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Context Medications that reduce breast cancer risk may have other potential benefits and harms. Contribution This review of 8 trials found that tamoxifen, raloxifene, and tibolone each reduced risk for invasive breast cancer in women more than placebo. Tamoxifen and raloxifene reduced risk for estrogen receptorpositive but not estrogen receptornegative breast cancer or death. All drugs reduced fracture risks. They also increased risk for thromboembolic events (tamoxifen and raloxifene), endometrial cancer (tamoxifen), and strokes (tibolone). Implication Although tamoxifen, raloxifene, and tibolone sometimes reduce risk for primary breast cancer, they also may increase a woman's risk for particular harmful events. The Editors Recent clinical trials have shown the efficacy of the selective estrogen receptor modulators tamoxifen citrate and raloxifene and of the selective tissue estrogenic activity regulator tibolone to reduce the risk for invasive breast cancer in women without preexisting cancer. Tamoxifen and raloxifene are approved by the U.S. Food and Drug Administration (FDA) for this purpose among women at high risk for breast cancer. The FDA indications define high risk as having a breast biopsy showing lobular carcinoma in situ or atypical hyperplasia, 1 or more first-degree relatives with breast cancer, or a 5-year predicted risk for breast cancer of 1.66% or more calculated by the modified Gail model (13). These are similar to entry criteria of the major U.S. clinical trials (48). Tamoxifen is also approved for treatment of early and advanced estrogen receptorpositive breast cancer in pre- and postmenopausal women. Raloxifene is most often used to prevent and treat osteoporosis in postmenopausal women. Tibolone is not currently approved for use in the United States, but it is approved to treat menopausal symptoms in 90 countries and to prevent osteoporosis in 45 (9, 10). In the United States, use of these medications for reducing breast cancer risk is low (4). This comparative effectiveness review summarizes the available evidence for the effectiveness and safety of tamoxifen citrate, raloxifene, and tibolone for reducing risk for primary breast cancer in women in general and among population subgroups of women. This review highlights outcomes that are most commonly associated with the medications and are clinically most important. Methods For all steps of the review, we followed a standard protocol that is consistent with the Agency for Healthcare Research and Quality Effective Healthcare Program Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews (11). Additional information about methods for this review, including detailed search strategies, inclusion criteria, extraction, and rating processes, is available in the appendices to this article (www.annals.org) and the full technical report (effectivehealthcare.ahrq.gov) (12). Key questions guiding this review were developed through the Effective Healthcare Program. Investigators created an analytic framework that incorporated the key questions and outlined the patient population, interventions, and clinical outcomes (Appendix Figure 1). Additional outcomes and evidence related to key questions about risk stratification and adherence to medications are available in the full technical report (12). The target population includes women who did not have preexisting invasive or noninvasive breast cancer or precursor conditions and were not known carriers of breast cancer susceptibility mutations (BRCA1, BRCA2, or others). Appendix Figure 1. Analytic framework and key questions for full comparative effectiveness review. *Detailed descriptions are provided in the inclusion and exclusion criteria in Appendix Figure 2. Data Sources and Searches In conjunction with a research librarian, the investigators searched MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from inception to January 2009 for relevant English-language reports of studies, systematic reviews, and meta-analyses. We also manually reviewed reference lists, citations for major trials in Web of Science, and clinical trial registries. We requested scientific information packets from manufacturers of the 3 medications, although the only packet provided was for raloxifene. We contacted investigators of the major trials for additional unpublished data specifically addressing population subgroups but received none. Study Selection Before reviewing abstracts and articles, we developed inclusion and exclusion criteria for studies based on the key questions and target population. We included studies with treatment durations of 3 months or more that enrolled 100 or more participants to ensure adequate drug exposure and power to support results. For comparative benefits, we included only double-blind, placebo-controlled, or head-to-head randomized, controlled trials (RCTs) of tamoxifen, raloxifene, or tibolone to reduce risk for breast cancer