Heidi D. Nelson, MD, MPH; M.E. Beth Smith, DO; Jessica C. Griffin, MS; Rongwei Fu, PhD
Disclaimer: The findings and conclusions in this article are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: Andrew Hamilton, MLS, MS, conducted literature searches, and Miranda Pappas, MA; Jennifer Mitchell, BA; and Amanda Brunton, BS, provided assistance (all are affiliated with the Oregon Health & Science University). Linda Humphrey MD, MPH (Portland Veterans Affairs Medical Center), and Peggy Nygren, MA, contributed to earlier versions of the evidence review.
Grant Support: By AHRQ (contract HHSA-290-2007-10057-1-EPC3).
Potential Conflicts of Interest: Dr. Nelson: Grant (money to institution): AHRQ. Support for travel to meetings (money to institution): AHRQ. Dr. Smith: Grant (money to institution): AHRQ. Ms. Griffin: None disclosed. Dr. Fu: Grant (money to institution): AHRQ. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2536.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Nelson and Fu and Ms. Griffin: Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.
Dr. Smith: Oregon Health & Science University, Mailcode L475, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.
Author Contributions: Conception and design: H.D. Nelson, M.E.B. Smith.
Analysis and interpretation of the data: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Drafting of the article: H.D. Nelson, M.E.B. Smith.
Critical revision of the article for important intellectual content: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Final approval of the article: H.D. Nelson, M.E.B. Smith, R. Fu.
Provision of study materials or patients: H.D. Nelson.
Statistical expertise: H.D. Nelson, R. Fu.
Obtaining of funding: H.D. Nelson.
Administrative, technical, or logistic support: H.D. Nelson, J.C. Griffin.
Collection and assembly of data: H.D. Nelson, M.E.B. Smith, J.C. Griffin, R. Fu.
Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low.
To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer.
MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists.
English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment.
Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria.
Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer–specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer.
Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking.
Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates.
Agency for Healthcare Research and Quality.
DCIS = ductal carcinoma in situ.
Summary of evidence search and selection.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Identified from reference lists, hand searching, and suggestions by experts.
‡ Studies that provided data and contributed to the body of evidence were considered “included.”
§ Some studies are included in more than 1 key question.
Appendix Table 1. Results of Primary Prevention Trials
Appendix Table 2. Descriptive Studies of Decisions to Use Risk-Reducing Medications
Appendix Table 3. Adherence and Persistence to Medications in Trials of Tamoxifen and Raloxifene
Appendix Table 4. Studies of Risk-Stratification Models
Appendix Table 5. Risk-Stratification Models
Table. Summary of Evidence
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Jikei University School of Medicine
April 26, 2013
Selective Estrogen Receptor Modulators for Breat Cancer Prevention
TO THE EDITOR:
Despite a comprehensive review of randomized controlled trials and cohort studies regarding the benefits and harms of selective estrogen receptor modulators (SERMs) for breast cancer prevention, Dr Belson and colleagues (1) do not clearly answer the question of who will realistically benefit from SERMs.
As discussed in this review, tamoxifen is likely more effective than raloxifene in breast cancer prevention but more frequently associated with life-threatening complications such as endometrial cancer and thromboembolic events. Given long-lasting increased risk of endometrial cancer due to tamoxifen (2), use of tamoxifen may have to be limited to women who are at a very high risk of breast cancer or those who had hysterectomy for benign disease. Antitumor actions of raloxifene, a short-acting SERM, seem to depend on the duration of administration. In the initial analysis of the STAR trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (relative risk 1.02, 95% CI 0.82-1.28) (3). in the updated analysis of STAR with extension of follow-up period from 47 months to 81 months after randomization (21 months after stopping SERM treatment), the risk of developing invasive breast cancer was significantly higher in the raloxifene group than in the tamoxifen group (relative risk 1.24, 95% CI 1.05-1.47) (2). Raloxifene is approved for the treatment of osteoporosis and prevention of vertebral fracture for an indefinite period of time because of its efficacy and safety (4). Since preventive agents for widespread use in an otherwise healthy population need to be virtually devoid of significant adverse effects, raloxifene, even if not superior to tamoxifen, may be more acceptable as a preventive drug (5).
In the light of reducing the burdens of both osteoporosis and breast cancer, all postmenopausal women with suspected osteoporosis might benefit form raloxifene, unless SERM is not contraindicated.
Tetsuji Fujita, MD
Department of SurgeryJikei University School of Medicine
Tokyo, Japan 105-8461
1. Nelson HD, Smith B, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013; 158: 604-14.
2. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al, National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706.
3. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. 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. JAMA 2006; 295: 2727-41.
4. Lippuner K, Buchard PA, De Geyter C, Imthurn B, Lamy O, Litschgi M, et al. Recommendations for raloxifene use in daily clinical practice in the Swiss setting. Eur Spine J 2012; 21: 2407-17.5. Gradishar WJ, Cella D. Selective estrogen receptor modulators and prevention of invasive breast cancer. JAMA 2006; 295: 2784-6.
Nelson HD, Smith MB, Griffin JC, et al. Use of Medications to Reduce Risk for Primary Breast Cancer: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:604–614. doi: 10.7326/0003-4819-158-8-201304160-00005
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Published: Ann Intern Med. 2013;158(8):604-614.
Breast Cancer, Cancer Screening/Prevention, Hematology/Oncology, Prevention/Screening.
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