Draft Recommendation Statement

Breast Cancer: Medication Use to Reduce Risk

January 15, 2019

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.

The U.S. 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 decisionmaking 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.

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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

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 women who will or will not develop breast cancer over time. Overall, the USPSTF determined that as a woman’s risk for breast cancer increases, the net benefit of taking medications to reduce risk of breast cancer increases.

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.

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Patient Population Under Consideration

This recommendation applies to asymptomatic women, 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 and Adverse Events

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,3 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 medications4 and should be offered them 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.5 However, when balancing the harms associated with these medications, the net benefit will be lower in 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, such as:

  • Atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy
  • Age 65 years or older with one first-degree relative with breast cancer
  • Age 45 years or older with more than one first-degree relative with breast cancer or one first- degree relative who developed breast cancer before age 50 years
  • Age 40 years or older with a first-degree relative with bilateral breast cancer

Women with documented BRCA genetic mutations 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.6 Women who carry a BRCA1 mutation have a cumulative risk for breast cancer of 72% by age 80 years and women who carry a BRCA2 mutation have a 69% cumulative risk7 (compared to a 12% lifetime risk in the general population8). Women who carry the BRCA1 mutation tend to develop ER-negative breast cancer,9 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 these populations, 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.

The potential benefit of risk reduction of breast cancer must be balanced against the potential harms of adverse medication effects. In general, women taking medications to reduce risk for breast cancer are less likely to experience a VTE with tamoxifen or raloxifene treatment if they are younger and have no other predisposition to thromboembolic events. Older women and women with a personal or family history of VTEs are at increased risk for these adverse effects. Similarly, younger women with no risk factors for cardiovascular disease are less likely to have a cardiovascular event with aromatase inhibitor treatment. Women without a uterus are not at risk for tamoxifen-related endometrial cancer, while older women with a uterus are at increased risk for endometrial cancer.

Women not at increased risk for breast cancer, such as women younger than age 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.

Risk-Reducing Medications

A systematic review conducted for the USPSTF found that compared to placebo, tamoxifen reduced the incidence of invasive breast cancer by 7 events per 1,000 women over 5 years (95% confidence interval [CI], 4 to 12), and raloxifene reduced incidence by 9 events (95% CI, 3 to 15) per 1,000 women over 5 years.5 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 to raloxifene, found that tamoxifen reduced breast cancer risk more than raloxifene after long-term followup5 (Table). For women with a predicted breast cancer risk of 3% or greater, the absolute benefits are likely even higher. Tamoxifen also reduces the incidence of invasive breast cancer in premenopausal women at increased risk for the disease; raloxifene should only be used in postmenopausal women.5 Tamoxifen and raloxifene have both been found to reduce risk for nonvertebral and vertebral fractures, respectively.5

Aromatase inhibitors were found to reduce the incidence of invasive breast cancer by 16 events per 1,000 women over 5 years (Table).5 As with tamoxifen and raloxifene, these absolute benefits are likely even higher for women with a predicted breast cancer risk of 3% or greater. 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).5,10,11

Duration of Medication Use and Persistence of Effects

In trials, participants typically used risk-reducing medications for 3 to 5 years.5 Benefits of tamoxifen have been found to persist up to 8 years beyond discontinuation,12,13 while risk for VTEs and endometrial cancer return to baseline after discontinuation of tamoxifen.14 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 cancer15 and for risk assessment, genetic counseling, and genetic testing for BRCA genetic mutations.16 NCI and the Centers for Disease Control and Prevention provide information about potential ways to reduce risk of cancer, including lifestyle and diet changes.17,18

Useful Resources

The USPSTF does not endorse any particular risk prediction tool. However, the NCI Breast Cancer Risk Assessment Tool3 and the Breast Cancer Surveillance Consortium Risk Calculator19 are based on models tested in U.S. populations and are publically available for clinicians and patients to use as part of the process of shared, informed decisionmaking about taking risk-reducing medications for breast cancer. Both tools have been calibrated in U.S. populations.

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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, and most have only done so a few times.20-22 The reported use of risk-reducing medications among women is also relatively low; one meta-analysis of 26 studies found that overall, 16.3% of women at increased risk for breast cancer used risk-reducing medications.23 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.24-28

Research Needs and Gaps

More research is needed to better identify which individuals 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 BRCA1 or BRCA2 mutations. Additionally, given the higher breast cancer mortality rates in black women, studies that include sufficient numbers of black 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.

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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 black women (128.6 vs 126.9 cases per 100,000 persons, respectively), mortality rates are higher among black women (28.7 deaths per 100,000 black persons vs. 20.3 deaths per 100,000 white persons).1 Incidence rates have increased among Asian/Pacific Islander, non-Hispanic black, and Hispanic women but have remained stable among non-Hispanic white and American Indian/Alaskan Native women.8

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).5 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 BRCA 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

The USPSTF reviewed evidence from 24 good- and fair-quality studies on 17 risk stratification models (n >5,000,000).5 Models reviewed included the Gail,29-35 Breast Cancer Surveillance Consortium,36-38 Rosner-Colditz,39-42 Tyrer-Cuzick,43-46 Chlebowski,47 and Italian48-50 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.5 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.29 The current version of the Gail model is used in the Breast Cancer Risk Assessment Tool, which is publicly accessible through the NCI Web site.3 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 U.S. 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.37 The Rosner-Colditz model was derived from 1,761 breast cancer cases that developed among 58,520 participants in the Nurses' Health Study.39 Chlebowski and colleagues developed a model based on 3,236 cases that developed in the Women's Health Initiative study.47 Models from Italy48-50 and the United Kingdom43-46 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 (i.e., 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 0.65.5 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.5

Effectiveness of Risk-Reducing Medications

The USPSTF reviewed evidence from 10 trials that evaluated the effect of risk-reducing medications for breast cancer.5 Four trials (n=28,193) evaluated tamoxifen in premenopausal and postmenopausal women at increased risk for breast cancer12-14,51-59 (in one additional trial of low-dose tamoxifen,60 the low dose was not found to reduce risk of breast cancer, so was not considered further by the USPSTF); two trials (n=17,806) evaluated raloxifene in postmenopausal women not at increased risk for breast cancer,61-77 one trial (n=19,747) directly compared raloxifene to tamoxifen in postmenopausal women at increased risk for breast cancer (STAR trial78-80), and two trials evaluated aromatase inhibitors (examestane81,82 [n=4,560] and anastrozole83-85 [n=3,864]) 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 to 67.5 years5) 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 to 53 years5). 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% to 97% white in studies that reported this information).5

In trials, all three types of medications reduced invasive and ER-positive breast cancer, but not ER-negative breast cancer.5 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 to 0.84]) and 8 fewer cases of ER-positive breast cancer (RR, 0.58 [95% CI, 0.42 to 0.81]) (unless otherwise stated, all numbers of cases are per 1,000 women over 5 years of medication use).5 Raloxifene use would result in 9 fewer cases of invasive breast cancer (RR, 0.44 [95% CI, 0.24 to 0.80]) and 8 fewer cases of ER-positive breast cancer (RR, 0.33 [95% CI, 0.15 to 0.73]).5 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 to 0.98]) and 7 fewer cases of vertebral fractures with raloxifene (RR, 0.61 [95% CI, 0.53 to 0.70]).5 Aromatase inhibitors would result in 16 fewer cases of invasive breast cancer (RR, 0.45 [95% CI, 0.26 to 0.70]) and 15 fewer cases of ER-positive breast cancer (RR, 0.37 [95% CI, 0.19 to 0.63]).5 Risk reduction of both invasive and ER-positive breast cancer persisted up to 8 years after discontinuation of tamoxifen use in two trials13,14 (data on similar length of long-term followup 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 tamoxifen52 and one of anastrazole83 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,5,52,77,79,82 and one study of tamoxifen also indicated that risk reduction may be greatest in the highest-risk groups.5,52

