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Journal of Oncology Practice, Vol 5, No 4 (July), 2009: pp. 196-199 © 2009 American Society of Clinical Oncology. DOI: 10.1200/JOP.0948502
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
To update ASCO's Clinical Practice Guideline on the use of pharmacologic interventions to reduce the risk of breast cancer, ASCO convened an Update Committee of the Breast Cancer Risk Reduction Expert Panel. ASCO published the first version of this guideline in 1999 and last updated it in 2002. This 2009 updated guideline1 addresses the roles of tamoxifen, raloxifene, aromatase inhibitors, and fenretinide in reducing the risk of breast cancer. Recommendations made in the guideline update are listed in Table 1. All of the trials that provide evidence for this guideline update used breast cancer incidence as an end point and were published between 2002 and 2007. This guideline update addresses the following clinical questions:
Women at risk are defined as those with:
Tamoxifen This recommendation is based on the review of results of four phase III randomized clinical trials that compared 5 years of tamoxifen with placebo. All of the women were at increased risk for breast cancer. Tamoxifen is approved by the US Food and Drug Administration (FDA) for reducing the risk of invasive breast cancer for women who are at increased risk of breast cancer and either premenopausal or postmenopausal. Tamoxifen (20 mg/d), taken for 5 years, may reduce the risk of developing estrogen receptor (ER)–positive invasive breast cancer for up to 10 years. In a 2003 meta-analysis of these trials, the risk of ER-positive breast cancer was decreased by 48%. (Note: The meta-analysis included data available an average of 3 years after last entry year of major trials and therefore did not include some subsequently released data considered in the guideline.) There are now follow-up data from one of the studies that the decrease in risk lasted for up to 10 years, but overall, the data on tamoxifen use for more than 5 years in the setting of risk reduction are limited. Therefore, it is recommended that the duration of tamoxifen be limited to 5 years outside of a clinical trial setting. Tamoxifen is not known to have an effect on overall or breast cancer–specific mortality, but a reduction in diagnoses of breast cancer should be considered an important health outcome in and of itself, even in the absence of ultimate reduction in breast cancer mortality. A possible benefit to taking tamoxifen is reduced risk of fractures, primarily in women who are postmenopausal, based on the result of one trial. Concurrent hormone therapy is not recommended with tamoxifen used for breast cancer risk reduction, given that the safety of the combination has not been established. Adverse events.Serious adverse events may result from tamoxifen use. Tamoxifen is not recommended in women with a prior history of deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack. Tamoxifen use in the prevention setting may increase the risk of ischemic stroke, particularly in women 50 years of age or older. Follow-up data indicate that the risk of serious adverse events, such as thromboembolism, decreases after active treatment. Two meta-analyses found the risk of uterine/endometrial cancer nearly doubled with tamoxifen use. In the largest individual clinical trial, the elevated risk of endometrial cancer was only for women 50 years of age and older. In all of the trials, the majority of uterine cancers were successfully treated stage 1 adenocarcinomas. The guideline recommends that women receiving tamoxifen have a baseline gynecologic examination before starting tamoxifen and annual follow-up continuing after treatment ends, with a timely thorough work-up for abnormal vaginal bleeding. Routine endometrial biopsy is not needed in the absence of abnormal vaginal bleeding. Women with abnormalities on endometrial biopsy performed because of abnormal vaginal bleeding may consider stopping tamoxifen use, in consultation with their gynecologist or primary care physician. A meta-analysis found the risk of thromboembolic events increased 1.9-fold with tamoxifen use; pulmonary emboli were the most common events. The risk of superficial thrombophlebitis was three-fold higher. Therefore, tamoxifen is not recommended for women with a prior history of thromboembolic events, stroke, or transient ischemic attack. Two trials found that the risk decreased after the course of active treatment. Tamoxifen may increase the incidence of cataracts, particularly in older women. Vaginal discharge and hot flashes were commonly reported adverse effects. However, some trials reported that the gynecologic and vasomotor symptoms were greatest during active treatment and did not increase post-treatment. Leg cramps and bladder control problems were also reported by women in the tamoxifen arms. Clinicians should help women become aware that such symptoms may arise with tamoxifen use. Reported effects of tamoxifen on cognition are inconsistent and inconclusive. Risks and benefits associated with tamoxifen use should be carefully considered during the decision making process.
