Heidi D. Nelson, MD, MPH; Rongwei Fu, PhD; Jessica C. Griffin, MS; Peggy Nygren, MA; M. E. Beth Smith, DO; Linda Humphrey, MD, MPH
Nelson HD, Fu R, Griffin JC, Nygren P, Smith MEB, Humphrey L. Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer. Ann Intern Med. 2009;151:703-715. doi: 10.7326/0000605-200911170-00147
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Published: Ann Intern Med. 2009;151(10):703-715.
Trials demonstrate the efficacy of medications to reduce the risk for invasive breast cancer.
To summarize benefits and harms of tamoxifen citrate, raloxifene, and tibolone to reduce the risk for primary breast cancer.
MEDLINE and Cochrane databases from inception to January 2009, Web of Science, trial registries, and manufacturer information.
Predefined eligibility criteria were used to select articles. English-language reports of randomized, controlled trials (RCTs) for benefits and RCTs and observational studies for harms were included.
Two reviewers assessed study data, quality, and applicability.
Seven placebo-controlled RCTs and 1 head-to-head trial provide results for main outcomes. Tamoxifen (risk ratio, 0.70 [95% CI, 0.59 to 0.82]; 4 trials), raloxifene (risk ratio, 0.44 [CI, 0.27 to 0.71]; 2 trials), and tibolone (risk ratio, 0.32 [CI, 0.13 to 0.80]; 1 trial) reduce risk for invasive breast cancer compared with placebo by 7 to 10 per 1000 women per year. Tamoxifen and raloxifene reduce estrogen receptorâ€“positive breast cancer but not estrogen receptorâ€“negative breast cancer, noninvasive breast cancer, or mortality. All medications reduce fractures. Tamoxifen (risk ratio, 1.93 [CI, 1.41 to 2.64]; 4 trials) and raloxifene (risk ratio, 1.60 [CI, 1.15 to 2.23]; 2 trials) increase thromboembolic events by 4 to 7 per 1000 women per year; raloxifene causes fewer events than tamoxifen. Tamoxifen increases risk for endometrial cancer (risk ratio, 2.13 [CI, 1.36 to 3.32]; 3 trials) compared with placebo by 4 per 1000 women per year and causes cataracts compared with raloxifene. Tibolone causes strokes in older women.
Bias, trial heterogeneity, and a dearth of head-to-head trials limit this review. Data are lacking on doses, duration, and timing of the medications; long-term effects; and nonwhite and premenopausal women.
Three medications reduce risk for primary breast cancer but increase risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone).
Agency for Healthcare Research and Quality.
Medications that reduce breast cancer risk may have other potential benefits and harms.
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 receptor–positive but not estrogen receptor–negative 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).
Although tamoxifen, raloxifene, and tibolone sometimes reduce risk for primary breast cancer, they also may increase a woman's risk for particular harmful events.
* Detailed descriptions are provided in the inclusion and exclusion criteria in Appendix Figure 2.
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 outcome—the main outcome of a study that the study was designed and powered to demonstrate; secondary outcome—major outcome of a study that the study was designed and powered to demonstrate, but not the primary outcome of the study; health outcomes—signs, symptoms, conditions, or events that persons experience, such as myocardial infarction, death, or hot flashes; intermediate outcomes—health 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).
Appendix Table 1.
Appendix Table 2.
Error bars represent 95% CIs. CORE = Continuing Outcomes Relevant to Evista; IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart.
* Per 1000 woman-years.
† Italian Tamoxifen Prevention Trial and RUTH reported mean or median duration of actual treatment period.
‡ Analysis included data from both MORE and CORE. Participants from MORE had 4-year treatment, and those who continued in CORE had 4 additional years of treatment. Total follow-up time is averaged over both MORE and CORE for 7705 participants.
Error bars represent 95% CIs. CORE = Continuing Outcomes Relevant to Evista; IBIS-I = International Breast Cancer Intervention Study; MORE = Multiple Outcomes of Raloxifene Evaluation; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart.
Error bars represent 95% CIs. IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1; RUTH = Raloxifene Use for the Heart.
† For tamoxifen trials, venous thromboembolic events include deep venous thrombosis and pulmonary embolism only. For other trials, additional thromboembolic events may be included.
‡ Events were reported from at least 3 months after treatment was stopped until the end of follow-up.
† Events were reported from at least 3 months after treatment was stopped until the end of follow-up.
Error bars represent 95% CIs. IBIS-I = International Breast Cancer Intervention Study; LIFT = Long-Term Intervention on Fractures with Tibolone; MORE = Multiple Outcomes of Raloxifene Evaluation; NR = not reported; NSABP P-1 = National Surgical Adjuvant Breast and Bowel Project P-1.
