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Clinical Guidelines |

Medications for Risk Reduction of Primary Breast Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement FREE ONLINE FIRST

Virginia A. Moyer, MD, MPH, on behalf of the U.S. Preventive Services Task Force*
[+] Article and Author Information

* For a list of the members of the USPSTF, see the Appendix.

This article was published at www.annals.org on 24 September 2013.


From the U.S. Preventive Services Task Force, Rockville, Maryland.

Editor's Note: This is an online-first article. This version will have minor typographical differences from the final, printed version.

Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Financial Support: The USPSTF is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.

Potential Conflicts of Interest: Disclosure forms from USPSTF members can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1993.

Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).


Ann Intern Med. Published online 24 September 2013 doi:10.7326/0003-4819-159-10-201311190-00718
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Description: Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on the use of medications for breast cancer risk reduction.

Methods: The USPSTF reviewed evidence on the effectiveness, adverse effects, and subgroup variations of medications to reduce the risk for breast cancer—specifically, the selective estrogen receptor modulators tamoxifen and raloxifene. The USPSTF also reviewed a meta-analysis of placebo-controlled trials to understand the relative benefits and harms of tamoxifen and raloxifene.

Population: This recommendation applies to asymptomatic women aged 35 years or older without a prior diagnosis of breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ.

Recommendation: The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene. (B recommendation)

The USPSTF recommends against the routine use of medications, such as tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at increased risk for breast cancer. (D recommendation)


The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene. (B recommendation)

See the Clinical Considerations section for additional information about risk factors.

The USPSTF recommends against the routine use of medications, such as tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at increased risk for breast cancer. (D recommendation)

See Figure 1 for a summary of the recommendation and suggestions for clinical practice.

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Figure 1.

Medications for risk reduction of primary breast cancer in women: clinical summary of U.S. Preventive Services Task Force recommendation.

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Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classification of levels of certainty about net benefit.

Table Jump PlaceholderAppendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice 
Table Jump PlaceholderAppendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit 
Importance

Breast cancer is the most common nonskin cancer in women. An estimated 232 340 new cases will be diagnosed in 2013, and 39 620 women will die of the disease (1). In the United States, mortality rates are highest among African American women. Screening for breast cancer may allow for early detection but does not prevent the development of the disease.

Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown in randomized, controlled trials to reduce the risk for estrogen receptor (ER)–positive breast cancer. They have been approved by the U.S. Food and Drug Administration (FDA) for this indication.

Assessment of Breast Cancer Risk Status

Important risk factors for breast cancer include increasing age, family history of breast or ovarian cancer (especially among first-degree relatives and onset before age 50 years), history of atypical hyperplasia or other nonmalignant high-risk breast lesions, previous breast biopsy, and extremely dense breast tissue. A history of these or other risk factors (see the Clinical Considerations) may prompt clinicians to conduct a formal breast cancer risk assessment.

Available risk assessment models can accurately estimate the number of breast cancer cases that may arise in certain study populations, but their ability to accurately predict which women will (and will not) develop the disease is modest. Only a small fraction of women are at increased risk for breast cancer; moreover, only a subset of those women will derive benefit from risk-reducing medications.

Information about the validity, feasibility, and effect of using risk assessment models to identify appropriate candidates for risk-reducing medications in primary care settings is limited (24).

Potential Benefits of Medications for Breast Cancer Risk Reduction

The USPSTF found adequate evidence that treatment with tamoxifen or raloxifene can significantly reduce the relative risk (RR) for invasive ER-positive breast cancer in postmenopausal women who are at increased risk for breast cancer.

A systematic review of clinical trials found that tamoxifen and raloxifene reduced the incidence of invasive breast cancer by 7 to 9 events per 1000 women over 5 years and that tamoxifen reduced breast cancer incidence more than raloxifene (Table) (57). Tamoxifen also reduces the incidence of invasive breast cancer in premenopausal women who are at increased risk for the disease.

Table Jump PlaceholderTable. Summary of Primary Prevention Trials 

Women who are at increased risk for breast cancer are more likely to benefit from risk-reducing medications. In general, women with an estimated 5-year risk of 3% or greater are, on the basis of model estimates (Figures 2, 3, 4, and 5) (8), more likely to benefit from tamoxifen or raloxifene. The USPSTF found that the benefits of tamoxifen and raloxifene for breast cancer risk reduction are no greater than small in women who are not at increased risk for the disease.

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Figure 2.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in white non-Hispanic women with uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 3.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in white non-Hispanic women without uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 4.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in black women with uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 5.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in black women without uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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In addition to breast cancer risk reduction, the USPSTF found adequate evidence that tamoxifen and raloxifene reduce the risk for nonvertebral and vertebral fractures, respectively, in postmenopausal women.

Potential Harms of Medications for Breast Cancer Risk Reduction

The USPSTF found adequate evidence that tamoxifen and raloxifene increase risk for venous thromboembolic events (VTEs) by 4 to 7 events per 1000 women over 5 years and that tamoxifen increases risk more than raloxifene (Table) (57). The USPSTF found that potential harms from thromboembolic events are small to moderate, with increased potential for harms in older women.

The USPSTF also found adequate evidence that tamoxifen but not raloxifene increases risk for endometrial cancer (4 more cases per 1000 women). Potential harms from tamoxifen-related endometrial cancer are small to moderate and depend on hysterectomy status and age. The potential risks for tamoxifen-related harms are higher in women older than 50 years and in women with a uterus. Tamoxifen may also increase the incidence of cataracts.

Vasomotor symptoms (hot flashes), a common adverse effect of both medications that is not typically classified as serious, may affect a patient's quality of life and willingness to use or adhere to these medications.