Raloxifene A reduction in risk was observed across the trials, primarily for ER-positive invasive breast cancer. Raloxifene has equal efficacy to tamoxifen in reducing breast cancer risk for women who are postmenopausal. Raloxifene did not reduce noninvasive breast cancer as much as tamoxifen, but this finding was not statistically significant. Raloxifene (60 mg/d), taken for 5 years, may be offered as an option to reduce the risk of ER-positive invasive breast cancer for women who are postmenopausal and at increased risk of breast cancer, and for women who are postmenopausal with osteoporosis in whom breast cancer risk reduction is a secondary benefit. The optimal duration of the use of raloxifene is not defined, but safety information for randomized trials is limited to 8 years. The guideline recommends the duration of no longer than 5 years for primary breast cancer prevention. Women who are postmenopausal and for whom breast cancer risk reduction is a secondary outcome (to addressing osteoporosis) may take raloxifene for more than 5 years. Raloxifene is not recommended for breast cancer risk reduction in premenopausal women. Raloxifene does not have demonstrated activity against established breast cancer and should not be used to treat breast cancer or prevent its recurrence. Raloxifene is not known to have an effect on overall or breast cancer–specific mortality, but a reduction in diagnoses of breast cancer should be considered an important health outcome in and of itself, even in the absence of ultimate reduction in breast cancer mortality. For women with osteoporosis at risk for breast cancer, breast cancer risk reduction is an additional potential benefit. Fracture does not seem to be a risk of raloxifene, so women with a prior history of fractures or osteoporosis should not be excluded from considering raloxifene. Adverse events.Raloxifene is not recommended for women with a prior history of deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack. In the three trials comparing raloxifene with placebo, thrombolic events increased with raloxifene, but in two trials, the increase was not statistically significant. Reported adverse effects included venous thromboembolism, vasomotor symptoms, gynecologic symptoms, musculoskeletal problems, dyspareunia, hot flashes, leg cramps, bladder control problems, and peripheral edema. Risks and benefits associated with raloxifene use should be carefully considered during the decision making process.
Adverse Effects: A Comparison of Tamoxifen and Raloxifene
Aromatase Inhibitors and Retinoids
Risk Assessment and Risk Communication If a clinician identifies a woman as being at elevated risk for breast cancer, an informed discussion of risk reduction strategies, including risks and benefits, should be initiated while being sensitive to her personal needs and values—including race, culture, and socioeconomic status. The guideline recommends that health care providers present women with both the risks and benefits in absolute and relative terms, which will help to avoid emphasizing the benefits or harms of medical approaches.
Because this clinical practice guideline represents expert recommendations on the best practices in breast cancer risk reduction, it notes that many women have limited access to medical care and that racial and ethnic disparities are often a reflection of limited access to health care in the United States. White women with health insurance are more likely to seek preventive health care than women from other racial/ethnic groups. Evidence suggests that white women were more than three times as likely as African American and Hispanic women, and insured women were twice as likely as uninsured women, to have had a breast biopsy. In addition, racial/ethnic differences seem to influence risk for breast cancer. Health care providers and researchers should consider these disparities in their assessments of risk, discussions with women at risk, and chosen interventions, and when recruiting women for breast cancer risk reduction trials.
The guideline includes a section on allelic variants of the CYP2D6 gene. The guideline does not recommend testing for variants in the risk reduction setting at the present time. There is a need to develop agents that prevent ER-negative breast cancer, as the benefit of tamoxifen and raloxifene seems limited to reducing the risk of ER-positive invasive breast cancers. The guideline reviewed literature regarding risk reduction agents and women with BRCA1 and BRCA2 mutations and found there were insufficient data on the preventive effect of tamoxifen, raloxifene, and aromatase inhibitors specifically in women who carry the BRCA mutation.
The ASCO Update Committee reviewed searches of MEDLINE and the Cochrane Collaboration Library and conducted a systematic review of the literature published between January 2002 and July 2007.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1935-469X. Print ISSN: 1554-7477
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Recommendations
1.66% (according to the National Cancer Institute [NCI] Breast Cancer Risk Assessment Tool
