The US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious 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.

Importance

Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death.^1,2 The median age at diagnosis is 62 years,¹ and an estimated 1 in 8 women will develop breast cancer at some point in their lifetime.² African American women are more likely to die of breast cancer compared with women of other races.¹

Assessment of Breast Cancer Risk Status

The USPSTF found convincing evidence that available risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer over time. Overall, the USPSTF determined that the net benefit of taking medications to reduce risk of breast cancer is larger in women who have a greater risk for developing breast cancer.

Potential Benefits of Risk-Reducing Medications

The USPSTF found convincing evidence that risk-reducing medications (tamoxifen, raloxifene, or aromatase inhibitors) provide at least a moderate benefit in reducing risk for invasive estrogen receptor (ER)–positive breast cancer in postmenopausal women at increased risk for breast cancer (Table).

Both tamoxifen and raloxifene can reduce risk of some types of skeletal fractures, independent from the risk of breast cancer.

The USPSTF found that the benefits of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk for breast cancer are no greater than small in women not at increased risk for the disease.

Potential Harms of Risk-Reducing Medications

The USPSTF found convincing evidence that tamoxifen and raloxifene are associated with small to moderate harms. Tamoxifen and raloxifene increase risk for venous thromboembolic events (VTEs); tamoxifen increases risk more than raloxifene (Table), and the potential for harms are greater in older women than in younger women. The USPSTF also found adequate evidence that tamoxifen, but not raloxifene, increases risk for endometrial cancer in women with a uterus. Tamoxifen also increases risk of cataracts. Vasomotor symptoms (hot flashes) are a common adverse effect of both medications.

The USPSTF found adequate evidence that the harms of aromatase inhibitors are also small to moderate. These harms include vasomotor symptoms, gastrointestinal symptoms, musculoskeletal pain, and possible cardiovascular events, such as stroke. Aromatase inhibitors do not reduce, and may even increase, risk of fractures.

USPSTF Assessment

The USPSTF concludes with moderate certainty that there is a moderate net benefit from taking tamoxifen, raloxifene, or aromatase inhibitors to reduce risk of invasive breast cancer in women at increased risk.

The USPSTF concludes with moderate certainty that the potential harms of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk of breast cancer outweigh the potential benefits in women not at increased risk for the disease.

Clinicians should discuss the limitations of current clinical risk assessment tools for predicting an individual’s future risk of breast cancer when discussing the benefits and harms of risk-reducing medications with women.

Patient Population Under Consideration

This recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ (DCIS).

Assessment of Risk for Breast Cancer

Various methods are available to identify women at increased risk for breast cancer, including formal clinical risk assessment tools or assessing breast cancer risk factors without using a formal tool.

Numerous risk assessment tools, such as the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool,⁵ estimate a woman’s risk of developing breast cancer over the next 5 years. There is no single cutoff for defining increased risk for all women. Women at greater risk, such as those with at least a 3% risk for breast cancer in the next 5 years, are likely to derive more benefit than harm from risk-reducing medications⁶ and should be offered these medications if their risk of harms is low. Some women at lower risk for breast cancer have also been included in trials documenting reduced risk for breast cancer when taking tamoxifen, raloxifene, or aromatase inhibitors.^3,4 However, when balancing the harms associated with these medications, the net benefit will be lower among women at lower risk.

Alternatively, clinicians may use combinations of risk factors (including some risk factors not included in risk assessment tools but that would have permitted enrollment in some of the risk reduction trials) to identify women at increased risk. Some examples of combinations of multiple risk factors in women at increased risk include (but are not limited to) age 65 years or older with 1 first-degree relative with breast cancer; 45 years or older with more than 1 first-degree relative with breast cancer or 1 first-degree relative who developed breast cancer before age 50 years; 40 years or older with a first-degree relative with bilateral breast cancer; presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy.

Women with documented pathogenic mutations in the breast cancer susceptibility 1 and 2 genes (BRCA1/2) and women with a history of chest radiation therapy (such as for treatment of childhood or adolescent Hodgkin or non-Hodgkin lymphoma) are at especially high risk for breast cancer. The cumulative absolute risk of developing breast cancer in a woman who received chest radiation at age 25 years increases from an estimated 1.4% at age 35 years to an estimated 29% by age 55 years,⁷ although this may vary by treatment regimen. Women who carry a BRCA1 mutation have a cumulative risk for breast cancer of 72% by age 80 years; women who carry a BRCA2 mutation have a 69% cumulative risk⁸ (compared with a 12% lifetime risk in the general population⁹). Women who carry the BRCA1 mutation tend to develop estrogen receptor (ER)–negative breast cancer,¹⁰ while women who carry the BRCA2 mutation tend to develop ER-positive breast cancer. However, the USPSTF was not able to find sufficient evidence on the benefits and harms of risk-reducing medications in women with BRCA1/2 gene mutations or women with a history of chest radiation, and the comprehensive management of these risk factors is beyond the scope of this Recommendation Statement. Further information on comprehensive management strategies, including risk-reducing medications, for women with these conditions is available from other organizations.

Women not at increased risk for breast cancer, such as women younger than 60 years with no additional risk factors for breast cancer, or women with a low 5-year risk of breast cancer should not be routinely offered medications to reduce risk of breast cancer, since the risk of harms from these medications likely outweighs their potential benefit.