USPSTF Assessment

The USPSTF concludes with moderate certainty that there is a moderate net benefit from use of tamoxifen and raloxifene to reduce the incidence of invasive breast cancer in women who are at increased risk for the disease.

The USPSTF concludes with moderate certainty that the potential harms of tamoxifen and raloxifene outweigh the potential benefits for breast cancer risk reduction in women who are not at increased risk for the disease.

Patient Population Under Consideration

This recommendation applies to asymptomatic women aged 35 years or older without a prior diagnosis of breast cancer, ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS). Neither tamoxifen nor raloxifene should be used in women who have a history of thromboembolic events (deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack). The USPSTF has issued separate recommendations for women with BRCA gene mutations (available at www.uspreventiveservicestaskforce.org).

Assessment of Breast Cancer Risk

If a family history of breast cancer or a personal history of breast biopsy is found during the usual patient assessment, clinicians may consider further evaluation using a breast cancer risk assessment tool. Risk assessment tools specifically for family history of breast cancer are available elsewhere (www.uspreventiveservicestaskforce.org).

The National Cancer Institute has developed a Breast Cancer Risk Assessment Tool (available at www.cancer.gov/bcrisktool) that is based on the Gail model and estimates the 5-year incidence of invasive breast cancer in women on the basis of characteristics entered into a risk calculator. This tool helps identify women who may be at increased risk for the disease. Other risk assessment models have been developed by the Breast Cancer Surveillance Consortium (BCSC), Rosner and Colditz, Chlebowski, Tyrer and Cuzick, and others (57).

Examples of risk factors elicited by risk assessment tools include patient age, race or ethnicity, age at menarche, age at first live childbirth, personal history of DCIS or LCIS, number of first-degree relatives with breast cancer, personal history of breast biopsy, body mass index, menopause status or age, breast density, estrogen and progestin use, smoking, alcohol use, physical activity, and diet.

These 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. Only a small fraction of women are at increased risk for breast cancer. Most who are at increased risk will not develop the disease, and most cases will arise in women who are not identified as being at increased risk. Risk assessment should be repeated when there is a significant change in breast cancer risk factors.

There is no single cutoff for defining increased risk. Most clinical trials defined increased risk as a 5-year risk for invasive breast cancer of 1.66% or greater, as determined by the BCPT (Breast Cancer Prevention Trial). At this cutoff, however, many women would not have a net benefit from risk-reducing medications. Freedman and colleagues (8) developed risk tables that incorporate the BCPT estimate of a woman's breast cancer risk as well as her age, race or ethnicity, and presence of uterus.

On the basis of the Freedman risk–benefit tables for women aged 50 years or older (Figures 2, 3, 4, and 5), the USPSTF concludes that many women with an estimated 5-year breast cancer risk of 3% or greater are likely to have more benefit than harm from using tamoxifen or raloxifene, although the balance depends on age, race or ethnicity, the medication used, and whether the patient has a uterus (8).

Assessment of Risk for Adverse Effects

In general, women receiving medications for breast cancer risk reduction are less likely to have a VTE if they are younger and have no other predisposition to thromboembolic events. Women with a personal or family history of venous thromboembolism are at higher risk for these adverse effects.

Women without a uterus are not at risk for tamoxifen-related endometrial cancer. Women with a uterus should have a baseline gynecologic examination before treatment with tamoxifen is started, with regular follow-up after the end of treatment.

Medications for Breast Cancer Risk Reduction

Selective estrogen receptor modulators (tamoxifen and raloxifene) have been shown to reduce the incidence of invasive breast cancer in several randomized, controlled trials. Tamoxifen has been approved for this use in women aged 35 years or older, and raloxifene has been approved for this use in postmenopausal women.

The usual daily doses for tamoxifen and raloxifene are 20 mg and 60 mg, respectively, for 5 years. Aromatase inhibitors (exemestane) have not been approved by the FDA for this indication and are therefore beyond the scope of this recommendation.

Tamoxifen is not recommended for use in combination with hormone therapy or hormonal contraception or in women who are pregnant, those who may become pregnant, or breastfeeding mothers.

Other Approaches to Prevention

The USPSTF recommendation on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer can be found at www.uspreventiveservicestaskforce.org. Clinical trials of tamoxifen and raloxifene have not been conducted specifically in women who are BRCA mutation carriers.

Other Resources

The National Cancer Institute provides information about potential ways to prevent cancer, including lifestyle and diet changes (available at www.cancer.gov/cancertopics/pdq/prevention/breast/Patient and www.cdc.gov/cancer/breast/basic_info/prevention.htm).

The USPSTF does not endorse any particular risk prediction model. However, the BCPT model (www.cancer.gov/bcrisktool) and the BCSC model (https://tools.bcsc-scc.org/BC5yearRisk) can be used by clinicians and patients as part of the process of shared, informed decision making. Both models have been calibrated in U.S. populations.

Implementation

In order to identify patients for whom the potential benefits of risk-reducing medications may outweigh the potential risks, clinicians should first identify those who may be at increased risk for breast cancer (see Assessment of Breast Cancer Risk).

Clinicians may use this opportunity to educate all women about their risk for breast cancer. Studies have shown that women tend to overestimate their risk for the disease.

For women whose 5-year projected risk for breast cancer is 3% or greater, clinicians should identify those for whom the potential benefits of risk-reducing medications may outweigh the potential risks. In doing so, clinicians should consider the woman's age, comorbid conditions, presence of uterus, and risks for thromboembolic or medication-related adverse events. Clinicians may refer to risk–benefit tables to complement clinical assessment (Figures 2, 3, 4, and 5) (89).

