stratification models, Dr. Nelson and coauthors found that most models “performed only slightly better than age alone as a risk predictor.”

She pointed out, “There are a few risk factors shown to be more important in the trials.” These include a personal history of a high-risk breast lesion, such as atypical ductal hyperplasia, and a family history with a high number of breast cancers. “A woman with a previous high-risk lesion is in a unique situation, and a model doesn’t necessarily have to be used to identify her.” According to the task force draft recommendation statement, the “models are not recommended for use in women with a personal history of breast cancer, a history of radiation treatment to the chest, or a possible family history of mutations in the BRCA1 or BRCA2 genes.”

Side Effects Are Deterrents

Women who are older and have a personal or family history of thromboembolic events are at higher risk for these events, but in general, the adverse effects of tamoxifen and raloxifene are hard to predict. In addition, “when considering a medication to reduce risk rather than to treat illness, it is important to factor the potential harms into the decision, because the women are healthy and we want to avoid making them unhealthy,” Dr. Nelson said. “The equation is different from when the patient has cancer and might more readily assume certain risks in order to be treated for the disease.” In a study of women with elevated breast cancer risk scores, 77% declined tamoxifen, most citing adverse effects.

Even side effects that are not life-threatening, but merely unpleasant, can be a deterrent. “If you are not feeling well because of the nuisance effects, 5 years of use may be intolerable,” Dr. Nelson commented. In the primary prevention trials of tamoxifen and raloxifene reporting adherence, “at least 70% of women used the planned treatment dose,” according to the evidence review. “Part of this high adherence rate is the result of women enrolled in trials being more committed than the average patient.  However, it also indicates that many patients persist with treatment, suggesting that the nuisance effects are tolerable for many women,” Dr. Nelson said.

Reluctance to Prescribe Medications

Three studies found that physicians’ recommendations were important influences on patients’ decisions to use risk-reduction medications, but a survey mailed to physicians found that only 27% of responding physicians had prescribed tamoxifen for breast cancer risk reduction in the past 12 months. “There has been low usage of these medications for risk reduction,” Dr. Nelson acknowledged. Part of the reason may be “the tendency to avoid drugs if one is healthy and how women view health and prevention in general,” Dr. Nelson stated.

Other health issues may be a higher priority. Physicians may be reluctant to prescribe breast cancer risk-reduction medications to women already taking medication for hypertension and other conditions. “It all comes down to very individualized stories,” Dr. Nelson said. “I think one of the reasons raloxifene may be more acceptable in primary care practices is because it has been used for years for osteoporosis. So it already is something that primary care doctors are familiar with, whereas tamoxifen has always been a drug that primarily oncologists use.”

Physicians who prescribed tamoxifen as well as those who did not mentioned the time needed to address risk and other relevant issues with patients. “It is a complex discussion that could derail an appointment, and it is hard to do well in the course of a routine visit,” Dr. Nelson acknowledged. “A good outcome of our analyses might be that our estimates are useful in these discussions.”

Unanswered Questions

“Not every question is answered by the trials,” Dr. Nelson acknowledged. “For instance, we don’t know the best age for women to take the medications. We don’t have good comparisons across different age or racial groups. There is limited information about premenopausal women.” Since raloxifene is approved for postmenopausal women only, premenopausal women were not included in the head-to-head trial.

The task force draft recommendation statement noted that while tamoxifen and raloxifene have been shown to reduce the risk of hormone receptor–positive breast cancer, these drugs “would not prevent the type of breast cancer that is the most difficult to treat.”

Dr. Nelson noted, “There are additional medications that also reduce risk, but have only been studied in one or two prevention trials so far.” Examples include tiboline, lasofoxifene, and exemestane. Although these agents are not FDA-approved for breast-cancer reduction and were therefore not included in the evidence review, “they may expand clinical options,” according to the report.

Tamoxifen and raloxifene reduced the incidence of invasive breast cancer, but “noninvasive breast cancer incidence and breast cancer–specific and all-cause mortality were not statistically significantly reduced by either medication, although trials were not powered for mortality,” the reviewers reported. Part of the reason for the lack of reduction in mortality is insufficient follow-up time.

“It takes a long time to accrue adequate data to determine mortality outcomes” in cancer prevention trials, Dr. Nelson said. “In these trials, participants are healthy at the beginning of the trial and need to tracked over time to measure mortality effects.”

Other “evidence gaps” include determination of optimal doses and duration. “The ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial recently reported reduced recurrence of estrogen receptor–positive breast cancer and reduced breast cancer–specific and all-cause mortality rates in women with breast cancer after 10 vs 5 years of adjuvant therapy,” the report noted. “Whether a longer course provides a more favorable benefit–harm tradeoff for risk reduction in women without breast cancer has yet to be determined.” ■

Disclosure: Dr. Nelson reported no potential conflicts of interest.


1. Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement (draft). April 2013. Available at Accessed May 14, 2013.

2. Nelson HD, Smith MEB, Griffin JC, et al: Use of medications to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 158:604-614, 2013.

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