• 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. Table 1 indicates how the estimated benefits of tamoxifen vary depending on age and family history. Other factors that contribute to risk include race, early age at menarche, pregnancy history (nulliparity or older age at first birth), and number of breast biopsies. The risk for developing breast cancer within the next 5 years can be estimated using risk factor information by completing the National Cancer Institute Breast Cancer Risk Tool (the "Gail model," available at https://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 has 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.

• 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.
  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 percent risk for developing breast cancer over the next 5 years (Table 1). On average, treating such women with tamoxifen for 5 years would prevent about three times as many invasive cancers (8 per 1,000) as the number of serious thromboembolic complications caused (1 stroke and 1 to 2 pulmonary emboli per 1,000). 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 percent 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 this drug'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.

Epidemiology and Clinical Consequences

Breast cancer is the most common non-skin cancer in women. An estimated 203,500 new cases of invasive breast cancer will be diagnosed in 2002, and 39,600 women will die from the disease.³ Although the USPSTF concluded that early detection of breast cancer through mammography has reduced deaths from breast cancer, the effectiveness of mammography is limited. Another approach to reducing breast cancer deaths is chemoprevention for primary prevention of cancer.

Potential Benefits of Chemoprevention

The use of agents to prevent the development of breast cancer was suggested by trials of breast cancer treatment with tamoxifen, a compound with both estrogen-like and anti-estrogen properties (a selective estrogen receptor modulator).⁴ A meta-analysis of 55 studies evaluating tamoxifen for the treatment of women with breast cancer found that the drug was associated with an approximately 50 percent reduction in the risk for developing new cancers in the opposite breast among women who took the drug for 5 years.⁵

The USPSTF found and evaluated 4 randomized controlled trials (RCTs) of breast cancer chemoprevention in women who had never had breast cancer.⁴ Three of these trials used tamoxifen as the chemopreventive agent,^6-8 one trial used raloxifene, another selective estrogen receptor modulator.⁹

Of the 3 RCTs of tamoxifen, the largest (the Breast Cancer Prevention Trial—BCPT), with 13,388 women enrolled, found a risk reduction of invasive cancer of 49 percent among women at high risk for breast cancer (estimated 5-year risk of 1.66 percent or greater).⁷ Over the course of the BCPT, a total of 264 women were diagnosed with invasive breast cancer: 175 in the placebo group and 89 in the tamoxifen group (RR, 0.51; 95 percent CI, 0.39-0.66). The absolute risk reduction was 21.4 cases per 1,000 women over 5 years.

The two other tamoxifen RCTs did not show a similar benefit. The relative risk reduction for breast cancer was 0.94 (95 percent CI, 0.59-1.43) for the Royal Marsden Hospital study⁶ and 0.87 (95 percent CI, 0.62-2.14) for the Italian Tamoxifen Prevention Study.[[8] Although the reasons for these discrepant results are not definitively established, possible explanations include differences in the duration of therapy and differences between women enrolled in each study.¹ The average duration of therapy was shorter in the European trials and, compared with the women enrolled in BCPT, the women in these trials were younger, had more estrogen-receptor-negative cancers, and were more likely to be taking hormone replacement therapy or to have had an oopherectomy.¹

The study evaluating raloxifene in postmenopausal women with osteoporosis found a 76 percent risk reduction (RR, 0.24; 95 percent CI, 0.13-0.44) in the development of invasive breast cancer.⁹ After a median followup of 40 months, the absolute risk reduction among women taking raloxifene was 7.9 cases per 1,000 women (number needed to treat, 126).⁹ When effective, both raloxifene and tamoxifen were effective only against estrogen receptor-positive tumors.¹

Potential Harms of Chemoprevention

Both tamoxifen and raloxifene increase the risk for thromboembolic events and hot flashes; tamoxifen increases the risk for endometrial cancer.¹ The number of total thromboembolic events in all four trials was small, and differences in specific complication rates between the treatment and placebo arms were statistically significant only for pulmonary embolism.¹ Among women aged 50 and older, for whom the potential harms of tamoxifen and raloxifene are more common than they are for younger women, the BCPT reported that after a median of 55 months of use, tamoxifen:

• Increased the rate of stroke from 1.3 cases/1,000 women in the placebo group to 2.2 cases/1,000 women in the study group (RR, 1.75; 95 percent CI, 0.98-3.20).
• Increased the rate of pulmonary embolism from 0.3 cases/1,000 women in the placebo group to 1.0 cases/1,000 women in the study group (RR, 3.19 percent; 95 percent CI, 1.12-11.15).
• Increased the rate of deep vein thrombosis from 0.9 cases/1,000 women in the placebo group to 1.5 cases/1,000 women in the study group (RR, 1.71; 95 percent CI, 0.85-3.58).⁷

Fewer thromboembolic events occurred among women younger than 50, and the trial found no significant difference in incidence between the tamoxifen and placebo groups in this age group.⁷ The relative risk increase in venous thromboembolism from tamoxifen or raloxifene appears similar to the risk for venous thromboembolism from oral contraceptives or hormone replacement therapy.¹

