Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force [Entered Retrospectively]

Project Summary Title and Description

Title
Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force [Entered Retrospectively]
Description
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 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.
Attribution
N/A
Authors of Report
N/A
Methodology description
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.
PROSPERO
N/A
DOI
10.26300/yqg2-xy52
Notes
Data was entered retrospectively via the upload of the evidence and quality appendix tables in a single Word file. The tables uploaded for this project include: Appendix B1. Quality Assessment of Diagnostic Accuracy Studies Appendix B2. Quality Assessment of Randomized Controlled Trials Appendix B3. Evidence Table of Trials of Risk Reducing Medications for Breast Cancer
Funding Source
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 (Contract No. HHSA290201500009I, Task Order No. 7)

Key Questions

1. Key Question 1. In adult women without preexisting breast cancer, what is the accuracy of risk assessment methods to identify women who could benefit from medications to reduce risk for primary breast cancer (e.g., clinical risk assessment models)? Key Question 1a. What is the optimal age at which to begin risk assessment to identify women who could benefit from medications to reduce risk for primary breast cancer? Key Question 1b. What is the optimal frequency of risk assessment to identify women who could benefit from medications to reduce risk for primary breast cancer?
2. Key Question 2. In adult women without preexisting breast cancer, what is the effectiveness and comparative effectiveness of medications to reduce risk for primary breast cancer on improvement in short- and long-term health outcomes, including invasive breast cancer, noninvasive breast cancer (including ductal carcinoma in situ), breast cancer mortality, all-cause mortality, and other beneficial outcomes (such as reduced fractures caused by certain medications and improved quality of life)? Key Question 2a. Does the effectiveness of risk-reducing medications vary by timing of initiation or duration of use? Key Question 2b. Does the effectiveness of risk-reducing medications persist beyond discontinuation of use?
3. Key Question 3. What are the harms of using medications to reduce risk for primary breast cancer? Key Question 3a. Do harms of risk-reducing medications vary by timing of initiation and/or duration of use? Key Question 3b. Do harms of risk-reducing medications persist beyond discontinuation of use?
4. Key Question 4. How do outcomes vary by population subgroups?

Associated Extraction Forms

Associated Studies (each link opens a new tab)

TitleAuthorsYear
Diagnostic accuracy of the Gail model in the Black Women's Health Study.-- Not Found --
Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme.2003
Prospective breast cancer risk prediction model for women undergoing screening mammography.
Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia.2010
Contribution of three components to individual cancer risk predicting breast cancer risk in Italy.2004
Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort.2015
Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density.2006
Predicting risk of breast cancer in postmenopausal women by hormone receptor status.
Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study.2000
Risk factors for breast cancer according to estrogen and progesterone receptor status.2004
Validation studies for models projecting the risk of invasive and total breast cancer incidence.1999
Gail model for prediction of absolute risk of invasive breast cancer: independent evaluation in the Florence-European Prospective Investigation Into Cancer and Nutrition cohort.2006
Absolute risk models for subtypes of breast cancer.2007
Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.1989
Risk prediction for estrogen receptor-specific breast cancers in two large prospective cohorts.2018
Projecting individualized absolute invasive breast cancer risk in Asian and Pacific Islander American women.2011
Risk factor modification and projections of absolute breast cancer risk.2011
Breast cancer risk prediction with a log-incidence model: evaluation of accuracy.2003
Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention.2001
Evaluation of a breast cancer risk prediction model expanded to include category of prior benign breast disease lesion.2010
Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model.2008
Breast Density and Benign Breast Disease: Risk Assessment to Identify Women at High Risk of Breast Cancer.2015
A breast cancer prediction model incorporating familial and personal risk factors.2004
Breast cancer risk assessment in women aged 70 and older.2011
Mammographic breast density refines Tyrer-Cuzick estimates of breast cancer risk in high-risk women: findings from the placebo arm of the International Breast Cancer Intervention Study I.2014
Effect of Raloxifene on all-cause mortality.2010
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.2004
Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial.2004
Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.2002
Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.2006
Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.2001
The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation.1999
Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial.2015
Tamoxifen and depression: more evidence from the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention (P-1) Randomized Study.2001
A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study.2013
Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial.2005
Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.2002
Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial.2003
Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene.-- Not Found --
Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.1999
Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk.2008
Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.2004
Raloxifene reduces risk of vertebral fractures corrected in postmenopausal women regardless of prior hormone therapy.2004
Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.2005
Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
Safety assessment of raloxifene over eight years in a clinical trial setting.2005
Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer.2014
Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial.
Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial.2014
Comparison of fracture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis.2004
Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.2005
Anastrozole-Induced Carpal Tunnel Syndrome: Results From the International Breast Cancer Intervention Study II Prevention Trial.2016
Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study.1998
Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women.2003
Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.2010
First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial.2002
Long-term results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the randomized IBIS-I trial.
Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial.2014
Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.2005
Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.1998
Exemestane for breast-cancer prevention in postmenopausal women.2011
Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.2006
Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial.2007
Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy.2007
Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.2006
Tamoxifen and mammographic breast densities.2000
Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial.2005
Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial.2005
A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness.2006
Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60.2000
Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.1997
Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial.2008
Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials.-- Not Found --
Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years.-- Not Found --
Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial.1998
Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene.-- Not Found --
Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group.1999
Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial.2003
Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women.1999
Raloxifene is not associated with biologically relevant changes in hot flushes in postmenopausal women for whom therapy is appropriate.2004
Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR).2011
Effect of Factor V Leiden and prothrombin G20210-->A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial.2006

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