Although evidence on the best interval at which to reassess risk and indications for risk-reducing medications is not available, a pragmatic approach would be to repeat risk assessment when there is a significant change in breast cancer risk factors, for instance when a family member is diagnosed with breast cancer or when there is a new diagnosis of atypical hyperplasia or lobular carcinoma in situ on breast biopsy.

When considering prescribing breast cancer risk-reducing medications, potential benefit of risk reduction of breast cancer must be balanced against the potential harms of adverse medication effects. See below for more information on potential harms from risk-reducing medications.

Risk-Reducing Medications

A systematic review of trials conducted for the USPSTF found that compared with placebo, tamoxifen reduced the incidence of invasive breast cancer by 7 events per 1000 women over 5 years (95% CI, 4-12), and raloxifene reduced incidence by 9 events (95% CI, 3-15) per 1000 women over 5 years.^3,4 Given that the study participants in tamoxifen vs placebo and raloxifene vs placebo trials differed with respect to breast cancer risk and age, direct comparisons of effectiveness between tamoxifen and raloxifene cannot be made based on these placebo-controlled trials. However, the large Study of Tamoxifen and Raloxifene (STAR) trial, which directly compared tamoxifen with raloxifene, found that tamoxifen reduced breast cancer risk more than raloxifene after long-term follow-up³ (Table). For women with a predicted 5-year breast cancer risk of 3% or greater, the absolute benefits are likely even higher. Tamoxifen and raloxifene have been found to reduce risk for nonvertebral and vertebral fractures, respectively.³ However, use of tamoxifen and raloxifene is also associated with increased risk for VTEs and vasomotor symptoms. Tamoxifen also increases the risk for endometrial cancer and cataracts. These risks are increased in older women, although women who have had a hysterectomy are not at risk for endometrial cancer.

Aromatase inhibitors were found to reduce the incidence of invasive breast cancer by 16 events per 1000 women over 5 years (Table).³ As with tamoxifen and raloxifene, these absolute benefits are likely even higher for women with a predicted breast cancer risk of 3% or greater. Harms of aromatase inhibitors include vasomotor symptoms, gastrointestinal symptoms, and musculoskeletal pain. Data on harms of aromatase inhibitors for the primary risk reduction of breast cancer are limited, especially long-term harms. A trend toward increased cardiovascular events (such as transient ischemic attack and cerebrovascular accident) has been observed in some aromatase inhibitor trials for treatment of women with early-stage breast cancer (or DCIS).^3,11,12 Younger women with no risk factors for cardiovascular disease are less likely to have a cardiovascular event with aromatase inhibitor treatment. Aromatase inhibitors do not reduce, and may even increase, risk of fractures.

Tamoxifen, raloxifene, and aromatase inhibitors all reduce primary breast cancer risk in postmenopausal women. Use of raloxifene and aromatase inhibitors is indicated only in postmenopausal women; only tamoxifen is indicated for risk-reduction of primary breast cancer in premenopausal women.

Duration of Medication Use and Persistence of Effects

In trials, participants typically used risk-reducing medications for 3 to 5 years.³ Benefits of tamoxifen have been found to persist up to 8 years beyond discontinuation,^13,14 whereas risk for VTEs and endometrial cancer return to baseline after discontinuation of tamoxifen.¹⁵ Data on similarly long-term persistence of effects are not available for raloxifene or aromatase inhibitors.

Additional Approaches to Prevention

The USPSTF has made recommendations on screening for breast cancer¹⁶ and for risk assessment, genetic counseling, and genetic testing for BRCA genetic mutations.¹⁷ The NCI and the Centers for Disease Control and Prevention provide information about potential ways to reduce risk of cancer, including lifestyle and diet changes.^18,19

Useful Resources

The USPSTF does not endorse any particular risk prediction tool. However, the NCI Breast Cancer Risk Assessment Tool⁵ and the Breast Cancer Surveillance Consortium Risk Calculator²⁰ are based on models tested in US populations and are publicly available for clinicians and patients to use as part of the process of shared, informed decision-making about taking risk-reducing medications for breast cancer. Both tools have been calibrated in US populations, but their discriminatory accuracy of predicting which women will develop breast cancer may be more limited and there is no single cutoff for defining increased risk for all women.

Implementation

Prescribing risk-reducing medications for breast cancer is an uncommon practice among primary care clinicians. Based on limited survey data, 10% to 30% (depending on medication type) of primary care clinicians report ever prescribing risk-reducing medications for primary prevention of breast cancer, and most have only done so a few times.^21-23 The reported use of risk-reducing medications among women is also relatively low; 1 meta-analysis of 26 studies found that overall, 16.3% of women at increased risk for breast cancer used risk-reducing medications.²⁴ Although only exploratory, a number of studies have suggested that even women who are well informed about the risks and benefits have relatively little interest in taking risk-reducing medications for breast cancer and are primarily concerned with potential harms.^25-29 When considering prescribing risk-reducing medications for breast cancer, clinicians should discuss each woman’s personal values and preferences with respect to breast cancer risk reduction, in addition to what is known about her personal risk for breast cancer and the potential benefits and harms of medications.