Clinicians should clearly discuss the potential benefits and risks of risk-reducing medications with women for whom the former may outweigh the latter. Clinicians should then strive to ensure that patients make a fully informed decision that incorporates their personal values and preferences, including their concerns about breast cancer and specific medication-related adverse events.

Research Needs and Gaps

Research to improve the ability to assess and accurately predict a woman's chance of developing breast cancer over a defined period is needed. The ideal candidates for risk-reducing medications are women who have not only a high probability of developing breast cancer over a defined period but also a low probability of thromboembolic and other medication-related adverse events. Models that can more precisely predict both of these events should be developed.

Clinical trials that provide more information about the safety and effectiveness of other medications for breast cancer risk reduction, such as aromatase inhibitors and tibolone, are needed. The aromatase inhibitor exemestane reduced the incidence of invasive breast cancer in postmenopausal women who were at moderately increased risk for the disease. There were no significant differences in the incidence of osteoporosis, cardiovascular events, other types of cancer, or death. However, these findings were reported from a randomized, clinical trial with a median follow-up of 3 years and will require long-term assessment. IBIS-II (International Breast Cancer Intervention Study II), an ongoing British study, is comparing the aromatase inhibitor anastrozole with placebo in women who are at increased risk for breast cancer.

Additional research could help clarify the optimum treatment duration, timing, and dose. Future studies should examine the benefits and harms of risk-reducing medications in racially diverse patient populations.

Burden of Disease

Breast cancer is the most common nonskin cancer in women. According to the National Cancer Institute, 12.4% (1 in 8) of women born today will be diagnosed with breast cancer during their lifetime (10). Between 2005 and 2009, the median age at diagnosis was 61 years, and the median age at death from the disease was 68 years. The age-adjusted mortality rate was 23.0 deaths per 100 000 women per year, with higher mortality rates among African American women (31.6 deaths per 100 000 women per year) (10).

Scope of Review

The USPSTF reviewed evidence on the effectiveness, adverse effects, and subgroup variations of medications to reduce the risk for breast cancer—specifically, the selective estrogen receptor modulators tamoxifen and raloxifene (57). The USPSTF reviewed randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer, precursor conditions, or known breast cancer susceptibility mutations. The USPSTF also reviewed a meta-analysis of placebo-controlled trials to understand the relative benefits and harms of tamoxifen and raloxifene (7).

Effectiveness of Risk Assessment

To understand the effectiveness of breast cancer risk assessment, the USPSTF reviewed 13 breast cancer risk assessment models that can be used in primary care. The original Gail model, the first to be used clinically, includes age, age at menarche, age at first childbirth, family history of breast cancer in first-degree relatives, number of prior breast biopsies, and history of atypical hyperplasia. Expanding on the Gail model, newer models include race or ethnicity, prior false-positive mammography results 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, breast density, and diet. Several models have been tested in large U.S. populations in studies that received good quality ratings but reported only modest accuracy. The BCSC Barlow model was derived from more than 11 638 breast cancer cases that developed among a cohort of almost 2.4 million women (11). The Rosner–Colditz model was derived from 1761 breast cancer cases that developed among 58 520 participants in the Nurses' Health Study (12). Chlebowski and colleagues developed a model based on 3236 cases that developed in the Women's Health Initiative study (13). Breast cancer risk assessment models from Italy and the United Kingdom were also based on large populations but were not tested in the United States.

All models predicted probabilities of breast cancer that were in general agreement with observed risk. Models had the best calibration in women older than 60 years, those who received annual breast cancer screening, and those with ER-positive breast cancer. However, most had a false-positive rate of 55% to 66%, indicating modest accuracy in predicting risk for individuals.

Information about the validity, feasibility, and effect of using risk assessment models to identify appropriate candidates for risk-reducing medications in primary care settings is limited (24).

Effectiveness of Risk-Reducing Medications

To understand the effectiveness of risk-reducing medications for breast cancer, the USPSTF reviewed 7 large randomized, controlled trials of breast cancer outcomes in women without preexisting breast cancer (57). Other relevant study outcomes included death, fractures, thromboembolic events, cardiovascular disease events, uterine abnormalities, cataracts, and other adverse effects.

STAR (Study of Tamoxifen and Raloxifene) was a head-to-head comparison of tamoxifen versus raloxifene with more than 9800 patients in each study group (1415). Four studies compared tamoxifen with placebo: NSABP-1 (National Surgical Adjuvant Breast and Bowel Project) (1619), IBIS-I (2021), the Royal Marsden Hospital trial (2223), and the Italian Tamoxifen Prevention Study (2427). Two studies compared raloxifene with placebo: the Multiple Outcomes of Raloxifene Evaluation study, with long-term follow-up in the Continuing Outcomes Relevant to Evista study (2841), and the Raloxifene Use for the Heart trial (4243). These were all multicenter trials that were relevant to primary care. They enrolled between 2471 and 19 747 women, predominantly in North America, Europe, and the United Kingdom. All trials met criteria for fair or good quality as well as high applicability to the U.S. primary care population.

For STAR, eligibility criteria included having a 5-year predicted breast cancer risk of 1.66% or greater; median follow-up was 81 months (15). For the placebo-controlled trials involving tamoxifen, eligibility criteria and duration of follow-up varied. Eligibility criteria for NSABP-1 included having a 5-year predicted breast cancer risk of 1.66% or greater, and median follow-up was about 7 years (16). Eligibility criteria for IBIS-I included having an estimated 10-year risk of 5% or greater; median follow-up was 96 months (21). For the Royal Marsden Hospital (23) and Italian Tamoxifen Prevention (27) trials, eligibility criteria did not include a prespecified breast cancer risk threshold, and median follow-up was 13 and 11 years, respectively. For placebo-controlled trials involving raloxifene (Multiple Outcomes of Raloxifene Evaluation and Continuing Outcomes Relevant to Evista), eligibility criteria did not include a prespecified breast cancer risk threshold; together, these trials provided 8 years of follow-up (39).

