The USPSTF found fair evidence that treatment with tamoxifen can significantly reduce the risk for invasive estrogen receptor–positive breast cancer in women at high risk for breast cancer and that the likelihood of benefit increases as the risk for breast cancer increases. The USPSTF found consistent but less abundant evidence for the benefit of raloxifene. The USPSTF found good evidence that tamoxifen and raloxifene increase the risk for thromboembolic events (for example, stroke, pulmonary embolism, and deep venous thrombosis) and symptomatic side effects (for example, hot flashes) and that tamoxifen, but not raloxifene, increases the risk for endometrial cancer. The USPSTF concluded that the balance of benefits and harms may be favorable for some high-risk women but will depend on breast cancer risk, risk for potential harms, and individual patient preferences.

Clinical Considerations

Clinicians should consider both the risk for breast cancer and the risk for adverse effects when identifying women who may be candidates for chemoprevention.

Risk for Breast Cancer

Older age; a family history of breast cancer in a mother, sister, or daughter; and a history of atypical hyperplasia on a breast biopsy are the strongest risk factors for breast cancer. The Table indicates how the estimated benefits of tamoxifen vary depending on age and family history. Other factors that contribute to risk include race or ethnicity, early age at menarche, pregnancy history (nulliparity or older age at first birth), and number of breast biopsies. Risk factor information can be used to estimate the risk for breast cancer within the next 5 years by completing the U.S. National Cancer Institute Breast Cancer Risk Tool (the Gail model [1], available at http://cancer.gov/bcrisktool/ or 800-4-CANCER). Clinicians can use this information to help individual patients considering tamoxifen therapy estimate the potential benefit. However, the validity, feasibility, and impact of using the Gail model to identify appropriate candidates for chemoprevention have not been tested in a primary care setting. The Gail model does not incorporate estradiol levels or estrogen use, factors that some studies suggest may influence the effectiveness of tamoxifen.

Risk for Adverse Effects

Women are at lower risk for adverse effects from chemoprevention if they are younger; have no predisposition to thromboembolic events such as stroke, pulmonary embolism, or deep venous thrombosis; or do not have a uterus.

Balance of Benefits and Harms

In general, the balance of benefits and harms of chemoprevention is more favorable for 1) women in their 40s who are at increased risk for breast cancer and have no predisposition to thromboembolic events and 2) women in their 50s who are at increased risk for breast cancer, have no predisposition to thromboembolic events, and do not have a uterus. For example, a woman who is 45 years of age and has a mother, sister, or daughter with breast cancer would have approximately a 1.6% risk for breast cancer over the next 5 years (Table 1). On average, treating such women with tamoxifen for 5 years would prevent approximately three times as many cases of invasive cancer (8 per 1000 women) as the number of serious thromboembolic complications caused (1 stroke and 1 to 2 pulmonary emboli per 1000 women). For example, among women 55 years of age, benefits exceed harms only for those who are not at risk for endometrial cancer, and the margin of benefit is small unless risk for breast cancer is substantially increased (for example, 4% over 5 years).

Women younger than 40 years of age have a lower risk for breast cancer and thus will not experience as large an absolute benefit from breast cancer chemoprevention as older women. Women 60 years of age and older, who have the highest risk for breast cancer, also have the highest risk for complications from chemoprevention, with a less favorable balance of benefits and harms.

The USPSTF found more evidence for the benefits of tamoxifen than for the benefits of raloxifene. Currently, only tamoxifen is approved by the U.S. Food and Drug Administration (FDA) for the specific indication of breast cancer chemoprevention. Although there are biological reasons to suspect that raloxifene should have similar benefits, trial data currently are limited to one study in which the primary outcome was fracture prevention. Additional trials to further evaluate raloxifene's efficacy for breast cancer chemoprevention are under way, including a trial comparing efficacy and safety of raloxifene and tamoxifen. Raloxifene is approved by the FDA for preventing and treating osteoporosis.

The brief review of the evidence that is normally included in USPSTF recommendations is available in the complete Recommendation and Rationale Statement on the USPSTF Web site (http://www.preventiveservices.ahrq.gov).

Recommendations of Others

The American College of Obstetricians and Gynecologists emphasizes the importance of clinician judgment and recommends that any decision to use tamoxifen be made on an individual basis after consideration of the patient's medical history, risk assessment, and preferences. It also stresses that ability to manage complications of therapy should be considered (2). The American Society of Clinical Oncology suggests that tamoxifen should be offered to women with a 5-year projected risk for breast cancer greater than or equal to 1.66% in order to reduce their risk. It also recommends that raloxifene use should be reserved for treatment of osteoporosis in postmenopausal women (3). The Canadian Task Force on Preventive Health Care recommends that clinicians counsel women at high risk for breast cancer (Gail index 1.66% for 5 years) about the potential benefits and harms of breast cancer prevention with tamoxifen (4).

Appendix

Members of the U.S. Preventive Services Task Force are Alfred O. Berg, MD, MPH, Chair, (University of Washington, Seattle, Washington); Janet D. Allan, PhD, RN, CS, Vice-Chair (University of Texas Health Science Center, San Antonio, Texas); Paul Frame, MD (Tri-County Family Medicine, Cohocton, and University of Rochester, Rochester, New York); Charles J. Homer, MD, MPH (National Initiative for Children's Healthcare Quality, Boston, Massachusetts); Mark S. Johnson, MD, MPH (University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, New Jersey); Jonathan D. Klein, MD, MPH (University of Rochester School of Medicine, Rochester, New York); Tracy A. Lieu, MD, MPH (Harvard Pilgrim Health Care and Harvard Medical School, Boston, Massachusetts); Cynthia D. Mulrow, MD, MSc (University of Texas Health Science Center and National Program Office for Robert Wood Johnson Generalist Physician Faculty Scholars Program, San Antonio, Texas); Tracy C. Orleans, PhD (The Robert Wood Johnson Foundation, Princeton, New Jersey); Jeffrey F. Peipert, MD, MPH (Women and Infants' Hospital, Providence, Rhode Island); Nola J. Pender, PhD, RN, (University of Michigan, Ann Arbor, Michigan); Albert L. Siu, MD, MSPH (Mount Sinai School of Medicine, New York, New York); Steven M. Teutsch, MD, MPH (Merck & Co., Inc., West Point, Pennsylvania); Carolyn Westhoff, MD, MSc (Columbia University, New York, New York); and Steven H. Woolf, MD, MPH (Virginia Commonwealth University, Fairfax, Virginia).