Research Needs and Gaps

More research is needed to better identify which individual women at increased risk for breast cancer could best benefit from risk-reducing medications. In particular, studies are needed that evaluate how medications may reduce breast cancer risk in women who are carriers of pathogenic BRCA1 or BRCA2 mutations. Additionally, given the higher breast cancer mortality rates in African American women, studies that include sufficient numbers of African American women are needed to better understand how medications may reduce risk in these women. Although currently available risk assessment tools can identify the number of cases of breast cancer expected to arise in a given population, better tools for predicting breast cancer risk in individual women are needed. Additionally, longer-term follow-up is needed for studies of raloxifene and aromatase inhibitors to better understand the persistence of both breast cancer risk reduction effects and potential harms from the medications. Longer-term data on harms of aromatase inhibitors for the risk reduction of primary breast cancer are also needed. This information could help clinicians weigh the benefits and harms of individual medications with their patients.

Burden of Disease

Breast cancer is the most common nonskin cancer and the second leading cause of cancer death in women.² In 2018, an estimated 266,120 new cases of breast cancer were diagnosed in women in the United States, representing 30% of all new cancer cases in women.² An estimated 40,920 women in the United States died of breast cancer, representing 14% of all cancer deaths in women.² Based on data from 2008 to 2014, the 5-year survival rate of breast cancer is an estimated 89.7%, ranging from 98.7% when cancer is diagnosed at localized stages to 27% when diagnosis occurs in the context of distant metastases.¹ Although incidence rates are similar among white and African American women (128.6 vs 126.9 cases per 100,000 persons, respectively), mortality rates are higher among African American women (28.7 deaths per 100,000 African American persons vs 20.3 deaths per 100,000 white persons).¹ Incidence rates have increased among Asian/Pacific Islander, non-Hispanic African American, and Hispanic women but have remained stable among non-Hispanic white and American Indian/Alaskan Native women.⁹

Scope of Review

The USPSTF reviewed evidence on the accuracy of risk assessment methods to identify women who could benefit from risk-reducing medications for breast cancer, as well as evidence on the effectiveness, adverse effects, and subgroup variations of these medications (specifically, the selective ER modulators tamoxifen and raloxifene and the aromatase inhibitors exemestane and anastrozole).^3,4 The USPSTF reviewed evidence from randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer or DCIS. Studies that included women with pathogenic BRCA1/2 genetic mutations were included in the review criteria; however, studies to understand the benefits and harms in this population were limited.

Effectiveness of Risk Assessment Models

The USPSTF reviewed evidence from 25 good- and fair-quality studies on 18 risk stratification models (n >5,000,000).^3,4 Models reviewed included the Gail,^30-36 Breast Cancer Surveillance Consortium,^37-39 Rosner-Colditz,^40-43 Tyrer-Cuzick,^44-47 Chlebowski,⁴⁸ and Italian^49-51 models, as well as variations of these models that focus on specific subpopulations or that include newer data on breast density or benign breast disease.³

The original Gail model, the first model used clinically, includes age, age at first menstruation, age at first childbirth, family history of breast cancer in first-degree relatives, number of prior breast biopsies, and history of atypical hyperplasia.³⁰ The current version of the Gail model is used in the Breast Cancer Risk Assessment Tool, which is publicly accessible through the NCI website.⁵ Expanding on the Gail model, newer models include race/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 US populations in good-quality studies that reported only low to modest accuracy. The Breast Cancer Surveillance Consortium model was derived from more than 11,638 breast cancer cases that developed among a cohort of almost 2.4 million women.³⁸ The Rosner-Colditz model was derived from 1761 breast cancer cases that developed among 58,520 participants in the Nurses’ Health Study.⁴⁰ Chlebowski and colleagues⁴⁸ developed a model based on 3236 cases that developed in the Women’s Health Initiative study. Models from Italy^49-51 and the United Kingdom^44-47 were also based on large populations but were not tested in the United States. Although these models demonstrate good calibration for predicting risk in a population (ie, the predicted number of breast cancer cases expected to arise in a population closely matched the observed number of cases), their discriminatory accuracy to correctly classify individual women who will develop breast cancer over the next 5 years from those who will not is modest at best; the C statistic for most models ranged from 0.55 to 0.65.³ Models that include breast density, postmenopausal hormone use, and a more extensive family history minimally improve predictive estimates.

Most models report performance slightly better than age alone as a risk predictor. No studies evaluated optimal ages or frequencies for risk assessment.³

Effectiveness of Risk-Reducing Medications

The USPSTF reviewed evidence from 10 trials that evaluated the effect of risk-reducing medications for breast cancer.^3,4 Four trials (n = 28,193) evaluated tamoxifen in premenopausal and postmenopausal women at increased risk for breast cancer^13-15,52-60 (in 1 additional trial of low-dose tamoxifen in postmenopausal women not at increased risk for breast cancer,⁶¹ the low dose was not found to reduce risk of breast cancer and so was not considered further by the USPSTF); 2 trials (n = 17,806) evaluated raloxifene in postmenopausal women not at increased risk for breast cancer,^62-78 1 trial (n = 19,747) directly compared raloxifene with tamoxifen in postmenopausal women at increased risk for breast cancer (STAR trial^79-81), and 2 trials evaluated aromatase inhibitors (examestane^82,83 [n = 4560] and anastrozole^84-86 [n = 3864]) in postmenopausal women at increased risk for breast cancer. Each of the studies that targeted women at increased risk for breast cancer used different combinations of risk criteria, such as age, family history, previous abnormal but benign breast pathology, or predicted breast cancer risk as estimated by a risk tool (most commonly >1.66% 5-year predicted risk of breast cancer, as calculated by the Gail model) to recruit participants. Women in the raloxifene trials were older (median age, 67-67.5 years)³ than women in the other trials, given that these trials targeted postmenopausal women not at increased risk for breast cancer (the primary aim was for outcomes other than breast cancer risk reduction). In contrast, women in the tamoxifen trials were slightly younger, given that these trials included premenopausal women (median age range, 47-53 years).³ Most trials were multicenter and conducted in numerous sites across several countries, predominantly in the United States, the United Kingdom, and Europe. Most trial participants were white (84%-97% white in studies that reported this information).³