that enrolled women without preexisting breast cancer. We included trials that were designed and powered to demonstrate invasive breast cancer incidence as a primary or secondary outcome. The technical expert panel for this project advised including only RCTs because of the lack of observational studies of tamoxifen and raloxifene with breast cancer outcomes in women without preexisting cancer and concerns for bias in observational studies in which women were using these medications for other indications. We defined our inclusion criteria for comparative harms more broadly. We included RCTs and observational studies of tamoxifen, raloxifene, or tibolone in women without breast cancer that were designed for multiple types of outcomes. However, studies must have had a nonuser comparison group or direct comparisons between tamoxifen, raloxifene, or tibolone to be included. We considered all adverse outcomes at all reported follow-up times to capture potential short- and long-term adverse effects. However, because the National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP P-1) trial was unblinded after investigators reported initial results in 1998, we focused on data from the earlier 1998 publication (8) and then compared these results with data from the subsequent 2005 publication (7). Appendix Figure 2, provides detailed inclusion and exclusion criteria for benefits and harms. Appendix Figure 2. Inclusion and exclusion criteria for studies. RCT = randomized, controlled trial. *Benefit outcomes are defined by key question 1 and include invasive breast cancer; noninvasive breast cancer, including ductal carcinoma in situ; breast cancer mortality; all-cause mortality; and osteoporotic fractures. Population subgroups are defined by key question 3 and include but are not limited to those based on age, menopausal status (pre-, peri-, postmenopausal), hysterectomy status, use of exogenous estrogen, level of risk for breast cancer (based on family history, body mass index, parity [number of pregnancies], age at first live birth, age at menarche, personal history of breast abnormalities, previous breast biopsy, estradiol levels, and breast density), ethnicity and race, metabolism status (CYP 2D6 mutation), and risk for thromboembolic events (obesity and other risk factors). Definitions of types of outcomes: primary outcomethe main outcome of a study that the study was designed and powered to demonstrate; secondary outcomemajor outcome of a study that the study was designed and powered to demonstrate, but not the primary outcome of the study; health outcomessigns, symptoms, conditions, or events that persons experience, such as myocardial infarction, death, or hot flashes; intermediate outcomeshealth measures that persons do not personally experience, such as laboratory test results or bone mineral density. Harms outcomes are defined by key question 2 and may include but are not limited to thromboembolic events (deep venous thrombosis, pulmonary embolism), cardiovascular events (coronary heart disease, stroke and transient ischemic attack, arrhythmias), metabolic disorders (diabetes), musculoskeletal symptoms (myalgia, leg cramps), mental health (depression, mood changes), genitourinary outcomes (vaginal dryness, uterine bleeding, hysterectomy, endometrial cancer, urinary symptoms), adverse breast outcomes (biopsies), other cancer (incidence, death), ophthalmologic disorders (cataracts), gastrointestinal/hepatobiliary disorders (abdominal pain, nausea), and other adverse events affecting quality of life (vasomotor symptoms, sexual function, sleep disturbances, headaches, cognitive changes, peripheral edema). After an initial review of abstracts, we retrieved full-text articles of potentially relevant material and conducted a second review to determine inclusion. A second reviewer confirmed results of the initial reviewer, and discrepancies were resolved by group consensus. Data Abstraction and Quality Assessment From the included studies, investigators abstracted study design, setting, participant characteristics, enrollment criteria, interventions, numbers enrolled and lost to follow-up, methods of outcome ascertainment, and results for each outcome. A second investigator confirmed the accuracy of the abstracted information. We used predefined criteria developed by the U.S. Preventive Services Task Force to assess the quality of individual studies (good, fair, or poor) (13). We assessed study applicability by following the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting format (good, fair, or poor) (11). Two investigators independently rated quality and applicability of each study, and final ratings were determined by consensus. Investigators determined the overall strength of the body of evidence through group consensus by using the Evidence-based Practice Center GRADE (Grading of Recommendations Assessment, Development, and Evaluation) appro

Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer