Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women

Breast cancer is the most frequently diagnosed noncutaneous cancer and the second leading cause of cancer death after lung cancer among women in the United States. In 2008, an estimated 182,460 cases of invasive breast cancer and 67,770 cases of in situ breast cancer were diagnosed, and 40,480 women died of breast cancer in the United States. Recent clinical trials have demonstrated the efficacy of three medications-tamoxifen citrate, raloxifene, and tibolone-to reduce the risk of invasive breast cancer in women without pre-existing cancer. This therapy is sometimes referred to as "chemoprevention" in the literature, although this is not a fully accurate representation of the intervention. Tamoxifen and raloxifene are approved by the U.S. Food and Drug Administration for this indication and tibolone is not. Raloxifene is approved for use by postmenopausal women only. Current clinical recommendations, including those from the U.S. Preventive Services Task Force issued in 2002, support tamoxifen use for primary breast cancer prevention in women considered at high risk for breast cancer by the Gail model or other criteria and low risk for adverse events. However, use of risk-reducing medications for breast cancer is believed to be low in the United States. The purpose of this review is to evaluate the comparative effectiveness of tamoxifen citrate, raloxifene, and tibolone to reduce the risk of primary breast cancer; assess the nature and magnitude of harms; and examine how benefits and harms vary by age, breast cancer risk status, and other factors. The review was originally entitled "Comparative Effectiveness of Chemotherapy Agents in the Prevention of Primary Breast Cancer in Women." Peer review comments suggested that the terms "chemotherapy" and "prevention" were misnomers. The term "medications to reduce risk" is a better representation of the intervention and therefore, all references to "chemoprevention" are edited, including the key questions and report title. The review also examines issues related to clinical effectiveness, such as patient choice, concordance, adherence, and persistence of use, and evaluates methods to appropriately select patients for risk-reducing medications for clinical applications. The target population includes women without pre-existing breast cancer, noninvasive breast cancer, or precursor conditions who are not known carriers of breast cancer susceptibility mutations (BRCA1, BRCA2, or others). Key questions addressed include: Key Question 1. In adult women without pre-existing breast cancer, what is the comparative effectiveness of selective estrogen receptor modulators (SERMs) tamoxifen citrate and raloxifene, and the selective tissue estrogenic activity regulator (STEAR) tibolone, when used to reduce risk for primary breast cancer on improving short-term and long-term outcomes including invasive breast cancer, noninvasive breast cancer, including ductal carcinoma in situ (DCIS), breast cancer mortality, all-cause mortality, and osteoporotic fractures? Key Question 2. What is the evidence for harms of tamoxifen citrate, raloxifene, and tibolone when used to reduce risk for primary breast cancer? Key Question 3. How do outcomes for tamoxifen citrate, raloxifene, and tibolone when used for primary prevention of breast cancer vary by heterogeneity in subpopulations? Key Question 4. What is the evidence that harms or secondary potential benefits listed above affect treatment choice, concordance, adherence, and persistence to treatment with tamoxifen citrate, raloxifene, and tibolone when used for primary prevention of breast cancer? Key Question 5. What methods, such as clinical risk-assessment models, have been used to identify women who could benefit from medications to reduce risk of breast cancer?