In placebo-controlled trials, tamoxifen and raloxifene significantly reduced the risk for invasive breast cancer (tamoxifen RR, 0.70 [95% CI, 0.59 to 0.82] [16, 21, 23, 26, 39]; raloxifene RR, 0.44 [CI, 0.27 to 0.71] [39, 42]). In STAR, tamoxifen reduced breast cancer more than raloxifene (raloxifene RR, 1.24 [CI, 1.05 to 1.47]) (14).

Both medications reduced breast cancer in all subgroups studied, although trial data for racial subgroups were not available. Tamoxifen reduced breast cancer outcomes in subgroups based on age, menopausal status, estrogen use, family history of breast cancer, and history of LCIS or atypical ductal hyperplasia. In NSABP-1, tamoxifen was most effective in preventing invasive breast cancer in high-risk groups, including women with LCIS, atypical ductal hyperplasia, the highest Gail risk scores, and the greatest number of relatives with breast cancer (16). Raloxifene reduced breast cancer outcomes in subgroups based on age, age at menarche, parity, age at first live childbirth, and body mass index. Effect estimates for raloxifene were limited by small sample size for subgroups based on prior estrogen use, family history of breast cancer, and prior hysterectomy or oophorectomy. Specific risk factors may be more useful than risk calculators in certain clinical settings.

Both medications reduced breast cancer risk in postmenopausal women. Tamoxifen also reduced the incidence of invasive breast cancer in premenopausal women who were at increased risk for the disease. Risk reduction with tamoxifen was greatest in women with 3 or more first-degree relatives with breast cancer, LCIS, or atypical hyperplasia.

Reduction of invasive breast cancer continued for at least 3 to 5 years after discontinuation of tamoxifen in the 2 trials providing posttreatment follow-up data. Neither medication significantly reduced the risk for ER-negative breast cancer, noninvasive breast cancer, or all-cause mortality. In the placebo-controlled trials and STAR, raloxifene reduced vertebral fractures (RR, 0.61 [CI, 0.54 to 0.69]) (32, 42), whereas tamoxifen reduced nonvertebral fractures (RR, 0.66 [CI, 0.45 to 0.98]) (17). Tamoxifen and raloxifene had similar effects on vertebral fractures in STAR (44).

The USPSTF could not assess the effect of these medications on mortality attributed to breast cancer or other causes. The effects of tamoxifen and raloxifene on mortality were not statistically significant in the clinical trials, which did not have sufficient long-term follow-up for this outcome. Although there is convincing evidence that these medications can reduce the incidence of invasive breast cancer (predominantly ER-positive cancer), whether reductions in breast cancer incidence lead to a corresponding reduction in mortality is unclear.

The USPSTF also considered meta-analysis summary calculations of the number of events reduced per 1000 women in placebo-controlled trials, assuming 5 years of treatment (Table) (7). Both medications reduced the incidence of invasive breast cancer, with 7 fewer events per 1000 women for tamoxifen (4 trials) and 9 fewer events per 1000 women for raloxifene (2 trials). When compared head-to-head in STAR, tamoxifen reduced breast cancer incidence by 5 more events per 1000 women than raloxifene. Compared with placebo, raloxifene reduced the incidence of vertebral fractures by 7 events per 1000 women (2 trials), whereas tamoxifen reduced the incidence of nonvertebral fractures by 3 events per 1000 women (1 trial). There were no significant differences in vertebral fractures when the drugs were compared head-to-head in STAR.

Potential Harms of Risk Assessment and Preventive Medications

No studies reported on the potential harms of breast cancer risk assessment in primary care settings. Clinical trials provided evidence on the potential harms of tamoxifen and raloxifene (57). Study outcomes included thromboembolic events, uterine abnormalities, cardiovascular disease events, cataracts, and other adverse effects.

In most trials, both tamoxifen and raloxifene nearly doubled the risk for all VTEs compared with placebo (tamoxifen RR, 1.93 [CI, 1.41 to 2.64] [17, 21, 2324]; raloxifene RR, 1.60 [CI, 1.15 to 2.23] [42, 45]). Tamoxifen increased risk for VTEs more than raloxifene in STAR. Risk returned to normal after discontinuation of tamoxifen in the 2 trials providing posttreatment data.

Compared with placebo, tamoxifen was associated with more cases of endometrial cancer (RR, 2.13 [CI, 1.36 to 3.32]) (17, 21, 23); more benign gynecologic conditions (21, 46); surgical procedures, including hysterectomy (21, 23, 46); and uterine bleeding (21, 46). Women without a uterus are not at increased risk for tamoxifen-related endometrial cancer. Raloxifene did not increase risk for endometrial cancer or uterine bleeding. In STAR, raloxifene was associated with fewer cases of endometrial cancer than tamoxifen (RR, 0.55 [CI, 0.36 to 0.83]) (14).

Tamoxifen and raloxifene did not increase risk for coronary heart disease events or stroke (16, 21, 23, 2627, 42). However, in 1 trial that was specifically designed to ascertain cardiovascular outcomes in postmenopausal women who had or were at increased risk for coronary heart disease, stroke mortality was higher with raloxifene than placebo (absolute increase, 0.7 events per 1000 women per year) (42).

Compared with women receiving placebo, those receiving tamoxifen more frequently had cataract surgery in 1 trial (17), although cataract risk was not increased in a meta-analysis of 3 tamoxifen trials (RR, 1.25 [CI, 0.93 to 1.67]) (16, 21, 23). Raloxifene did not increase risk for cataracts or cataract surgery compared with placebo (42, 45) and caused fewer cataracts than tamoxifen in STAR (14).