In trials, all 3 types of medications reduced invasive and ER-positive breast cancer but not ER-negative breast cancer.³ Using pooled results of the placebo-controlled trials and projecting benefits over 5 years, the use of tamoxifen would result in 7 fewer cases of invasive breast cancer (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]) and 8 fewer cases of ER-positive breast cancer (RR, 0.58 [95% CI, 0.42-0.81]) (unless otherwise stated, all numbers of cases are per 1000 women over 5 years of medication use).³ Raloxifene use would result in 9 fewer cases of invasive breast cancer (RR, 0.44 [95% CI, 0.24-0.80]) and 8 fewer cases of ER-positive breast cancer (RR, 0.33 [95% CI, 0.15-0.73]).³ Furthermore, in addition to reducing breast cancer risk, tamoxifen and raloxifene were also found to reduce risk for fractures: 3 fewer cases of nonvertebral fractures with tamoxifen (RR, 0.66 [95% CI, 0.45-0.98]) and 7 fewer cases of vertebral fractures with raloxifene (RR, 0.61 [95% CI, 0.53-0.70]).³ Aromatase inhibitors would result in 16 fewer cases of invasive breast cancer (RR, 0.45 [95% CI, 0.26-0.70]) and 15 fewer cases of ER-positive breast cancer (RR, 0.37 [95% CI, 0.19-0.63]).³ Risk reduction of both invasive and ER-positive breast cancer persisted up to 8 years after discontinuation of tamoxifen use in 2 trials^14,15 (data on similar length of long-term follow-up for raloxifene and aromatase inhibitors are not currently available). Effectiveness of medications (within trials) did not vary by age or menopausal status. One trial of tamoxifen⁶⁰ and 1 of anastrazole⁸⁴ found that risk reduction was greater for women with a history of breast abnormalities on biopsy, such as atypical hyperplasia or lobular carcinoma in situ. Most trials that reported on subpopulation results by 5-year predicted risk category (as determined by the Gail model) showed risk reduction across all risk categories,^{3,60,78,80,83} and 1 study of tamoxifen also indicated that risk reduction may be greatest in the highest-risk groups.^3,60

Although comparisons of effectiveness between the 3 medication types (tamoxifen, raloxifene, and aromatase inhibitors) cannot be made because of the different participant characteristics among the placebo-controlled trials, the large STAR trial directly compared tamoxifen with raloxifene for breast cancer risk reduction and found that tamoxifen provided a greater risk reduction for invasive breast cancer on long-term follow-up (5 fewer cases [95% CI, 1-9]).³

Potential Harms of Risk Assessment and Risk-Reducing Medications

The same 10 trials described above that reported on benefits of risk-reducing medications for breast cancer also reported harms.^3,4 When compared with placebo, tamoxifen was associated with 5 more cases of VTEs (RR, 1.93 [95% CI, 1.33-2.68]), 4 more cases of endometrial cancer (RR, 2.25 [95% CI, 1.17-4.41]), and 26 more cases of cataracts (RR, 1.22 [95% CI, 1.08-1.48]).³ Vasomotor symptoms were also increased with tamoxifen use. No significant differences were found with tamoxifen use on rates of deep vein thrombosis, pulmonary embolism, coronary heart disease (CHD) events, or stroke.³

When compared with placebo, raloxifene was associated with 7 more cases of VTE (RR, 1.56 [95% CI, 1.11-2.60]).³ Vasomotor symptoms were also increased with raloxifene use. No significant differences were found with raloxifene use on rates of CHD events, stroke, endometrial cancer, or cataracts. Based on the STAR trial, more harms were reported with tamoxifen compared with raloxifene: 4 more cases of VTE (95% CI, 1-7), 3 more cases of deep vein thrombosis (95% CI, 1-5), 5 more cases of endometrial cancer (95% CI, 2-9), and 15 more cases of cataracts (95% CI, 8-22) with tamoxifen than with raloxifene.³ Both aromatase inhibitor trials reported more vasomotor and musculoskeletal symptoms with aromatase inhibitors compared with placebo.^3,82-84 No significant differences in rates of VTEs, deep vein thrombosis, pulmonary embolism, CHD events, stroke, endometrial cancer, or cataracts were reported for aromatase inhibitors;^3,82-84 however, primary prevention studies were likely underpowered to detect any differences in these outcomes.

