U.S. Preventive Services Task Force banner
U.S. Preventive Services Task Force

You Are Here: U.S. Preventive Services Task Force > Draft Recommendation Statement


 

 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 
DRAFT
 

Draft Recommendation Statement


Note: This draft Recommendation Statement is not the final recommendation of the U.S. Preventive Services Task Force (USPSTF). This draft is distributed solely for the purpose of pre-release review. It has not been disseminated otherwise by the USPSTF. It does not represent and should not be interpreted to represent a USPSTF determination or policy.

This draft Recommendation Statement is based on an evidence review that was published on April 16, 2013 (available at: http://www.uspreventiveservicestaskforce.org/uspstf13/breastcanmeds/breastcanmedsart.htm).

The USPSTF makes recommendations about the effectiveness of specific clinical preventive 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 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.

This draft Recommendation Statement is available for comment from April 16 until May 13, 2013, at 5:00 PM ET. You may wish to read the entire Recommendation Statement before you comment. A fact sheet that explains the draft recommendations in plain language is available here.


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

Summary of Recommendations and Evidence

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians engage in shared decisionmaking with women at increased risk of breast cancer regarding 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.

This is a B recommendation.
(Go to the Clinical Considerations 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.

This is a D recommendation.

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

Rationale

Importance

Breast cancer is the most common nonskin cancer in women. An estimated 232,340 new cases of breast cancer will be diagnosed in 2013, and 39,620 women will die from 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 breast cancer.

Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown in randomized, controlled trials to reduce the risk of hormone receptor (HR)-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/or 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 predict the number of breast cancer cases that may arise in certain study populations, but their ability to accurately predict which individual women will (and will not) develop breast cancer is modest.

There is limited information about the validity, feasibility, and impact of using risk assessment models to identify appropriate candidates for risk-reducing medications in primary care settings (2-4).

Potential Benefits of Medications for Breast Cancer Risk Reduction

For postmenopausal women who are at increased risk for breast cancer, the USPSTF found adequate evidence that treatment with tamoxifen or raloxifene can significantly reduce the relative risk for invasive HR-positive breast cancer.

Tamoxifen and raloxifene reduced the incidence of invasive breast cancer by 7 to 9 fewer events per 1,000 women over 5 years, and tamoxifen reduced breast cancer incidence more than raloxifene. Tamoxifen also reduces the incidence of invasive breast cancer in premenopausal women who are at increased risk for breast cancer.

Women who are at increased risk for breast cancer are more likely to benefit from medications for breast cancer risk reduction. In general, women with an estimated 5-year breast cancer risk of 3% or greater are more likely to benefit from tamoxifen or raloxifene, based on estimates in models. For women who are not at increased risk for breast cancer, the USPSTF found that the benefits of tamoxifen and raloxifene for breast cancer risk reduction were no greater than small.

In addition to breast cancer risk reduction, the USPSTF found adequate evidence that tamoxifen or raloxifene reduce the risk of nonvertebral or 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 1,000 women over 5 years, and tamoxifen increases risk more than raloxifene. The USPSTF found that potential harms due to thromboembolic events are small to moderate, with increased potential for harms among older women.

The USPSTF also found adequate evidence that tamoxifen, but not raloxifene, increases the risk for endometrial cancer (4 cases per 1,000 women). Potential harms from tamoxifen-related endometrial cancer are small to moderate, depending on hysterectomy status and age. The potential risks for tamoxifen-related harms are higher in women older than age 50 years and in women with a uterus.

Tamoxifen and, to a lesser extent, raloxifene may increase the risk for ischemic stroke. Tamoxifen may also increase the incidence of cataracts.

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

USPSTF Assessment

For women at increased risk for breast cancer, 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.

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

Clinical Considerations

Patient Population Under Consideration

This recommendation applies to asymptomatic women between the ages of 40 and 70 years 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 (e.g., deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack).

Assessment of Breast Cancer Risk

If during the usual assessment of a patient's history it is found that a patient has a family history of breast cancer or a personal history of breast biopsy, the clinician may consider using a breast cancer risk assessment tool.

The National Cancer Institute has developed a Breast Cancer Risk Assessment Tool based on the Gail model (available at www.cancer.gov/bcrisktool/), which estimates the 5-year incidence of invasive breast cancer among women based on characteristics entered into the tool's risk calculator. This tool may help identify women who might experience a positive net health benefit from tamoxifen or raloxifene. Other risk assessment models include those developed by the Breast Cancer Surveillance Consortium, Colditz-Rosner, Chlebowski, Tyrer-Cuzick, and others described in the evidence report (5-7).