Among women aged 50 and older in the BCPT, participants who received tamoxifen, compared with those who took placebo, had a 4.0 times greater risk (95 percent CI, 1.70-10.90) of developing Stage 1 endometrial cancer (0.8 cancers/1,000 women taking placebo vs 3.1 cancers/1,000 women taking tamoxifen for a median of 55 months).⁷ Among women younger than 50, the BCPT found no significant difference in endometrial cancer rates between the two groups. No deaths attributed to endometrial cancer occurred in the trial.⁷ Raloxifene has not been associated with an increase in endometrial cancer.⁹

The BCPT reported that women in the tamoxifen group were at increased risk for developing cataracts and having cataract surgery compared with placebo (RR, 1.14 [95 percent CI, 1.01-1.29] and 1.57 [95 percent CI, 1.16-2.14], respectively).⁷

Quality-of-life issues have also been of concern and were addressed in the BCPT. Women in the BCPT reported increased rates of bothersome hot flashes (45.7 percent in the tamoxifen group vs 28.7 percent in the placebo group) and bothersome vaginal discharge (12.4 percent in the tamoxifen group vs 4.5 percent in the placebo group).⁷ Women given raloxifene also noted higher rates of hot flashes than women given placebo (10.7 percent in the ralixifene group vs 6.4 percent in the placebo group).⁹

Although long-term adherence for highly motivated women was about 80 percent in the BCPT trial and about 90 percent in the raloxifene trial, adherence rates in the general population are unknown.²

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, and with attention to the ability to manage complications of therapy.¹⁰ The American Society of Clinical Oncology suggests that women with a 5-year projected risk for breast cancer greater than or equal to 1.66 percent may be offered tamoxifen to reduce their risk. They also recommend that raloxifene use should be reserved for treatment of osteoporosis in postmenopausal women.¹¹ The Canadian Task Force on Preventive Health Care recommends that clinicians counsel women at high risk for breast cancer (Gail index ≥1.66 percent for 5 years) about the potential benefits and harms of breast cancer prevention with tamoxifen.¹²

Members of the U.S. Preventive Services Task Force are Alfred O. Berg, M.D., M.P.H., Chair, USPSTF (Professor and Chair, Department of Family Medicine, University of Washington, Seattle, WA); Janet D. Allan, Ph.D., R.N., C.S., F.A.A.N., Vice-chair, USPSTF (Dean and Professor, School of Nursing, University of Texas Health Science Center, San Antonio, TX); Paul Frame, M.D. (Tri-County Family Medicine, Cohocton, NY, and Clinical Professor of Family Medicine, University of Rochester, Rochester, NY); Charles J. Homer, M.D., M.P.H. (Executive Director, National Initiative for Children's Healthcare Quality, Boston, MA); Mark S. Johnson, M.D., M.P.H. (Chair, Department of Family Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ); Jonathan D. Klein, M.D., M.P.H. (Associate Professor, Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY); Tracy A. Lieu, M.D., M.P.H. (Associate Professor, Department of Ambulatory Care and Prevention, Harvard Pilgrim Health Care and Harvard Medical School, Boston, MA); Cynthia D. Mulrow, M.D., M.Sc. (Clinical Professor and Director, Department of Medicine, University of Texas Health Science Center, and Director, National Program Office for Robert Wood Johnson Generalist Physician Faculty Scholars Program, San Antonio, TX); Tracy C. Orleans, Ph.D. (Senior Scientist and Senior Program Officer, The Robert Wood Johnson Foundation, Princeton, NJ); Jeffrey F. Peipert, M.D., M.P.H. (Director of Research, Women and Infants' Hospital, Providence, RI); Nola J. Pender, Ph.D., R.N., F.A.A.N. (Professor Emeritus, University of Michigan, Ann Arbor, MI); Albert L. Siu, MD., MSPH (Professor of Medicine, Chief of Division of General Internal Medicine, Mount Sinai School of Medicine, New York, NY); Steven M. Teutsch, M.D., M.P.H. (Senior Director, Outcomes Research and Management, Merck & Company, Inc., West Point, PA); Carolyn Westhoff, M.D., M.Sc. (Professor, Department of Obstetrics and Gynecology, Columbia University, New York, NY); and Steven H. Woolf, M.D., M.P.H. (Professor, Department of Family Practice and Department of Preventive and Community Medicine, Virginia Commonwealth University, Fairfax, VA).

*These estimates are based on the Gail model, outcomes from the Breast Cancer Prevention Trial, and baseline rates of harms from Gail et al.¹³
† No family history = no first-degree relatives with breast cancer; family history = 1 first-degree relative with breast cancer.
‡Based on menarche at 12 years of age, first birth at "22" years of age, and no history of breast biopsy, as calculated from the Gail model.
§ Modified from Gail et al.¹³