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Medication Use for the Risk Reduction of Primary Breast Cancer in Women: a Systematic Review for the U.S

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Medication Use for the Risk Reduction of Primary Breast Cancer in Women: a Systematic Review for the U.S Evidence Synthesis Number 180 Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. HHSA-290-2015-00009-I, Task Order No. 7 Prepared by: Pacific Northwest Evidence-Based Practice Center Oregon Health & Science University Mail Code: BICC 3181 SW Sam Jackson Park Road Portland, OR 97239 www.ohsu.edu/epc Investigators: Heidi D. Nelson, MD, MPH Rongwei Fu, PhD Bernadette Zakher, MBBS Marian McDonagh, PharmD Miranda Pappas, MA Lucy Stillman, BS AHRQ Publication No. 19-05249-EF-1 September 2019 This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (HHSA-290-2015-0000-9I, Task Order No. 7). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information (i.e., in the context of available resources and circumstances presented by individual patients). This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report. Acknowledgments The authors thank AHRQ Medical Officers Ernie Sullivent, MD, MPH, and Tina Fan, MD, MPH; U.S. Preventive Services Task Force leads Alex Krist, MD, MPH, Carol Mangione, MD, MSPH, and Michael Barry, MD; expert reviewers of the draft report; expert consultant Rachel Yung, MD; and research librarian Andrew Hamilton, MLS, MS. Suggested Citation Nelson HD, Fu R, Zakher B, McDonagh M, Pappas M, Stillman L. Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 180. AHRQ Publication No. 19-05249-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2019. Risk-Reducing Medications for Breast Cancer ii Pacific Northwest EPC Structured Abstract Background: Medications to reduce breast cancer risk are an effective prevention intervention for women at increased risk, although medications also cause adverse effects. Purpose: To update the 2013 U.S. Preventive Services Task Force (USPSTF) systematic review on the use of medications to reduce the risk of primary breast cancer. Data Sources: Searches included the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013 to February 1, 2019); and manual review of reference lists. Studies published before 2013 were identified from prior systematic reviews for the USPSTF. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; double-blind, placebo-controlled or head-to-head randomized controlled trials (RCT) of tamoxifen, raloxifene, and aromatase inhibitors for primary prevention of breast cancer that enrolled women without preexisting breast cancer; and RCTs and observational studies of harms of medications. Data Extraction: One investigator abstracted data on study methods; setting; population characteristics; eligibility criteria; interventions; numbers enrolled and lost to followup; method of outcome ascertainment; and results for each outcome and a second investigator checked abstractions for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF. Data Synthesis (Results): Eighteen risk models evaluated in 25 studies had generally low discriminatory accuracy in predicting the probability of breast cancer in an individual (c-statistics 0.55 to 0.65). Most models performed only slightly better than age alone as a risk predictor. No studies evaluated optimal ages or frequencies of risk assessment. In placebo-controlled trials, tamoxifen (risk ratio [RR] 0.69; 95% confidence interval [CI], 0.59 to 0.84; 7 fewer cases per 1000 women over 5 years of use [95% CI, 4 to 12]; 4 trials), raloxifene (RR 0.44; 95% CI, 0.24 to 0.80; 9 fewer cases [95% CI, 3 to 15]; 2 trials), and the aromatase inhibitors exemestane and anastrozole (RR 0.45; 95% CI, 0.26 to 0.70; 16 fewer cases [95% CI, 8 to 24]; 2 trials) reduced invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in the Study of Tamoxifen And Raloxifene (STAR) head-to-head trial (RR, 1.24; 95% CI, 1.05 to 1.47) after long-term followup. Effects did not differ by age of initiation or duration of use (3 to 5 years), although these effects were not directly compared. Risk reduction persisted at least 8 years after discontinuation in tamoxifen trials with long-term followup. All medications reduced estrogen receptor positive, but not estrogen receptor negative invasive breast cancer; tamoxifen reduced noninvasive cancer in two trials; and breast-cancer specific and all-cause mortality were not reduced. In placebo-controlled trials, raloxifene (RR 0.61; 95% CI, 0.53 to 0.73; 2 trials) reduced vertebral fractures; tamoxifen reduced nonvertebral fractures in the National Surgical Adjuvant Breast and Bowel Project (NSABP P-1) trial (RR 0.66; 95% CI, 0.45 to 0.98); while the aromatase inhibitors had no effect on fractures. Tamoxifen and raloxifene had similar effects on Risk-Reducing Medications for Breast Cancer iii Pacific Northwest EPC reducing fractures at multiple vertebral and nonvertebral sites in the STAR head-to-head trial. In placebo-controlled trials, tamoxifen (RR 1.93; 95% CI, 1.33 to 2.68; 4 trials) and raloxifene (RR 1.56; 95% CI, 1.11 to 2.60; 2 trials) increased thromboembolic events, while aromatase inhibitors did not. Raloxifene caused fewer thromboembolic events (RR 0.75; 95% CI, 0.60 to 0.93) than tamoxifen in the STAR head-to-head trial. Tamoxifen, raloxifene, and aromatase inhibitors did not increase coronary heart disease events or strokes. In placebo-controlled trials, tamoxifen increased endometrial cancer (RR 2.25; 95% CI, 1.17 to 4.41; 3 trials), while raloxifene and aromatase inhibitors did not. In the STAR head-to-head trial, raloxifene caused fewer cases of endometrial cancer (RR 0.55; 95% CI, 0.36 to 0.83) and endometrial hyperplasia (RR 0.19; 95% CI, 0.12 to 0.29), and fewer hysterectomies (RR 0.45; 95% CI, 0.37 to 0.54) than tamoxifen. Tamoxifen increased cataracts (RR 1.22; 95% CI, 1.08 to 1.48; 3 trials) and cataract surgery compared with placebo, while raloxifene and aromatase inhibitors did not. Risks for thromboembolic events and endometrial cancer with tamoxifen were higher for older compared with younger women and returned to normal after discontinuation. All medications caused adverse effects, such as vasomotor or musculoskeletal symptoms, that varied by medication. Risks for invasive cancer were generally reduced in all population subgroups evaluated based on menopausal status (pre and postmenopausal); family history of breast cancer; body mass index categories; modified Gail model risk categories; and age at menarche, parity, or age at first live birth, although results varied. Tamoxifen and anastrozole had larger effects in reducing invasive breast cancer in women with previous breast lesions (lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia). Limitations: Trials were limited by clinical heterogeneity related to different medications, exposure durations, eligibility criteria, adherence, and ascertainment of outcomes. No trials compared timing and duration directly. Long-term followup data were lacking from most trials, and followup was particularly short for the aromatase inhibitors. Trials were not designed for subgroup comparisons and analysis of differences may be underpowered. Conclusions: Tamoxifen, raloxifene, and the aromatase inhibitors exemestane and anastrozole reduce invasive breast cancer in women without preexisting breast cancer, but also cause adverse effects that vary by medication. Tamoxifen and raloxifene increase thromboembolic events and tamoxifen increases endometrial cancer and cataracts. Identifying candidates for therapy is complicated by risk stratification methods that demonstrate low accuracy. Risk-Reducing Medications for Breast Cancer iv Pacific Northwest EPC Table of Contents Chapter 1. Introduction and Background ...................................................................................1 Purpose..........................................................................................................................................1
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