|Use of medications to reduce risk for primary breast cancer: a systematic review for the US Preventive Services Task Force
|Nelson HD, Smith ME, Griffin JC, Fu R
The authors concluded that tamoxifen and raloxifene reduced the incidence of invasive breast cancer and fractures, but increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene, but it increased the incidence of endometrial cancer and cataracts. Overall, these conclusions are likely to be reliable.
The aim was to update the evidence on the effectiveness and adverse effects of medications to reduce the risk of breast cancer; patient use of these medications; and methods for identifying women at an increased risk of breast cancer. This updated a review (see Other Publications of Related Interest), and this abstract is on the effectiveness and adverse effects only.
The authors searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews, for studies in English, from inception to December 2012. Reference lists were reviewed, as were citations in Web of Science and Scopus, and clinical trial registries. Further information was sought from the medication manufacturers.
To be eligible for the review of effectiveness, studies had to be double-blind, placebo-controlled or head-to-head randomised controlled trials (RCTs) of tamoxifen, raloxifene or both. They had to recruit women without breast cancer and to investigate the reduction in the risk of breast cancer. For the review of adverse effects, RCTs and observational studies were included if they directly compared tamoxifen and raloxifene or if there was a control group who were not offered any preventative medications. They had to recruit women without pre-existing breast cancer, and investigate adverse effects at any time point.
The mean age at enrolment in the included randomised trials was 47 to 50 years for tamoxifen, 67 years for raloxifene, and 59 years for one trial that compared the two medications. Trials were conducted mainly in the UK, mainland Europe, or North America.
Two reviewers were involved in the selection of studies, with discrepancies resolved by consensus.
Assessment of study quality
Studies (and subsequently the overall evidence) were rated as good, fair or poor, using the US Preventive Services Task Force guidelines. Two reviewers assessed quality, with discrepancies resolved by consensus.
Two reviewers were extracted the data, with discrepancies resolved by consensus.
Methods of synthesis
Risk ratios and 95% confidence intervals, for the benefits and harms, in each trial, were pooled in meta-analyses.
Results of the review
Seven RCTs were included for effectiveness; four of tamoxifen, two of raloxifene, and one head-to-head trial. All trials were rated as fair or good quality, and they enrolled between 2,471 and 19,747 women. Twenty studies were found for adverse effects, but the meta-analyses were based on the seven RCTs that contributed to effectiveness.
Tamoxifen reduced the incidence of breast cancer, compared with placebo (RR 0.70, 95% CI 0.59 to 0.82; four trials). Raloxifene reduced the incidence of breast cancer, compared with placebo (RR 0.44, 95% CI 0.27 to 0.71; two trials). In the trial comparing the two drugs, more women receiving raloxifene had breast cancer than those receiving tamoxifen (RR 1.24, 95% CI 1.05 to 1.47). Breast cancer-specific and all-cause mortality were not reduced with either drug, compared with placebo, and they were similar in the direct comparison.
The incidence of thromboembolic events increased with tamoxifen (RR 1.93, 95% CI 1.41 to 2.64; four trials) and with raloxifene (RR 1.60, 95% CI 1.15 to 2.23; two trials), compared with placebo. In the head-to-head trial, raloxifene caused fewer events than tamoxifen. Tamoxifen increased the incidence of endometrial cancer and cataracts, compared with placebo and raloxifene.
Further results were reported for the benefits and harms, for population subgroups, and for adherence to medication.
Both tamoxifen and raloxifene reduced the incidence of invasive breast cancer and fractures, but they increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene, but it increased the incidence of endometrial cancer and cataracts.
This review was based on defined inclusion criteria, and was underpinned by a search of a range of sources. The restriction to studies published in English, could have resulted in missed studies. Study quality was assessed and the results focused on the RCTs, which provided fair to good evidence. Two reviewers were involved in study selection, data extraction and quality assessment, which should minimise errors and bias. The meta-analyses appear to have been appropriate.
The conclusions are likely to be reliable and the recommendations for research were appropriate.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that continued follow-up of women in existing trials was needed to provide data on long-term outcomes. Data were needed on non-White, premenopausal and elderly women, with comorbid conditions, or taking medications for other diseases. Evidence was needed on the best dose, duration and timing of use, persistence of effects after treatment, and outcomes in population subgroups. The relative benefits and harms of a longer course of medication, such as 10 years instead of five, should be investigated. There was a need to improve the identification of those who could benefit from the drugs.
Funded by the Agency for Healthcare Research and Quality, USA.
Nelson HD, Smith ME, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: a systematic review for the US Preventive Services Task Force. Annals of Internal Medicine 2013; 158(8): 604-614
Other publications of related interest
Nelson HD, Fu R, Humphrey L, Smith ME, Griffin JC, Nygren P. Comparative effectiveness of medications to reduce risk of primary breast cancer in women. Rockville, MD, USA: Agency for Healthcare Research and Quality. Comparative Effectiveness Review; 17. 2009.
Nelson HD, Fu R, Griffin JC, Nygren P, Smith ME, Humphrey L. Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Annals of Internal Medicine 2009; 151(10): 703-715.
Subject indexing assigned by CRD
Breast Neoplasms; Endometrial Neoplasms; Estrogen Receptor Modulators; Humans; Tamoxifen; Raloxifene
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.