Examples of risk factors elicited by risk assessment tools include patient age, race/ethnicity, age at menarche, age at first live childbirth, personal history of DCIS or LCIS, number of first-degree relatives who have had breast cancer, and personal history of breast biopsy.

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. Most women identified as “high risk” will not develop breast cancer, and the majority of breast cancer cases will arise in women who are not identified as having increased risk. Risk assessment should be repeated when there is a significant change in breast cancer risk factors.

Based on the Freedman risk/benefit indices for women age 50 years and older (Figures 1-4), the USPSTF concludes that many women with an estimated 5-year breast cancer risk of ≥3% are likely to have more benefit than harm from using tamoxifen or raloxifene, although the balance depends on age, race/ethnicity, the medication used, and whether or not the patient has a uterus (8).

Assessment of Risk for Adverse Effects

In general, women taking medications for breast cancer risk reduction are less likely to experience 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 prior to starting tamoxifen, with regular followup after the end of treatment.

Freedman et al have considered breast cancer risk, age, race, and hysterectomy status to assess the magnitude of potential benefits and harms (Figures 1-4).

Medications for Breast Cancer Risk Reduction

Selective estrogen receptor modulators (e.g., tamoxifen and raloxifene) have been shown to reduce the incidence of invasive breast cancer in several randomized, controlled trials. For this indication, the usual daily doses for tamoxifen and raloxifene are 20 mg and 60 mg, respectively, for 5 years. Aromatase inhibitors (e.g., exemestane) have not been approved by the FDA for this indication and are therefore beyond the scope of this recommendation.

Other Considerations

Implementation

In order to identify patients for whom the potential benefits of risk-reducing medications could outweigh potential risks, clinicians should first identify patients 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 developing breast cancer; studies have shown that women tend to overestimate their individual breast cancer risk.

For women whose 5-year projected risk for breast cancer is ≥3%, clinicians should identify women for whom the potential benefits of risk-reducing medications could outweigh the potential risks. In doing so, clinicians should consider the woman's age, comorbidities, presence of uterus, and risks for thromboembolic or medication-related adverse events. To complement clinical assessment, clinicians may refer to risk-benefit tables (Figures 1-4) (8, 9).

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

Research Needs and Gaps

Research is needed to improve the ability to assess and accurately predict an individual woman's chance of developing breast cancer over a defined time period. The ideal candidates for medications to reduce risk of breast cancer are women who not only have a high probability of developing breast cancer over a defined period of time, but also have a low probability of thromboembolic and other medication-related adverse events; models should be developed to more precisely predict both of these events. Models that perform well in other countries could also be validated in U.S. populations.

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

Long-term followup is needed to understand the duration of potential protective effects of risk-reducing medications. Future studies should examine the benefits and harms of risk-reducing medications in racially diverse patient populations.

Discussion

Burden of Disease

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

Scope of Review

The USPSTF reviewed evidence regarding the effectiveness, adverse effects, and subgroup variations of medications to reduce the risk of breast cancer, specifically the selective estrogen receptor modulators tamoxifen and raloxifene (5-7).The USPSTF reviewed randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models among women without pre-existing breast cancer, precursor conditions, or known breast cancer susceptibility mutations. The USPSTF reviewed results of a meta-analysis of placebo-controlled trials in order to understand the relative benefits and harms of tamoxifen and raloxifene (5).

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/ethnicity, prior false-positive mammography 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 very large U.S. populations in studies that received good-quality ratings, but reported only modest accuracy. The Breast Cancer Surveillance Consortium's 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 1,761 breast cancer cases that developed among 58,520 participants in the Nurses' Health Study (12). Chlebowski and colleagues developed a model based on 3,236 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 they 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 age 60 years, women who received annual breast cancer screening, and women with HR-positive breast cancer. However, most breast cancer risk assessment models had a false-positive rate of 55% to 66%, indicating modest accuracy in predicting risk for individuals.

There is limited information about the validity, feasibility, and impact of using risk assessment models to identify appropriate candidates for risk-reducing medications in primary care settings (2-4).

Effectiveness of Risk-Reducing Medications

To understand the effectiveness of medications for breast cancer risk reduction, the USPSTF reviewed seven large randomized, controlled trials of breast cancer outcomes in women without pre-existing breast cancer. Other relevant study outcomes included mortality, fractures, thromboembolic events, cardiovascular disease events, uterine abnormalities, cataracts, and other adverse effects.