Other studies have evaluated the use of aromatase inhibitors for indications other than risk reduction of primary breast cancer. A recent meta-analysis of trials that evaluated extended aromatase inhibitor use for adjuvant treatment in women with early-stage ER-positive breast cancer suggests a potential increase in cardiovascular disease events (odds ratio [OR], 1.18 [95% CI, 1.00-1.40]; 7 studies; n = 16,349) with aromatase inhibitors compared with placebo or no treatment.¹² Another study that compared anastrozole with tamoxifen in treating women with DCIS found a significant increase in cerebrovascular events (OR, 3.36 [95% CI, 1.04-14.18]) and a nonsignificant increase in transient ischemic attacks (OR, 2.69 [95% CI, 0.90-9.65]) with anastrozole.¹¹ Another meta-analysis that evaluated studies of aromatase inhibitors compared with tamoxifen for treatment of early-stage breast cancer found no difference in VTEs, cerebrovascular events, or coronary artery disease events.⁸⁷ Literature from these other studies also suggest that aromatase inhibitors may increase the risk of fractures. Compared with tamoxifen (which reduces risk of fractures), more fractures were seen with aromatase inhibitors.^11,87 The meta-analysis that evaluated extended use of aromatase inhibitors compared with placebo or no treatment also found increased fractures associated with aromatase inhibitors (OR, 1.34 [95% CI, 1.16-1.55]); however, some of the participants who received placebo or no treatment in the extended treatment period may have received tamoxifen or raloxifene during the initial treatment period.¹² Given that these studies focused on treatment of women with breast cancer or DCIS and were often conducted in comparison with tamoxifen rather than placebo, it is unclear whether these findings are generalizable to a primary prevention population.

Estimate of Magnitude of Net Benefit

Whether risk-reducing medications provide a net benefit depends on a woman’s risk for breast cancer, balanced with the potential for harms from the medications. Accordingly, the USPSTF recommendation for women at low risk for breast cancer is different than its recommendation for women at increased risk.

For women at increased risk for breast cancer, the USPSTF concludes with moderate certainty that taking medications to reduce risk for breast cancer confer a moderate net benefit. Tamoxifen is associated with a greater risk reduction of breast cancer compared with raloxifene but also with a greater risk of endometrial cancer (in women with a uterus), cataracts, and VTEs. These risks increase with age. Both tamoxifen and raloxifene decrease risk of fractures but increase risk of vasomotor symptoms. Aromatase inhibitors also decrease risk of breast cancer in women at increased risk for the disease. No studies are currently available that compare aromatase inhibitors with tamoxifen or raloxifene for risk reduction of primary breast cancer. Some trials of aromatase inhibitors used for the treatment of women with early-stage breast cancer or DCIS suggest that there may be a small increase in cardiovascular disease, such as stroke, with aromatase inhibitors; compared with tamoxifen, which reduces risk of fractures, aromatase inhibitors increase risk of fractures. Whether aromatase inhibitors increase risk of fractures compared with placebo or no treatment is unclear.

For women not at increased risk for breast cancer, the USPSTF found that tamoxifen, raloxifene, and aromatase inhibitors provide only a small benefit in reducing risk for breast cancer but are associated with moderate harms. Overall, the USPSTF concludes with moderate certainty that the potential harms of tamoxifen, raloxifene, and aromatase inhibitors outweigh the potential benefits in women at low risk of breast cancer.

Response to Public Comment

A draft version of this recommendation statement was posted for public comment on the USPSTF website from January 15 to February 11, 2019. In response to comments received, the USPSTF has clarified that the recommendation statement does not list every scenario in which medications could be considered but rather provides information on risk factors that clinicians could consider in assessing breast cancer risk with their patients. Some examples are provided to help clinicians understand how to consider these risk factors, but these examples should not be interpreted as a definitive list. Some comments expressed concern that the USPSTF was recommending risk-reducing medications at a lower 5-year breast cancer risk threshold than previously. The USPSTF has not lowered its risk threshold for which it has found a net benefit with risk-reducing medications. Instead, the current recommendation acknowledges the uncertainty around relying on a specific threshold calculated by risk assessment tools to identify women who may benefit from risk-reducing medications and offers an alternative approach to risk assessment of women, which includes clinician consideration of clinical risk factors. Some comments also expressed concern that the USPSTF was no longer recommending “shared, informed decision making.” As with all of its recommendations, the USPSTF encourages clinicians to discuss with patients the risks and benefits of clinical preventive services in the context of each individual’s personal health values and preferences when considering a service. Language clarifying this has been added to the Clinical Considerations section. Last, as requested, additional information is provided on selection of medications and menopausal status, and information on harms of aromatase inhibitors has been clarified in the Clinical Considerations section.

How Does Evidence Fit With Biological Understanding?

Tamoxifen and raloxifene are selective ER modulators that inhibit ERs in breast tissue and reduce risk for ER-positive breast cancer by blocking the proliferation of estrogen-sensitive epithelial cells where breast cancer can develop. These medications have been approved by the US Food and Drug Administration for risk reduction of breast cancer. Aromatase inhibitors inhibit conversion of androgen to estrogen and can reduce risk of ER-positive breast cancer by decreasing the amount of estrogen available to bind to estrogen-sensitive epithelial cells. Aromatase inhibitors have been evaluated for risk reduction of breast cancer in clinical trials, although they are primarily used for treatment rather than risk reduction of primary cancer. Aromatase inhibitors are not currently approved by the US Food and Drug Administration for risk reduction of primary breast cancer.

This recommendations is consistent with the 2013 USPSTF recommendation.⁸⁸ As before, the USPSTF recommends offering risk-reducing medications to women at increased risk for breast cancer and at low risk for adverse medication effects (B recommendation) and recommends against routine use of risk-reducing medications in women not at increased risk (D recommendation). The current recommendation now includes aromatase inhibitors among medications that can reduce risk of breast cancer.