† Rates were based on number of women with an intact uterus.
‡ The rate and risk ratio were recalculated on the basis of the number of women at risk (having an intact uterus). The values reported by the study were based on all randomly assigned participants.
§ The number of women at risk (having an intact uterus) was not reported, and the risk ratio is calculated on the basis of the number of randomly assigned participants at baseline.
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November 25, 2009
Screening for Breast Cancer: An Update for the US Preventive Services Task Force
The recent changes to the U.S. Preventive Services Task Force (USPSTF) breast cancer screening recommendations are welcome and reflect the best available current evidence (1). The updated systematic review by Heidi Nelson and colleagues, which is the basis for the changes, concurs substantially with the relevant Cochrane review on mammography and indeed also the Cochrane review of breast self-examination or clinical examination(2,3,4).
Those raising concerns about the Nelson review should be reassured that the summary breast cancer mortality reduction of 15% from screening mammography is a comparable figure to that presented in the Cochrane review, which was performed independently, and leads to similar estimates of the numbers needed to invite for examination to prevent or delay one death from breast cancer.
Perhaps the most important addition to the revised USPSTF recommendations is the examination of harms from screening, in particular false positive results and over-diagnosis. Again, the figures for false positive results are similar across the two reviews, and suggest that almost half of the women screened 10 times in the US may expect at least one falsely positive result as a consequence of mammography. Both the USPSTF and Cochrane reviews found over-diagnosis related to mammography to be a concern, although the estimation of its frequency varies between the two assessments.
Evidence-based decision making requires high quality reliable reviews. The similar findings of the Nelson and Cochrane reviews should be reassuring to women working with their doctors to make an evidence- informed decision about screening mammography.
1. US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009; 151:716-726.
2. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. Ann Intern Med 2009; 151: 727-37.
3. Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD001877. DOI: 10.1002/14651858.CD001877.pub3.
4. Kosters JP, Gotzsche PC. Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD003373. DOI: 10.1002/14651858.CD003373.
All authors are members of the Cochrane Collaboration, which has published related reviews.
Rowan T Chlebowski
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
January 7, 2010
Tibolone and Breast Cancer Risk Reduction
Based on their review of eight randomized controlled clinical trials Nelson and colleagues in their systematic review conclude that tamoxifen, raloxifene as well as tibolone reduce risk for primary breast cancer (1). However, tibolone was evaluated in only one of the eight trials, in the one tibolone study breast cancer was a secondary endpoint, findings were reported after a median of only 34 months of follow-up and no information on tumor stage was provided (2). Prior to the publication of the review of Nelson and colleagues, 1 tibolone was compared to placebo in a randomized clinical trial of 3148 women with early stage breast cancer with vasomotor symptoms where breast cancer recurrence (secondary breast cancer prevention) was the primary study endpoint. The trial was stopped early when a statistically significant (P=0.001), 40% increase in breast cancer recurrence was seen with tibolone, suggesting this agent directly stimulates breast cancer growth (3). Given the short follow-up in the tibolone trial reported by Cummings and colleagues, (2) it has been suggested that the lower breast cancer incidence seen potentially could be related to diagnostic delay, since in the same time-frame in the Womens Health Initiative trial evaluating combined menopausal hormone therapy, an ultimate increase in breast cancer incidence with hormone use was not initially recognized secondary to interference with mammographic identification and diagnostic delay (4). These findings seriously question the inclusion of tibolone as an established breast cancer risk reduction intervention and have led others to not include tibolone in breast cancer prevention guidelines (5). Since tibolone might be an attractive choice, since it alone, unlike tamoxifen and raloxifene, is an effective therapy for climacteric symptoms, clinicians need to be aware of these tibolone findings regarding breast cancer which speak against consideration of tibolone as a breast cancer prevention agent.
1. Nelson HD, Fu R, Griffin JC, et al. Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Annals of Int Med 2009;151(10): 703-175.
2. Cummings SR, Ettinger N, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708.
3. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: a double- blind, randomized, non-inferiority trial. Lancet 2009;10:135-146.
4. Chlebowski RT, Prentice R. Tibolone in older postmenopausal women. N Engl J Med 2008;359(20):2172-2173.
5. Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology 2008 clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009; 27(19):3235-58.
Dr. Chlebowski has disclosed that he is a consultant for AstraZeneca, Novartis, Pfizer, Amgen, and Eli Lilly
Breast Cancer, Hematology/Oncology, High Value Care, Prevention/Screening.
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