The USPSTF review included seven primary prevention randomized, controlled trials. The Study of Tamoxifen and Raloxifene (STAR) was a head-to-head comparison of tamoxifen versus raloxifene, with more than 9,800 patients in each study group (14, 15). Four studies compared tamoxifen with placebo: the National Surgical Adjuvant Breast and Bowel Project (NSABP-1) (16-19), IBIS-I (20, 21), the Royal Marsden Hospital Trial (22, 23), and the Italian Tamoxifen Prevention Study (24-27). Two studies compared raloxifene with placebo: the Multiple Outcomes of Raloxifene (MORE) study, with long-term followup in the Continuing Outcomes Relevant to Evista (CORE) study (28-41), as well as the Raloxifene Use for the Heart (RUTH) trial (42, 43).

Trials included a head-to-head comparison of tamoxifen and raloxifene (STAR), four placebo-controlled trials of tamoxifen, and two placebo-controlled trials of raloxifene. All trials were multicenter, relevant to primary care, and enrolled between 2,471 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 for 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%; median followup was for 81 months (15). For the placebo-controlled trials involving tamoxifen, eligibility criteria and duration of followup varied. For NSABP-1, eligibility criteria included having a 5-year predicted breast cancer risk of ≥1.66%; median followup was for about 7 years (15, 17). For IBIS-I, eligibility criteria included having an estimated 10-year risk of ≥5%; median followup was for 96 months (21). For the Royal Marsden (24) and Italian Tamoxifen Prevention (27) trials, eligibility criteria did not include a prespecified breast cancer risk threshold; median followup was for 13 and 11 years, respectively. For placebo-controlled trials involving raloxifene (i.e., MORE and CORE), eligibility criteria did not include a prespecified breast cancer risk threshold; together, these trials provided 8 years of followup (39).

The USPSTF also reviewed a meta-analysis using results from the placebo-controlled trials in order to better understand the relative benefits and harms of tamoxifen and raloxifene (5). In placebo-controlled trials, tamoxifen and raloxifene significantly reduced the risk of invasive breast cancer (tamoxifen relative risk [RR], 0.70 [95% CI, 0.59 to 0.82] [16, 21, 23, 26]; raloxifene RR, 0.44 [95% CI, 0.27 to 0.71] [39, 42]). In STAR, tamoxifen reduced breast cancer more than raloxifene (raloxifene RR, 1.24 [95% CI, 1.05 to 1.47]) (14).

Both medications reduced breast cancer in all subgroups studied, though trial data for racial subgroups were not available. Tamoxifen reduced breast cancer outcomes in all 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 among 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 all subgroups based on age, age at menarche, parity, age at first live childbirth, and body mass index. For raloxifene, effect estimates 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 at increased risk for breast cancer. The risk reduction with tamoxifen was greatest among women with three 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 two trials providing post-treatment followup data. Neither medication significantly reduced the risk of estrogen receptor-negative breast cancer, noninvasive breast cancer, or all-cause mortality. In the placebo-controlled trials and STAR, raloxifene reduced vertebral fractures (RR, 0.61 [95% CI, 0.54 to 0.69]) (32, 42), while tamoxifen reduced nonvertebral fractures (RR, 0.66 [95% 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 impact 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 followup for this outcome. While there is convincing evidence that these medications can reduce the incidence of invasive breast cancer, it is unclear whether reductions in breast cancer incidence will lead to a corresponding reduction in mortality.

The USPSTF also considered meta-analysis summary calculations of the number of events reduced per 1,000 women in placebo-controlled trials, assuming 5 years of treatment (5). Both medications reduced the incidence of invasive breast cancer, with 7 fewer events per 1,000 women for tamoxifen (four trials) and 9 fewer events per 1,000 women for raloxifene (two trials). When compared head-to-head in STAR, tamoxifen reduced breast cancer incidence more than raloxifene by 5 events per 1,000 women. Compared with placebo, raloxifene reduced the incidence of vertebral fractures by 7 events per 1,000 women (two trials), while tamoxifen reduced the incidence of nonvertebral fractures by 3 events per 1,000 women (one 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 Medication

The USPSTF review found no studies on the potential harms of breast cancer risk assessment in primary care settings. The USPSTF did find evidence on the potential harms of tamoxifen and raloxifene.

In almost all clinical trials, both tamoxifen and raloxifene nearly doubled the risk for all VTEs compared with placebo (tamoxifen RR, 1.93 [95% CI, 1.41 to 2.64] [17, 21, 23, 24]; raloxifene RR, 1.60 [95% CI, 1.15 to 2.23] [42, 45]). Tamoxifen increased thromboembolic events more than raloxifene in STAR. Risk returned to normal after discontinuation of tamoxifen in the two trials providing post-treatment data.