Although comparisons of effectiveness between the three 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 to raloxifene for breast cancer risk reduction and found that tamoxifen provided a greater risk reduction for invasive breast cancer on long-term followup (5 fewer cases [95% CI, 1 to 9]).5

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.5 When compared to placebo, tamoxifen was associated with 5 more cases of  VTEs (RR, 1.93 [95% CI, 1.33 to 2.68]), 4 more cases of endometrial cancer (RR, 2.25 [95% CI, 1.17 to 4.41]), and 26 more cases of cataracts (RR, 1.22 [95% CI, 1.08 to 1.48]).5 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.5

When compared to placebo, raloxifene was associated with 7 more cases of VTE (RR, 1.56 [95% CI, 1.11 to 2.6]).5 Vasomotor symptoms were also increased with raloxifene use. No significant differences were found with raloxifene use on rates of coronary heart disease events, stroke, endometrial cancer, or cataracts. Based on the STAR trial, more harms were reported with tamoxifen compared to raloxifene: 4 more cases of VTE (95% CI, 1 to 7), 3 more cases of deep vein thrombosis (95% CI, 1 to 5), 5 more cases of endometrial cancer (95% CI, 2 to 9), and 15 more cases of cataracts (95% CI,  8 to 22) with tamoxifen than with raloxifene.5 Both aromatase inhibitor trials reported more vasomotor and musculoskeletal symptoms with aromatase inhibitors compared to placebo.5,81-83 No significant differences in rates of VTEs, deep vein thrombosis, pulmonary embolism, coronary heart disease events, stroke, endometrial cancer, or cataracts were reported;5,81-83 however, 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 to 1.40]; 7 studies; n=16,349) with aromatase inhibitors compared to placebo or no treatment.86 Another study that compared anastrozole to tamoxifen in treating women with DCIS found a significant increase in cerebrovascular events (OR, 3.36 [95% CI, 1.04 to 14.18]) and a nonsignificant increase in transient ischemic attacks (OR, 2.69 [95% CI, 0.90 to 9.65]) with anastrozole.10 Another meta-analysis that evaluated studies of aromatase inhibitors compared to 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 to tamoxifen (which reduces risk of fractures), more fractures were seen with aromatase inhibitors.10,87 The meta-analysis that evaluated extended use of aromatase inhibitors compared to placebo or no treatment also found increased fractures with aromatase inhibitors (OR, 1.34 [95% CI, 1.16 to 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.86 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 her potential for harms from the medications. Accordingly, the USPSTF's 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 to 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 to 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 to tamoxifen, which reduces risk of fractures, aromatase inhibitors increase risk of fractures. Whether aromatase inhibitors increase risk of fractures compared to 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.

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. They have been approved by the U.S. 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 U.S. Food and Drug Administration for risk reduction of primary breast cancer.

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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 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.

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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 age 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-reduction agents for women age 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 tamoxifen and raloxifene may be considered for risk reduction of breast cancer in women with BRCA genetic mutations and raloxifene should only be considered in postmenopausal women.91 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.

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Outcome Tamoxifen Raloxifene Aromatase Inhibitors
Benefits: Events Reduced (95% CI)
Breast Cancer
Invasive 7 (4-12) 9 (3-15) 16 (8-24)
ER+ 16 (8-24) 8 (4-13) 15 (8-20)
ER- - - -
Noninvasive - - -
Mortality
Breast cancer - NR NR
All-cause - - -
Fracture
Vertebral - 7 (5-9) -
Nonvertebral 3 (0-5) - -
Harms: Events Increased (95% CI)
Vascular
Venous thromboembolic event 5 (2-9) 7 (0-17) -
Deep vein thrombosis - - NR
Pulmonary embolism - - NR
Coronary heart disease events - - -
Other
Endometrial cancer 4 (1-8) - -
Cataracts 26 (5-50) - -

* Trials included women whose 5-year risk of breast cancer may have been lower than 3%.
Per 1,000 women over 5 years of use.
Results from the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) trial.

Abbreviations: CI = confidence interval; ER- = estrogen-receptor negative; ER+ = estrogen-receptor positive; NR = not reported.

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