In 2013, the American Society of Clinical Oncology recommended discussing tamoxifen as an option to reduce risk of breast cancer in women at increased risk who are 35 years and older. It also recommended that raloxifene and exemestane be discussed as additional options for risk reduction in postmenopausal women.⁸⁹ The National Comprehensive Cancer Network recommends risk-reducing agents for women 35 years and older and tamoxifen for premenopausal women only; tamoxifen, raloxifene, anastrozole, or exemestane may be used in postmenopausal women.⁹⁰ The American College of Obstetricians and Gynecologists states that the risk-reduction agents tamoxifen and raloxifene (in postmenopausal women) may be considered for breast cancer risk reduction in BRCA mutation carriers.⁹¹ Given the protective effects in other at-risk populations, aromatase inhibitors may be an alternative for women who cannot take tamoxifen.⁹¹ Postmenopausal women taking tamoxifen should be closely monitored for symptoms of endometrial hyperplasia and cancer.⁹² The American Academy of Family Physicians supports the 2013 USPSTF recommendation.⁹³ The American Cancer Society does not have formal recommendations on the use of risk-reducing medications for breast cancer.

The US Preventive Services Task Force (USPSTF) members include the following individuals: Douglas K. Owens, MD, MS (Veterans Affairs Palo Alto Health Care System, Palo Alto, California, and Stanford University, Stanford, California); Karina W. Davidson, PhD, MASc (Feinstein Institutes for Medical Research at Northwell Health, Manhasset, New York); Alex H. Krist, MD, MPH (Fairfax Family Practice Residency, Fairfax, Virginia, and Virginia Commonwealth University, Richmond); Michael J. Barry, MD (Harvard Medical School, Boston, Massachusetts); Michael Cabana, MD, MA, MPH (University of California, San Francisco); Aaron B. Caughey, MD, PhD (Oregon Health & Science University, Portland); Chyke A. Doubeni, MD, MPH (Mayo Clinic, Rochester, MN); John W. Epling Jr, MD, MSEd (Virginia Tech Carilion School of Medicine, Roanoke); Martha Kubik, PhD, RN (Temple University, Philadelphia, Pennsylvania); C. Seth Landefeld, MD (University of Alabama at Birmingham); Carol M. Mangione, MD, MSPH (University of California, Los Angeles); Lori Pbert, PhD (University of Massachusetts Medical School, Worcester); Michael Silverstein, MD, MPH (Boston University, Boston, Massachusetts); Melissa A. Simon, MD, MPH (Northwestern University, Evanston, Illinois); Chien-Wen Tseng, MD, MPH, MSEE (University of Hawaii, Honolulu); John B. Wong, MD (Tufts University School of Medicine, Boston, Massachusetts).

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Authors followed the policy regarding conflicts of interest described at https://www.uspreventiveservicestaskforce.org/Page/Name/conflict-of-interest-disclosures. Dr Barry reported receiving grants and personal fees from Healthwise, a nonprofit, outside the submitted work. All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings.

Funding/Support: The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF.

Disclaimer: Recommendations made by the USPSTF are independent of the US government. They should not be construed as an official position of AHRQ or the US Department of Health and Human Services.

Copyright Notice: USPSTF recommendations are based on a rigorous review of existing peer-reviewed evidence and are intended to help primary care clinicians and patients decide together whether a preventive service is right for a patient's needs. To encourage widespread discussion, consideration, adoption, and implementation of USPSTF recommendations, AHRQ permits members of the public to reproduce, redistribute, publicly display, and incorporate USPSTF work into other materials provided that it is reproduced without any changes to the work of portions thereof, except as permitted as fair use under the US Copyright Act.

AHRQ and the US Department of Health and Human Services cannot endorse, or appear to endorse, derivative or excerpted materials, and they cannot be held liable for the content or use of adapted products that are incorporated on other Web sites. Any adaptations of these electronic documents and resources must include a disclaimer to this effect. Advertising or implied endorsement for any commercial products or services is strictly prohibited.

This work may not be reproduced, reprinted, or redistributed for a fee, nor may the work be sold for profit or incorporated into a profit-making venture without the express written permission of AHRQ. This work is subject to the restrictions of Section 1140 of the Social Security Act, 42 U.S.C. §320b-10. When parts of a recommendation statement are used or quoted, the USPSTF Web page should be cited as the source.