The most commonly reported adverse effects in these trials were vasomotor symptoms and vaginal discharge, itching, or dryness for tamoxifen and vasomotor symptoms and leg cramps for raloxifene. In STAR, raloxifene users reported more musculoskeletal problems, dyspareunia, and weight gain, whereas tamoxifen users had more gynecologic problems, vasomotor symptoms, leg cramps, and bladder control symptoms.

The USPSTF also considered meta-analysis summary calculations of the number of adverse health events per 1000 women caused by these medications in placebo-controlled trials, assuming 5 years of treatment (Table) (7). Tamoxifen was associated with 4 VTEs per 1000 women (4 trials), whereas raloxifene was associated with 7 VTEs per 1000 women (2 trials). Tamoxifen increased thromboembolic events by 4 more events per 1000 women than raloxifene in STAR. Tamoxifen was also associated with 4 cases of endometrial cancer per 1000 women (3 trials).

Risk Perception and Decision Making

In studies describing how women decide whether to take medications to reduce risk for primary breast cancer, women had substantial concerns about potential serious adverse events, especially when they were informed of the medications' risks and benefits. In 1 study of women who were at increased risk for breast cancer, only 12% selected tamoxifen for risk reduction; most (77%) declined, primarily because of concerns about serious adverse events and small therapeutic benefit (3). Women who were interested in receiving risk-reducing medications often overestimated their own risk for breast cancer (that is, erroneously thought they were at high risk). Women placed great emphasis on recommendations from their physicians.

Estimate of Magnitude of Net Benefit

One breast cancer risk model found that for many women with an increased 5-year risk for breast cancer, the benefits of risk-reducing medication outweigh the potential harms (Figures 2, 3, 4, and 5) (8). Whether there is a net benefit depends on a woman's risk for breast cancer, age, and race and whether she has a uterus. Accordingly, the USPSTF's recommendations are different for women with low risk for breast cancer than for those with high risk.

The USPSTF concludes with moderate certainty that medications to reduce risk for breast cancer confer moderate net benefit in women who are at increased risk for the disease. Tamoxifen is associated with moderate benefit, with adequate evidence for risk reduction of invasive breast cancer. Raloxifene is associated with slightly smaller benefit for breast cancer risk reduction but no risk for endometrial cancer. The USPSTF found adequate evidence of small benefit for reduction of nonvertebral fractures with tamoxifen, whereas raloxifene reduces vertebral fractures.

The USPSTF found adequate evidence of small to moderate risk for medication-associated VTEs (depending on age), as well as small to moderate risk for medication-associated endometrial cancer with tamoxifen (depending on hysterectomy status and age).

The USPSTF concludes that both tamoxifen and raloxifene confer a benefit no greater than small, with moderate harms, for women who are not at increased risk for breast cancer.

How Does Evidence Fit With Biological Understanding?

Tamoxifen and raloxifene are selective estrogen receptor modulators. Because ER-positive cancer is believed to be more amenable to therapy than ER-negative cancer, these medications would not prevent the type of breast cancer that is most difficult to treat.

Response to Public Comments

A draft version of this recommendation statement was posted for public comment on the USPSTF Web site from 16 April through 13 May 2013. In response to public comment and in consideration of FDA-approved indications, the USPSTF provided more information about the target patient population for this recommendation. The USPSTF clarified that the recommendation applies to asymptomatic women aged 35 years or older without a prior diagnosis of breast cancer, DCIS, or LCIS. The final recommendation statement further clarifies that raloxifene has been approved for breast cancer risk reduction in postmenopausal women and that other groups of women should not use tamoxifen. The USPSTF reiterated that only a small fraction of women are candidates for and would derive benefit from risk-reducing medications.

The USPSTF also provided a more comprehensive list of breast cancer risk factors and links to additional resources in response to comments, as well as summary tables to help readers understand the risk–benefit balance of these medications, links to online breast cancer risk assessment models, and updated recommendations of other groups.

In 2002, the USPSTF issued a B recommendation for clinicians to discuss risk-reducing medications with women who are at high risk for breast cancer and at low risk for medication adverse effects. The USPSTF issued a D recommendation against the routine use of tamoxifen or raloxifene for breast cancer risk reduction in women who are at low or average risk.

This recommendation reaffirms the USPSTF's 2002 recommendation and provides updated evidence on the risks and benefits of risk-reducing medications for women who are at increased risk for breast cancer.

In 2013, the American Society of Clinical Oncology recommended that tamoxifen should be discussed as an option to reduce risk for ER-positive breast cancer in women aged 35 years or older who are at increased risk for breast cancer. It also recommended that raloxifene and exemestane should be discussed as options for breast cancer risk reduction in postmenopausal women (47). In 2013, the National Institute for Health and Care Excellence recommended that clinicians offer tamoxifen or raloxifene for 5 years to postmenopausal women with a uterus who are at high risk for breast cancer unless they have a history of or may be at increased risk for thromboembolic disease or endometrial cancer (48). The guideline also included recommendations for different age and risk groups. In 2011, the American Cancer Society recommended that women who are considering medications for breast cancer risk reduction should discuss their personal health situations with their physicians (49). In 2001, the Canadian Task Force on Preventive Health Care recommended that women who are at high risk for breast cancer should receive counseling about the risks and benefits of tamoxifen for cancer prevention; it found fair evidence to recommend against the use of tamoxifen in women who are at low or normal risk for breast cancer (50).

