Chemoprevention of Breast Cancer: A Summary of the Evidence for the U.S. Preventive Services Task Force

Despite improvements in the rates of screening and early detection, treatment advances, and healthier lifestyles, breast cancer remains the most common nonskin cancer among women in the United States. In 2002, it will account for an estimated 203 500 new cases of invasive cancer and 54 300 cases of in situ cancer (1). Although mortality rates for some groups of women have modestly decreased in recent years, 39 600 women are expected to die of breast cancer in 2002 (1-3). The strongest risk factors for breast cancerincreasing age, family history, and hormonal factors (age at menarche and menopause)are not easily modifiable (4-12). Although obesity and alcohol intake are associated with increased risk, prospective studies have not yet shown that modifying these risk factors prevents the disease. Thus, other preventive strategies must be considered. Evidence that chemopreventive drugs might be able to prevent breast cancer first came to light in trials testing tamoxifen as adjuvant chemotherapy in women with breast cancer (13). Tamoxifen is a compound with both estrogen-like and antiestrogen properties (known as a selective estrogen-receptor modulator). A meta-analysis of 55 studies of adjuvant tamoxifen therapy demonstrated that it reduced the risk for new cancer in the opposite breast by 47% (P < 0.001) among women who took the drug for 5 years, suggesting a potential role in primary prevention (14). Tamoxifen also reduces the occurrence of invasive breast cancer in women with ductal carcinoma in situ (15). Another selective estrogen-receptor modulator, raloxifene, has also been studied as a possible chemopreventive agent. Although vitamin A analogues, such as fenretinide, have been investigated as potential drugs for chemoprevention, trial results have been disappointing (16). Staff members of the Research Triangle InstituteUniversity of North Carolina Evidence-based Practice Center, together with two members of the U.S. Preventive Services Task Force (USPSTF), reviewed the scientific evidence on issues related to the benefits and harms of chemoprevention of breast cancer in women without a history of breast cancer. This review was performed to assist the USPSTF in making recommendations for clinicians about chemoprevention for breast cancer (17). Methods Using USPSTF methodology, we first developed an analytic framework and a set of key questions to guide the search (18). (Details about the framework, key questions, and search strategy are available at www.annals.org). In general, we focused on evidence from randomized, controlled trials (RCTs) on the effectiveness of chemopreventive agents in reducing incidence of and death from breast cancer, as well as other potential beneficial and adverse effects. We also examined studies of the cost-effectiveness of these agents. Briefly, our search strategy involved two phases. The first used broad search terms and review criteria to maximize the probability of identifying all potentially relevant articles, and the second applied more stringent review criteria to focus on studies directly applicable to the key questions. We limited the search to English-language articles included in MEDLINE from 1966 to December 2001. Two authors and two other staff members from the Evidence-based Practice Center independently reviewed the titles and abstracts of articles identified by this search strategy and excluded those that they agreed clearly did not meet eligibility criteria. The authors fully reviewed articles that met the criteria. This research was funded by the U.S. Agency for Healthcare Research and Quality. Agency staff and USPSTF members participated in the initial design of the study and reviewed interim analyses and the final manuscript. Results Four RCTs examined the benefits of chemoprevention of breast cancer for women without previous breast cancer (19-22) (Table 1). Three trials used tamoxifen (20 mg/d) as the chemopreventive agent: the Royal Marsden Hospital (United Kingdom) Tamoxifen Chemoprevention Trial (19); the Italian Tamoxifen Prevention Study (21); and the National Surgical Adjuvant Breast and Bowel Project P-1 Study, known as the Breast Cancer Prevention Trial (BCPT) (20). One trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) (22), studied raloxifene. All four trials were well designed and conducted; all were double-blind, used concealed allocation to intervention and control groups, based their study size on calculations of statistical power, had defined study outcomes and data monitoring boards, and used intention-to-treat analysis. Table 1. Summary of Four Randomized, Controlled Trials of Breast Cancer Chemoprevention Effectiveness of Chemoprevention Neither of the two European tamoxifen trials found a reduction in overall breast cancer incidence. The Royal Marsden Trial (19) included 2471 women between 30 and 70 years of age with at least one first-degree relative who developed