Breast Cancer: Preventive Medications --Women at increased risk for breast cancer


General

Grade: 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.

Specific Recommendations

The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects.

Frequency of Service

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 Factor Information

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 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. 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.


Clinical

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.34However, 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 (< i>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 < i>BRCA1 mutation have a cumulative risk for breast cancer of 72% by age 80 years; women who carry a < i>BRCA2mutation have a 69% cumulative risk8 (compared with a 12% lifetime risk in the general population9). Women who carry the < i>BRCA1mutation tend to develop estrogen receptor (ER)–negative breast cancer,10 while women who carry the < i>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 < i>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.34 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).31112 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,1314 whereas risk for VTEs and endometrial cancer return to baseline after discontinuation of tamoxifen.15Data 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 < i>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.1819

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.


Rationale

Importance

Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death.12The 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.2African 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.


Others

Other Considerations 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 < i>BRCA1 or < i>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.   Update of Previous USPSTF Recommendations 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.   Recommendations of Others 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 < i>BRCA mutation carriers.91Given 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.92The 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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