Appendix: U.S. Preventive Services Task Force

Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized† are Virginia A. Moyer, MD, MPH, Chair (American Board of Pediatrics, Chapel Hill, North Carolina); Michael L. LeFevre, MD, MSPH, Co-Vice Chair (University of Missouri School of Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Sinai School of Medicine, New York, and James J. Peters Veterans Affairs Medical Center, Bronx, New York); Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens, Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Francisco A.R. García, MD, MPH (Pima County Department of Health, Tucson, Arizona); Adelita Gonzales Cantu, RN, PhD (University of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); Douglas K. Owens, MD, MS (Veterans Affairs Palo Alto Health Care System, Palo Alto, and Stanford University, Stanford, California); William R. Phillips, MD, MPH (University of Washington, Seattle, Washington); and Michael P. Pignone, MD, MPH (University of North Carolina, Chapel Hill, North Carolina).

† For a list of current Task Force members, go to www.uspreventiveservicestaskforce.org/members.htm.

National Cancer Institute.  Breast Cancer. Bethesda, MD: National Cancer Institute; 2013. Accessed at www.cancer.gov/cancertopics/types/breast on 16 August 2013.
 
Brewster AM, Christo DK, Lai H, Helzlsouer K.  Breast carcinoma chemoprevention in the community setting. Estimating risks and benefits. Cancer. 2005;103:1147-53. [PMID: 15674856]
 
Armstrong K, Quistberg DA, Micco E, Domchek S, Guerra C.  Prescription of tamoxifen for breast cancer prevention by primary care physicians. Arch Intern Med. 2006;166:2260-5. [PMID: 17101945]
 
Owens WL, Gallagher TJ, Kincheloe MJ, Ruetten VL.  Implementation in a large health system of a program to identify women at high risk for breast cancer. J Oncol Pract. 2011;7:85-8. [PMID: 21731514]
 
Nelson HD, Fu R, Griffin JC, Nygren P, Smith ME, Humphrey L.  Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Ann Intern Med. 2009;151:703-15, W-226-35. [PMID: 19920271]
 
Nelson HD, Fu R, Humphrey L, Smith ME, Griffin JC, Nygren P.  Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women. Comparative Effectiveness Review no. 17. AHRQ publication no. 09-EHC028-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK36430 on 16 August 2013.
 
Nelson HD, Smith ME, Griffin JC, Fu R.  Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:604-14. [PMID: 23588749]
 
Freedman AN, Yu B, Gail MH, Costantino JP, Graubard BI, Vogel VG, et al.  Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol. 2011;29:2327-33. [PMID: 21537036]
 
Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al.  Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829-46. [PMID: 10547390]
 
National Cancer Institute.  SEER Stat Fact Sheets: Breast. Bethesda, MD: National Cancer Institute; 2013. Accessed at http://seer.cancer.gov/statfacts/html/breast.html on 16 August 2013.
 
Tice JA, Cummings SR, Smith-Bindman R, Ichikawa L, Barlow WE, Kerlikowske K.  Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med. 2008;148:337-47. [PMID: 18316752]
 
Colditz GA, Rosner B.  Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol. 2000;152:950-64. [PMID: 11092437]
 
Chlebowski RT, Anderson GL, Lane DS, Aragaki AK, Rohan T, Yasmeen S, et al; Women's Health Initiative Investigators.  Predicting risk of breast cancer in postmenopausal women by hormone receptor status. J Natl Cancer Inst. 2007;99:1695-705. [PMID: 18000216]
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; National Surgical Adjuvant Breast and Bowel Project.  Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706. [PMID: 20404000]
 
Vogel VG, Costantino JP, Wickerham DL, McCaskill-Stevens W, Clarfeld RB, Grant MD, et al.  Carcinoma in situ outcomes in National Surgical Adjuvant Breast and Bowel Project Breast Cancer Chemoprevention Trials. J Natl Cancer Inst Monogr. 2010;2010:181-6. [PMID: 20956826]
 
Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al.  Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-62. [PMID: 16288118]
 
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-88. [PMID: 9747868]
 
Day R; National Surgical Adjuvant Breast and Bowel Projet P-1 study (NSABP-1).  Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci. 2001;949:143-50. [PMID: 11795346]
 
Day R, Ganz PA, Costantino JP.  Tamoxifen and depression: more evidence from the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention (P-1) Randomized Study. J Natl Cancer Inst. 2001;93:1615-23. [PMID: 11698565]
 
Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al; IBIS investigators.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360:817-24. [PMID: 12243915]
 
Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al; International Breast Cancer Intervention Study I Investigators.  Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-82. [PMID: 17312304]
 
Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al.  Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101. [PMID: 9672274]
 
Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M.  Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007;99:283-90. [PMID: 17312305]
 
Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, et al; Italian Tamoxifen Study Group.  Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation. 2005;111:650-6. [PMID: 15699284]
 
Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al.  Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998;352:93-7. [PMID: 9672273]
 
Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al; Italian Tamoxifen Study Group.  Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007;99:727-37. [PMID: 17470740]
 
Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, et al; Italian Tamoxifen Study Group.  Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst. 2003;95:160-5. [PMID: 12529349]
 
Barrett-Connor E, Cauley JA, Kulkarni PM, Sashegyi A, Cox DA, Geiger MJ.  Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. J Bone Miner Res. 2004;19:1270-5. [PMID: 15231013]
 
Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al; MORE Investigators (Multiple Outcomes of Raloxifene Evaluation).  Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287:847-57. [PMID: 11851576]
 
Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, et al.  Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001;65:125-34. [PMID: 11261828]
 
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-97. [PMID: 10376571]
 
Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al; Mulitple Outcomes of Raloxifene Evaluation Investigators.  Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609-17. [PMID: 12161484]
 
Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, et al.  Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33:522-32. [PMID: 14555255]
 
Duvernoy CS, Kulkarni PM, Dowsett SA, Keech CA.  Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene. Menopause. 2005;12:444-52. [PMID: 16037760]
 