In comparison with placebo, tamoxifen was associated with more cases of endometrial cancer (RR, 2.13 [95% 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). 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 [95% CI, 0.36 to 0.83]) (14).

In the placebo-controlled trials and STAR, tamoxifen and raloxifene did not increase risk for coronary heart disease events or stroke (16, 21, 23, 26, 27, 42). In one trial, however, stroke mortality was higher for raloxifene than placebo (42).

Women using tamoxifen compared with placebo more frequently had cataract surgery in one trial (17), though cataract risk was not increased in a meta-analysis of three tamoxifen trials (RR, 1.25 [95% CI, 0.93 to 1.67]) (16, 21, 23). Raloxifene compared with placebo did not increase risk for cataracts or cataract surgery (42, 45), and caused fewer cataracts than tamoxifen in STAR (14).

The most commonly reported side 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, while tamoxifen users had more gynecological 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 1,000 women caused by these medications in placebo-controlled trials, assuming 5 years of treatment (5). Tamoxifen was associated with 4 VTEs per 1,000 women (four trials), while raloxifene was associated with 7 VTEs per 1,000 women (two trials). Tamoxifen increased thromboembolic events by 4 more events per 1,000 women than raloxifene in STAR. Tamoxifen was also associated with 4 cases of endometrial cancer per 1,000 women (three trials).

Risk Perception and Decisionmaking

In studies describing how women decide whether to take medications to reduce risk of primary breast cancer, women had significant concerns about potential serious adverse events, especially when they were informed of the medications' risks and benefits. In one study of women who were at increased risk for breast cancer, only 12% selected tamoxifen for breast cancer risk reduction; the vast majority (77%) declined, primarily because of concerns about serious adverse events and small therapeutic benefit (3). Women who were interested in taking risk-reducing medications often overestimated their own risk for breast cancer, thinking they were at high risk when they were actually not. Women placed great emphasis on recommendations from their physicians.

Estimate of Magnitude of Net Benefit

A model of breast cancer risk found that for women whose 5-year risk for breast cancer is ≥3%, the benefits of preventive medication start to outweigh the potential harms (Figures 1-4) (8). Accordingly, the USPSTF's recommendations are different for women with low versus high risk of breast cancer.

For women at increased risk for breast cancer, the USPSTF concluded with moderate certainty that medications to prevent breast cancer would confer moderate net benefit. Tamoxifen was associated with moderate benefit, with adequate evidence for risk reduction of invasive breast cancer. Raloxifene was associated with slightly smaller benefits for breast cancer risk reduction, but no risk of endometrial cancer. For reduction of nonvertebral fractures, there was adequate evidence of small benefit with tamoxifen.

Regarding evidence of harms, the USPSTF found adequate evidence of small-to-moderate risk for a medication-related VTE (depending on age), as well as small-to-moderate risk of medication-related endometrial cancer (depending on hysterectomy status and age).

For women not at increased risk for breast cancer, the USPSTF concluded that both tamoxifen and raloxifene confer a benefit no greater than small, with moderate harms.

How Does Evidence Fit With Biological Understanding?

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

Update of Previous USPSTF Recommendation

In 2002, the USPSTF issued a “B” recommendation for clinicians to discuss risk-reducing medications with women 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 at low or average risk for breast cancer.

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

Recommendations of Others

In 2002, the American College of Obstetricians and Gynecologists recommended that clinicians offer tamoxifen to women at increased risk for breast cancer (47). In 2001, the Canadian Task Force on Preventive Health Care recommended that women at high risk of 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 at low or normal risk of breast cancer (48).

In 2009, the American Society of Clinical Oncology recommended offering tamoxifen to women at increased risk for breast cancer or raloxifene to postmenopausal women at increased risk for breast cancer (49). 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 (50).

Table 1: What the Grades Mean and Suggestions for Practice

Grade Definition Suggestions for Practice
A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service.
B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service.
C The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances.
D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service.
I Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.


Table 2: Levels of Certainty Regarding Net Benefit

Level of Certainty* Description
High The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.
Moderate The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as:
  • The number, size, or quality of individual studies.
  • Inconsistency of findings across individual studies.
  • Limited generalizability of findings to routine primary care practice.
  • Lack of coherence in the chain of evidence.

As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.