1. National Cancer Institute (NCI). SEER Cancer Stat Facts: Female Breast Cancer 2018. NCI website. https://seer.cancer.gov/statfacts/html/breast.html. Published 2018. Accessed August 1, 2019.
2. American Cancer Society (ACS). Cancer Facts & Figures 2018. ACS website.  https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. Published 2018. Accessed August 1, 2019.
3. Nelson HD, Fu R, Zakher B, et al. Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 180. AHRQ Publication No. 19-05249-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2019.
4. Nelson HD, Fu R, Zakher B, et al. Medication use for the risk reduction of primary breast cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA.
5. National Cancer Institute (NCI). The Breast Cancer Risk Assessment Tool. NCI website. https://bcrisktool.cancer.gov/. 2017. Accessed November 23, 2018.
6. Freedman AN, Yu B, Gail MH, 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(17):2327-2333.
7. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97(19):1428-1437.
8. Kuchenbaecker KB, Hopper JL, Barnes DR, et al; BRCA1 and BRCA2 Cohort Consortium. Risks of breast, ovarian and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416.
9. American Cancer Society (ACS). Breast Cancer Facts & Figures: 2017-2018. ACS website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. 2017. Accessed August 1, 2019.
10. National Cancer Institute (NCI). BRCA Mutations: Cancer Risk and Genetic Testing. NCI website. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. 2018. Accessed November 16, 2018.
11. Forbes JF, Sestak I, Howell A, et al; IBIS-II Investigators. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomized controlled trial. Lancet. 2016;387(10021):866-873.
12. Goldvaser H, Barnes TA, Šeruga B, et al. Toxicity of extended adjuvant therapy with aromatase inhibitors in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2018;110(1).
13. Cuzick J, Forbes JF, Sestak I, 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(4):272-282.
14. 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(4):283-290.
15. Cuzick J, Sestak I, Cawthorn S, et al; IBIS-I Investigators. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16(1):67-75.
16. U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296.
17. US Preventive Services Task Force (USPSTF). Recommendations for Primary Care Practice. USPSTF website. https://www.uspreventiveservicestaskforce.org/Page/Name/recommendations. 2018. Accessed November 23, 2018.
18. PDQ® Screening and Prevention Editorial Board, National Cancer Institute (NCI). PDQ Breast Cancer Prevention (PDQ®)—Patient Version. NCI website. https://www.cancer.gov/types/breast/patient/breast-prevention-pdq. Updated June 20, 2019. Accessed August 6, 2019.
19. Centers for Disease Control and Prevention (CDC). What can I do to reduce my risk of breast cancer? CDC website. https://www.cdc.gov/cancer/breast/basic_info/prevention.htm. September 11, 2018. Accessed August 2, 2019.
20. Breast Cancer Surveillance Consortium (BCSC). Breast Cancer Surveillance Consortium Risk Calculator. BCSC website. https://tools.bcsc-scc.org/bc5yearrisk/calculator.htm. 2015. Accessed November 23, 2018.
21. Kaplan CP, Haas JS, Pérez-Stable EJ, Des Jarlais G, Gregorich SE. Factors affecting breast cancer risk reduction practices among California physicians. Prev Med. 2005;41(1):7-15.
22. Corbelli J, Borrero S, Bonnema R, et al. Use of the Gail model and breast cancer preventive therapy among three primary care specialties. J Womens Health (Larchmt). 2014;23(9):746-752.
23. 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(20):2260-2265.
24. Smith SG, Sestak I, Forster A, et al. Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis. Ann Oncol. 2016;27(4):575-590.
25. Fagerlin A, Zikmund-Fisher BJ, Nair V, et al. Women’s decisions regarding tamoxifen for breast cancer prevention: responses to a tailored decision aid. Breast Cancer Res Treat. 2010;119(3):613-620.
26. Melnikow J, Paterniti D, Azari R, et al. Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. Cancer. 2005;103(10):1996-2005.
27. McKay A, Martin W, Latosinsky S. How should we inform women at higher risk of breast cancer about tamoxifen? An approach with a decision guide. Breast Cancer Res Treat. 2005;94(2):153-159.
28. Paterniti DA, Melnikow J, Nuovo J, et al. "I'm going to die of something anyway": women's perceptions of tamoxifen for breast cancer risk reduction. Ethn Dis. 2005;15(3):365-372.
29. Fagerlin A, Dillard AJ, Smith DM, et al. Women’s interest in taking tamoxifen and raloxifene for breast cancer prevention: response to a tailored decision aid. Breast Cancer Res Treat. 2011;127(3):681-688.
30. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886.
31. Adams-Campbell LL, Makambi KH, Palmer JR, Rosenberg L. Diagnostic accuracy of the Gail model in the Black Women’s Health Study. Breast J. 2007;13(4):332-336.
32. Chen J, Pee D, Ayyagari R, et al. Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst. 2006;98(17):1215-1226.
33. Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999;91(18):1541-1548.
34. Gail MH, Costantino JP, Pee D, et al. Projecting individualized absolute invasive breast cancer risk in African American women. J Natl Cancer Inst. 2007;99(23):1782-1792.
35. Matsuno RK, Costantino JP, Ziegler RG, et al. Projecting individualized absolute invasive breast cancer risk in Asian and Pacific Islander American women. J Natl Cancer Inst. 2011;103(12):951-961.
36. Rockhill B, Spiegelman D, Byrne C, Hunter DJ, Colditz GA. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst. 2001;93(5):358-366.
37. 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(5):337-347.
38. Barlow WE, White E, Ballard-Barbash R, et al. Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst. 2006;98(17):1204-1214.
39. Tice JA, Miglioretti DL, Li CS, Vachon CM, Gard CC, Kerlikowske K. Breast density and benign breast disease: risk assessment to identify women at high risk of breast cancer. J Clin Oncol. 2015;33(28):3137-3143.
40. 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(10):950-964.
41. Rockhill B, Byrne C, Rosner B, Louie MM, Colditz G. Breast cancer risk prediction with a log-incidence model: evaluation of accuracy. J Clin Epidemiol. 2003;56(9):856-861.
42. Tamimi RM, Rosner B, Colditz GA. Evaluation of a breast cancer risk prediction model expanded to include category of prior benign breast disease lesion. Cancer. 2010;116(21):4944-4953.
43. Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst. 2004;96(3):218-228.
44. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111-1130.