breast cancer before 50 years of age, one first-degree relative with bilateral breast cancer, or one affected first-degree relative of any age plus another first-degree or second-degree relative with the disease. In an interim analysis (median follow-up, almost 6 years), the Royal Marsden investigators found that 34 cases of breast cancer had been detected in the tamoxifen group and 36 in the placebo group (relative risk [RR], 0.94 [95% CI, 0.59 to 1.43]). The Italian Tamoxifen Prevention Study (21, 23) enrolled 5408 women aged 35 to 70 years who had had a hysterectomy for an indication other than cancer. Almost 67% of these women had also had bilateral (48.3%) or unilateral (18.6%) oophorectomy before menopause. At a median follow-up of almost 4 years, 41 cases of breast cancer had been diagnosed, 19 in the tamoxifen group and 22 in the placebo group (P > 0.2). Because relative risk was not provided, we calculated it to be 0.87 (CI, 0.62 to 2.14). After 6.75 years of follow-up, this study reported a nonstatistically significant trend toward a reduction in breast cancer incidence for all trial participants (hazard ratio [HR], 0.75 [CI, 0.48 to 1.18]). For the 29% of women (similar in each group) who took hormone replacement therapy during the trial, the difference was statistically significant (HR, 0.36 [CI, 0.14 to 0.91]) (23). In contrast to the European trials, the BCPT (21) found that the incidence of invasive breast cancer decreased by 50% over a median follow-up of 54.6 months. The BCPT, the largest chemoprevention trial, enrolled 13 388 women aged 35 years and older who had an estimated 5-year risk for breast cancer of at least 1.66%. This risk was calculated by applying a multivariate logistic regression model developed by Gail and colleagues (25) from data from a large cohort study of breast cancer screening. The factors that determine risk in this model include age, number of first-degree female relatives with breast cancer, nulliparity or age at first birth, number of breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche. Participants were stratified by age (35 to 49 years, 50 to 59 years, and 60 years) and estimated 5-year risk for breast cancer (<2.5%, 2.5% to 3.9%, and 4.0%). Over the course of the BCPT, a total of 264 women (175 in the placebo group and 89 in the tamoxifen group) received a diagnosis of invasive breast cancer (RR, 0.51 [CI, 0.39 to 0.66]). The absolute risk reduction was 21.4 cases per 1000 women over 5 years. The number of women who would need to be treated with tamoxifen for 5 years to prevent one case of breast cancer (number needed to treat for benefit [NNTB]) was 47. The BCPT found 69 cases of noninvasive breast cancer in the placebo group and 35 in the tamoxifen group (RR, 0.50; P < 0.002). The absolute risk reduction was 8.2 cases per 1000 women (NNTB, 122). The relative risk reduction was similar across all age groups and all risk levels. The drug was effective only against estrogen receptor-positive tumors (130 placebo cases vs. 41 tamoxifen cases) (RR, 0.31 [CI, 0.22 to 0.45]); it did not reduce the incidence of estrogen receptor-negative tumors (31 placebo cases vs. 38 tamoxifen cases). Given the relatively short follow-up, few deaths from breast cancer occurred in any of these trials. No study found statistically significant differences in mortality between study groups. The MORE trial (22) was designed primarily to examine the effect of raloxifene on osteoporosis fracture risk; breast cancer incidence was also assessed. It involved 7705 women with osteoporosis or previous vertebral fractures who were at least 2 years past menopause and were no older than 80 years of age (median age, 66.5 years). Participants were randomly assigned to receive raloxifene or placebo. Although the MORE investigators did not formally calculate breast cancer risk, the study groups were balanced in such breast cancer risk factors as age, body mass index, alcohol intake, and family history. After a median follow-up of 40 months, 40 cases of invasive breast cancer were confirmed: 13 cases in the 5129 women assigned to raloxifene and 27 in the 2576 women assigned to placebo (RR, 0.24 [CI, 0.13 to 0.44]). The absolute risk reduction was approximately 7.9 cases per 1000 women over 40 months (NNTB, 126). Raloxifene reduced the incidence of estrogen receptor-positive cancer by 90% (RR, 0.10 [CI, 0.04 to 0.24]) but had no effect on estrogen receptor-negative tumors (RR, 0.88 [CI, 0.26 to 3.00]) or on 12 cases of ductal carcinoma in situ. Data from longer follow-up (48 months) continued to show a substantial decrease in total incidence of invasive breast cancer (RR, 0.28 [CI, 0.17 to 0.46]) and incidence of estrogen receptor-positive cancer (RR, 0.16 [CI, 0.09 to 0.30]) but no effect on estrogen receptor-negative tumors (RR, 1.13 [CI, 0.35 to 3.66]) (24). We compared the studies in terms of factors that might explain their discrepant results: family history of breast cancer among the participants, estrogen receptor status of