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al.  Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-45. [PMID: 10517716]
 
Johnell O, Cauley JA, Kulkarni PM, Wong M, Stock JL.  Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy. J Fam Pract. 2004;53:789-96. [PMID: 15469774]
 
Keech CA, Sashegyi A, Barrett-Connor E.  Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Curr Med Res Opin. 2005;21:135-40. [PMID: 15881485]
 
Lippman ME, Cummings SR, Disch DP, Mershon JL, Dowsett SA, Cauley JA, et al.  Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk. Clin Cancer Res. 2006;12:5242-7. [PMID: 16951244]
 
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al; CORE Investigators.  Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751-61. [PMID: 15572757]
 
Silverman SL, Delmas PD, Kulkarni PM, Stock JL, Wong M, Plouffe L Jr.  Comparison of fracture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis. J Am Geriatr Soc. 2004;52:1543-8. [PMID: 15341559]
 
Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, et al; Continuing Outcomes Relevant to Evista (CORE) Investigators.  Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res. 2005;20:1514-24. [PMID: 16059623]
 
Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators.  Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-37. [PMID: 16837676]
 
Grady D, Cauley JA, Geiger MJ, Kornitzer M, Mosca L, Collins P, et al; Raloxifene Use for The Heart Trial Investigators.  Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100:854-61. [PMID: 18544744]
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP).  Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-41. [PMID: 16754727]
 
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al; Multiple Outcomes of Raloxifene Evaluation Investigators.  Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104:837-44. [PMID: 15458908]
 
Chalas E, Costantino JP, Wickerham DL, Wolmark N, Lewis GC, Bergman C, et al.  Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol. 2005;192:1230-7. [PMID: 15846210]
 
Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, et al.  Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:2942-62. [PMID: 23835710]
 
National Institute for Health and Care Excellence.  Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People With a Family History of Breast Cancer. London: National Institute for Health and Care Excellence; 2013. Accessed at http://publications.nice.org.uk/familial-breast-cancer-cg164 on 16 August 2013.
 
American Cancer Society.  Medicines to Reduce Breast Cancer Risk. Atlanta, GA: American Cancer Society; 2013. Accessed at www.cancer.org/cancer/breastcancer/moreinformation/medicinestoreducebreastcancer/medicines-to-reduce-breast-cancer-risk-toc on 16 August 2013.
 
Levine M, Moutquin JM, Walton R, Feightner J; Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.  Chemoprevention of breast cancer. A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ. 2001;164:1681-90. [PMID: 11450210]
 

Figures

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Figure 1.

Medications for risk reduction of primary breast cancer in women: clinical summary of U.S. Preventive Services Task Force recommendation.

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Figure 2.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in white non-Hispanic women with uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 3.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in white non-Hispanic women without uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 4.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in black women with uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Figure 5.

Benefit–risk indices for tamoxifen and raloxifene chemoprevention in black women without uterus, by age group and level of 5-y projected risk for invasive breast cancer.

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Tables

Table Jump PlaceholderAppendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice 
Table Jump PlaceholderAppendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit 
Table Jump PlaceholderTable. Summary of Primary Prevention Trials 

References

National Cancer Institute.  Breast Cancer. Bethesda, MD: National Cancer Institute; 2013. Accessed at www.cancer.gov/cancertopics/types/breast on 16 August 2013.
 
Brewster AM, Christo DK, Lai H, Helzlsouer K.  Breast carcinoma chemoprevention in the community setting. Estimating risks and benefits. Cancer. 2005;103:1147-53. [PMID: 15674856]
 
Armstrong K, Quistberg DA, Micco E, Domchek S, Guerra C.  Prescription of tamoxifen for breast cancer prevention by primary care physicians. Arch Intern Med. 2006;166:2260-5. [PMID: 17101945]
 
Owens WL, Gallagher TJ, Kincheloe MJ, Ruetten VL.  Implementation in a large health system of a program to identify women at high risk for breast cancer. J Oncol Pract. 2011;7:85-8. [PMID: 21731514]
 
Nelson HD, Fu R, Griffin JC, Nygren P, Smith ME, Humphrey L.  Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Ann Intern Med. 2009;151:703-15, W-226-35. [PMID: 19920271]
 
Nelson HD, Fu R, Humphrey L, Smith ME, Griffin JC, Nygren P.  Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women. Comparative Effectiveness Review no. 17. AHRQ publication no. 09-EHC028-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK36430 on 16 August 2013.
 
Nelson HD, Smith ME, Griffin JC, Fu R.  Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:604-14. [PMID: 23588749]
 
Freedman AN, Yu B, Gail MH, Costantino JP, Graubard BI, Vogel VG, et al.  Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol. 2011;29:2327-33. [PMID: 21537036]
 
Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, et al.  Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829-46. [PMID: 10547390]
 
National Cancer Institute.  SEER Stat Fact Sheets: Breast. Bethesda, MD: National Cancer Institute; 2013. Accessed at http://seer.cancer.gov/statfacts/html/breast.html on 16 August 2013.
 