Low The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of:
  • The limited number or size of studies.
  • Important flaws in study design or methods.
  • Inconsistency of findings across individual studies.
  • Gaps in the chain of evidence.
  • Findings not generalizable to routine primary care practice.
  • A lack of information on important health outcomes.

More information may allow an estimation of effects on health outcomes.

*The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.

References

1. National Cancer Institute. Breast Cancer. Bethesda, MD: National Cancer Institute; 2013. Accessed at http://www.cancer.gov/cancertopics/types/breast on 2 April 2013.
2. Brewster AM, Christo DK, Lai H, Helzlsouer K. Breast carcinoma chemoprevention in the community setting. Estimating risks and benefits. Cancer. 2005;103(6):1147-53.
3. 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):2260-5.
4. 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(2):85-8.
5. Nelson HD, Smith ME, Griffin J, Fu R. Use of medications to reduce risk for primary breast cancer: systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013 (in press).
6. 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(10):703-15.
7. 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. Rockville, MD: Agency for Healthcare Research and Quality; 2009.
8. 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(17):2327-33.
9. 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(21):1829-46.
10. National Cancer Institute. SEER Stat Fact Sheets: Breast. Bethesda, MD: National Cancer Institute; 2012. Accessed at http://seer.cancer.gov/statfacts/html/breast.html on 2 April 2013.
11. Barlow WE, White E, Ballard-Barbash R, Vacek PM, Titus-Ernstoff L, Carney PA, et al. Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst. 2006;98(17):1204-14.
12. 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):950-64.
13. Chlebowski RT, Anderson GL, Lane DS, Aragaki AK, Rohan T, Yasmeen S, et al. Predicting risk of breast cancer in postmenopausal women by hormone receptor status. J Natl Cancer Inst. 2007;99(22):1695-705.
14. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. 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.
15. 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(41):181-6.
16. 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(22):1652-62.
17. 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(18):1371-88.
18. Day R; National Surgical Adjuvant Breast and Bowel Project 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. Ann N Y Acad Sci. 2001;949:143-50.
19. 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):1615-23.
20. Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360(9336):817-24.
21. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al. 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):272-82.
22. 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(9122):98-101.
23. 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):283-90.
24. Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, et al. Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial. Circulation. 2005;111(5):650-6.
25. 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. Lancet. 1998;352(9122):93-7.
26. Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, et al. 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):727-37.
27. Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, et al. Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst. 2003;95(2):160-5.
28. 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):1270-5.
29. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. 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):847-57.
30. 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. Breast Cancer Res Treat. 2001;65(2):125-34.
31. 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. JAMA. 1999;281(23):2189-97.
32. Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al. 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):3609-17.
33. 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(4):522-32.
34. 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):444-52.
35. 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. JAMA. 1999;282(7):637-45.
36. 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(10):789-96.
37. 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):135-40.
38. 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(17):5242-7.
39. Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al. Continuing Outcomes Relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96(23):1751-61.
40. 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):1543-8.
41. Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, et al. Skeletal effects of raloxifene after 8 years: results from the Continuing Outcomes Relevant to Evista (CORE) study. J Bone Miner Res. 2005;20(9):1514-24.
42. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. New Engl J Med. 2006;355(2):125-37.
43. Grady D, Cauley JA, Geiger MJ, Kornitzer M, Mosca L, Collins P, et al. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100(12):854-61.
44. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. 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):2727-41.
45. Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104(4):837-44.
46. 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(4):1230-7.
47. American College of Obsterticians and Gynecologists Committee on Practice Bulletins–Gynecology. ACOG Practice Bulletin: selective estrogen receptor modulators. Number 39, October 2002 (replaces Committee Opinion Number 224, October 1999). Int J Gynaecol Obstet. 2002;79(3):289-98.
48. 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(12):1681-90.
49. Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, et al. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27(19):3235-58.
50. American Cancer Society. Medicines to Reduce Breast Cancer Risk. Atlanta: American Cancer Society; 2013. Accessed at http://www.cancer.org/Cancer/BreastCancer/MoreInformation/MedicinestoReduceBreastCancer/medicines-to-reduce-breast-cancer-risk-toc on 2 April 2013.

AHRQ Publication No. 13-05189-EF-2
Current as of April 2013


Internet Citation:

U.S. Preventive Services Task Force. Medications for Risk Reduction of Primary Breast Cancer in Women: Draft Recommendation Statement. AHRQ Publication No. 13-05189-EF-2. http://www.uspreventiveservicestaskforce.org/draftrec4.htm.



USPSTF Program Office   540 Gaither Road, Rockville, MD 20850