45. Amir E, Evans DG, Shenton A, et al. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet. 2003;40(11):807-814.
46. Boughey JC, Hartmann LC, Anderson SS, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28(22):3591-3596.
47. Brentnall AR, Harkness EF, Astley SM, et al. Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort [published online December 1, 2015]. Breast Cancer Res. 2015;17(1):147.
48. Chlebowski RT, Anderson GL, Lane DS, 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(22):1695-1705.
49. Boyle P, Mezzetti M, La Vecchia C, Franceschi S, Decarli A, Robertson C. Contribution of three components to individual cancer risk predicting breast cancer risk in Italy. Eur J Cancer Prev. 2004;13(3):183-191.
50. Decarli A, Calza S, Masala G, Specchia C, Palli D, Gail MH. Gail model for prediction of absolute risk of invasive breast cancer: independent evaluation in the Florence-European Prospective Investigation Into Cancer and Nutrition Cohort. J Natl Cancer Inst. 2006;98(23):1686-1693.
51. Petracci E, Decarli A, Schairer C, et al. Risk factor modification and projections of absolute breast cancer risk. J Natl Cancer Inst. 2011;103(13):1037-1048.
52. Cuzick J, Forbes J, Edwards R, et al; IBIS Investigators. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360(9336):817-824.
53. Fisher B, Costantino JP, Wickerham DL, 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(18):1371-1388.
54. 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(21):1615-1623.
55. Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352(9122):98-101.
56. Veronesi U, Maisonneuve P, Costa A, et al; Italian Tamoxifen Prevention Study. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Lancet. 1998;352(9122):93-97.
57. Veronesi U, Maisonneuve P, Rotmensz N, 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(9):727-737.
58. Veronesi U, Maisonneuve P, Rotmensz N, 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(2):160-165.
59. Decensi A, Maisonneuve P, Rotmensz N, et al; Italian Tamoxifen Study Group. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation. 2005;111(5):650-656.
60. Fisher B, Costantino JP, Wickerham DL, 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(22):1652-1662.
61. DeCensi A, Bonanni B, Maisonneuve P, et al; Italian HOT Study Group. A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study. Ann Oncol. 2013;24(11):2753-2760.
62. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637-645.
63. Cummings SR, Eckert S, Krueger KA, 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(23):2189-2197.
64. Cauley JA, Norton L, Lippman ME, 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(2):125-134.
65. Barrett-Connor E, Grady D, Sashegyi A, 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(7):847-857.
66. Delmas PD, Ensrud KE, Adachi JD, et al; Multiple 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(8):3609-3617.
67. Delmas PD, Genant HK, Crans GG, et al. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone. 2003;33(4):522-532.
68. Grady D, Ettinger B, Moscarelli E, et al; Multiple Outcomes of Raloxifene Evaluation Investigators. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104(4):837-844.
69. 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(8):1270-1275.
70. 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(9):1543-1548.
71. Martino S, Disch D, Dowsett SA, Keech CA, Mershon JL. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin. 2005;21(9):1441-1452.
72. 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(4):444-452.
73. 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(1):135-140.
74. Siris ES, Harris ST, Eastell R, 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(9):1514-1524.
75. Lippman ME, Cummings SR, Disch DP, 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(17):5242-5247.
76. Barrett-Connor E, Mosca L, Collins P, 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(2):125-137.
77. Ensrud KE, Stock JL, Barrett-Connor E, et al. Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res. 2008;23(1):112-120.
78. Grady D, Cauley JA, Geiger MJ, 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(12):854-861.
79. Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2742-2751.
80. Vogel VG, Costantino JP, Wickerham DL, 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(23):2727-2741.
81. Vogel VG, Costantino JP, Wickerham DL, 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(6):696-706.
82. Maunsell E, Goss PE, Chlebowski RT, et al. Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer. J Clin Oncol. 2014;32(14):1427-1436.
83. Goss PE, Ingle JN, Alés-Martínez JE, et al; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381-2391.
84. Cuzick J, Sestak I, Forbes JF, et al; IBIS-II Investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. [published correction appears in Lancet. 2014;383(9922):1040]. Lancet. 2014;383(9922):1041-1048.
85. Sestak I, Singh S, Cuzick J, et al. Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. [Erratum appears in Lancet Oncol. 2014;15(13):e587]. Lancet Oncol. 2014;15(13):1460-1468.
86. Spagnolo F, Sestak I, Howell A, Forbes JF, Cuzick J. Anastrozole-induced carpal tunnel syndrome: results from the International Breast Cancer Intervention Study II Prevention Trial. J Clin Oncol. 2016;34(2):139-143.
87. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352
88. U.S. Preventive Services Task Force. Medications to decrease the risk for breast cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(10):698-708.
89. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(23):2942-2962.
90. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer Risk Reduction, Version 2. NCCN website.https://www.nccn.org/professionals/physician_gls/default.aspx. 2018. Accessed August 1, 2019.
91. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology. Practice Bulletin No. 182: hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2017;130(3):e110-e126.
92. Committee Opinion No. 601: tamoxifen and uterine cancer. Obstet Gynecol. 2014;123(6):1394-1397.
93. American Academy of Family Physicians (AAFP). Clinical preventive service recommendation: medications to reduce breast cancer risk. AAFP website. https://www.aafp.org/patient-care/clinical-recommendations/all/breast-cancer-medication.html.

Note: See Nelson et al.^3,4 Trials included women whose 5-year risk of breast cancer may have been lower than 3%.
a Per 1,000 women over 5 years of use.
b Results from the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) trial.

Abbreviations: ER−, estrogen receptor–negative; ER+, estrogen receptor–positive; ND, no difference; NR, not reported.