Tice JA, Cummings SR, Smith-Bindman R, Ichikawa L, Barlow WE, Kerlikowske K.  Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med. 2008;148:337-47. [PMID: 18316752]
 
Colditz GA, Rosner B.  Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol. 2000;152:950-64. [PMID: 11092437]
 
Chlebowski RT, Anderson GL, Lane DS, Aragaki AK, Rohan T, Yasmeen S, et al; Women's Health Initiative Investigators.  Predicting risk of breast cancer in postmenopausal women by hormone receptor status. J Natl Cancer Inst. 2007;99:1695-705. [PMID: 18000216]
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; National Surgical Adjuvant Breast and Bowel Project.  Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706. [PMID: 20404000]
 
Vogel VG, Costantino JP, Wickerham DL, McCaskill-Stevens W, Clarfeld RB, Grant MD, et al.  Carcinoma in situ outcomes in National Surgical Adjuvant Breast and Bowel Project Breast Cancer Chemoprevention Trials. J Natl Cancer Inst Monogr. 2010;2010:181-6. [PMID: 20956826]
 
Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al.  Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-62. [PMID: 16288118]
 
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-88. [PMID: 9747868]
 
Day R; National Surgical Adjuvant Breast and Bowel Projet P-1 study (NSABP-1).  Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci. 2001;949:143-50. [PMID: 11795346]
 
Day R, Ganz PA, Costantino JP.  Tamoxifen and depression: more evidence from the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention (P-1) Randomized Study. J Natl Cancer Inst. 2001;93:1615-23. [PMID: 11698565]
 
Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al; IBIS investigators.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360:817-24. [PMID: 12243915]
 
Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al; International Breast Cancer Intervention Study I Investigators.  Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:272-82. [PMID: 17312304]
 
Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al.  Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101. [PMID: 9672274]
 
Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M.  Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007;99:283-90. [PMID: 17312305]
 
Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, et al; Italian Tamoxifen Study Group.  Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation. 2005;111:650-6. [PMID: 15699284]
 
Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, et al.  Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998;352:93-7. [PMID: 9672273]
 
Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al; Italian Tamoxifen Study Group.  Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007;99:727-37. [PMID: 17470740]
 
Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, et al; Italian Tamoxifen Study Group.  Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst. 2003;95:160-5. [PMID: 12529349]
 
Barrett-Connor E, Cauley JA, Kulkarni PM, Sashegyi A, Cox DA, Geiger MJ.  Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. J Bone Miner Res. 2004;19:1270-5. [PMID: 15231013]
 
Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al; MORE Investigators (Multiple Outcomes of Raloxifene Evaluation).  Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002;287:847-57. [PMID: 11851576]
 
Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, et al.  Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001;65:125-34. [PMID: 11261828]
 
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-97. [PMID: 10376571]
 
Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al; Mulitple Outcomes of Raloxifene Evaluation Investigators.  Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609-17. [PMID: 12161484]
 
Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, et al.  Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33:522-32. [PMID: 14555255]
 
Duvernoy CS, Kulkarni PM, Dowsett SA, Keech CA.  Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene. Menopause. 2005;12:444-52. [PMID: 16037760]
 
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al.  Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-45. [PMID: 10517716]
 
Johnell O, Cauley JA, Kulkarni PM, Wong M, Stock JL.  Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy. J Fam Pract. 2004;53:789-96. [PMID: 15469774]
 
Keech CA, Sashegyi A, Barrett-Connor E.  Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Curr Med Res Opin. 2005;21:135-40. [PMID: 15881485]
 
Lippman ME, Cummings SR, Disch DP, Mershon JL, Dowsett SA, Cauley JA, et al.  Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk. Clin Cancer Res. 2006;12:5242-7. [PMID: 16951244]
 
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al; CORE Investigators.  Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751-61. [PMID: 15572757]
 
Silverman SL, Delmas PD, Kulkarni PM, Stock JL, Wong M, Plouffe L Jr.  Comparison of fracture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis. J Am Geriatr Soc. 2004;52:1543-8. [PMID: 15341559]
 
Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, et al; Continuing Outcomes Relevant to Evista (CORE) Investigators.  Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res. 2005;20:1514-24. [PMID: 16059623]
 
Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators.  Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-37. [PMID: 16837676]
 
Grady D, Cauley JA, Geiger MJ, Kornitzer M, Mosca L, Collins P, et al; Raloxifene Use for The Heart Trial Investigators.  Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100:854-61. [PMID: 18544744]
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP).  Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-41. [PMID: 16754727]
 
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al; Multiple Outcomes of Raloxifene Evaluation Investigators.  Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104:837-44. [PMID: 15458908]
 
Chalas E, Costantino JP, Wickerham DL, Wolmark N, Lewis GC, Bergman C, et al.  Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol. 2005;192:1230-7. [PMID: 15846210]
 
Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, et al.  Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:2942-62. [PMID: 23835710]
 
National Institute for Health and Care Excellence.  Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People With a Family History of Breast Cancer. London: National Institute for Health and Care Excellence; 2013. Accessed at http://publications.nice.org.uk/familial-breast-cancer-cg164 on 16 August 2013.
 
American Cancer Society.  Medicines to Reduce Breast Cancer Risk. Atlanta, GA: American Cancer Society; 2013. Accessed at www.cancer.org/cancer/breastcancer/moreinformation/medicinestoreducebreastcancer/medicines-to-reduce-breast-cancer-risk-toc on 16 August 2013.
 
Levine M, Moutquin JM, Walton R, Feightner J; Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.  Chemoprevention of breast cancer. A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ. 2001;164:1681-90. [PMID: 11450210]
 

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Summary for Patients

Medications for Risk Reduction of Primary Breast Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement

 Description:Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on the use of medications for breast cancer risk reduction. Methods:The USPSTF reviewed evidence on the effectiveness, adverse effects, and subgroup variations of medications to reduce the risk for breast cancer—specifically, the selective estrogen receptor modulators tamoxifen and raloxifene. The USPSTF also reviewed a meta-analysis of placebo-controlled trials to understand the relative benefits and harms of tamoxifen and raloxifene. Population:This recommendation applies to asymptomatic women aged 35 years or older without a prior diagnosis of breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ. Recommendation:The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications, such as tamoxifen or raloxifene. (B recommendation) The USPSTF recommends against the routine use of medications, such as tamoxifen or raloxifene, for risk reduction of primary breast cancer in women who are not at increased risk for breast cancer. (D recommendation)

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