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.

CONTEXT Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. OBJECTIVE To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. DESIGN, SETTING, AND PATIENTS The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. INTERVENTION Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. MAIN OUTCOME MEASURES Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. RESULTS There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. CONCLUSIONS Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00003906.

[1]  C. Deangelis.  The influence of money on medical science. , 2006, JAMA.

[2]  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 , 2006 .

[3]  Joan G. Jones,et al.  Malignant Mixed Müllerian Tumor of the Uterus in a Patient Taking Raloxifene , 2005, Obstetrics and gynecology.

[4]  S. Cummings,et al.  RESPONSE: Re: Continuing Outcomes Relevant to Evista: Breast Cancer Incidence in Postmenopausal Osteoporotic Women in a Randomized Trial of Raloxifene , 2005 .

[5]  B. Kimler,et al.  Selective estrogen-receptor modulators for primary prevention of breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  B. Bonanni,et al.  Effect of Tamoxifen on Venous Thromboembolic Events in a Breast Cancer Prevention Trial , 2005, Circulation.

[7]  S. Cummings,et al.  Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. , 2004, Journal of the National Cancer Institute.

[8]  L. Goldstein,et al.  Risk of ischemic stroke with tamoxifen treatment for breast cancer , 2004, Neurology.

[9]  S. Cummings,et al.  Safety and Adverse Effects Associated With Raloxifene: Multiple Outcomes of Raloxifene Evaluation , 2004, Obstetrics and gynecology.

[10]  J. Cauley,et al.  Risk‐Benefit Profile for Raloxifene: 4‐Year Data From the Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  M. Sporn,et al.  Role of raloxifene in breast cancer prevention in postmenopausal women: clinical evidence and potential mechanisms of action. , 2004, Clinical therapeutics.

[12]  John Robbins,et al.  National cross sectional survey to determine whether the decision to delivery interval is critical in emergency caesarean section , 2004, BMJ : British Medical Journal.

[13]  N. Facione,et al.  Predictors of perceived breast cancer risk and the relation between perceived risk and breast cancer screening: a meta-analytic review. , 2004, Preventive medicine.

[14]  A. Molinolo,et al.  Differential Effects of Raloxifene, Tamoxifen and Fulvestrant on a Murine Mammary Carcinoma , 2003, Breast Cancer Research and Treatment.

[15]  T. Powles,et al.  Continued Breast Cancer Risk Reduction in Postmenopausal Women Treated with Raloxifene: 4-Year Results from the MORE Trial , 2004, Breast Cancer Research and Treatment.

[16]  C. Kooperberg,et al.  Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. , 2003, JAMA.

[17]  Z. Vered,et al.  LINCS: L-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock: a prospective randomized study. , 2003, European heart journal.

[18]  J. Hochman,et al.  Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. , 2003, Circulation.

[19]  J Cuzick,et al.  Overview of the main outcomes in breast-cancer prevention trials , 2003, The Lancet.

[20]  J. Costantino,et al.  National surgical adjuvant breast and bowel project update: prevention trials and endocrine therapy of ductal carcinoma in situ. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  M Baum,et al.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial , 2002, The Lancet.

[22]  J. Costantino,et al.  The study of tamoxifen and raloxifene: preliminary enrollment data from a randomized breast cancer risk reduction trial. , 2002, Clinical breast cancer.

[23]  E. Barrett-Connor,et al.  Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women: Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial , 2002 .

[24]  S. Cummings,et al.  Serum estradiol level and risk of breast cancer during treatment with raloxifene. , 2002, JAMA.

[25]  V. Jordan,et al.  Selective Estrogen Receptor Modulation , 2001 .

[26]  N. Wolmark,et al.  Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. , 2001, Seminars in oncology.

[27]  V. Jordan,et al.  Selective estrogen receptor modulation: a personal perspective. , 2001, Cancer research.

[28]  S. Cummings,et al.  Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M H Gail,et al.  Validating and improving models for projecting the absolute risk of breast cancer. , 2001, Journal of the National Cancer Institute.

[30]  Z. Vered,et al.  L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock. , 2000, Circulation.

[31]  S. Cummings,et al.  The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial , 2000 .

[32]  C C Glüer,et al.  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, JAMA.

[33]  S. Cummings,et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. , 1999, JAMA.

[34]  T. Powles.  COMMENT ON: TAMOXIFEN FOR PREVENTION OF BREAST CANCER : REPORT OF THE NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT P-1 STUDY , 1999 .

[35]  C K Redmond,et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. , 1999, Journal of the National Cancer Institute.

[36]  T. Powles,et al.  Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial , 1998, The Lancet.

[37]  P. Boyle,et al.  Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women , 1998, The Lancet.

[38]  Mike Clarke,et al.  Tamoxifen for early breast cancer: an overview of the randomised trials , 1998, The Lancet.

[39]  L. Kuller,et al.  Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. , 1998, JAMA.

[40]  C. Christiansen,et al.  EFFECTS OF RALOXIFENE ON BONE MINERAL DENSITY, SERUM CHOLESTEROL CONCENTRATIONS, AND UTERINE ENDOMETRIUM IN POSTMENOPAUSAL WOMEN , 1998 .

[41]  C. Redmond,et al.  Long-term tamoxifen citrate use and potential ocular toxicity. , 1998, American journal of ophthalmology.

[42]  C. D. Jones,et al.  Molecular determinants of tissue selectivity in estrogen receptor modulators. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Larson.  The MOS 36-Item Short form Health Survey , 1997, Evaluation & the health professions.

[44]  S. Cummings,et al.  Bone Mineral Density and Risk of Breast Cancer in Older Women: The Study of Osteoporotic Fractures , 1996 .

[45]  S. Cummings,et al.  Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. , 1996, JAMA.

[46]  C. Roberts,et al.  Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins. , 1996, Endocrinology.

[47]  R. Bing,et al.  Involvement of inducible nitric oxide synthase in the inflammatory process of myocardial infarction. , 1995, International journal of cardiology.

[48]  J. Pike,et al.  Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. , 1995, Molecular endocrinology.

[49]  C. Sherbourne,et al.  The MOS 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. , 1994 .

[50]  C. McHorney,et al.  The MOS 36‐Item Short‐Form Health Survey (SF‐36): II. Psychometric and Clinical Tests of Validity in Measuring Physical and Mental Health Constructs , 1993, Medical care.

[51]  C. Sherbourne,et al.  The MOS 36-Item Short-Form Health Survey (SF-36) , 1992 .

[52]  Anastasia E. Raczek,et al.  The validity and relative precision of MOS short- and long-form health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. , 1992, Medical care.

[53]  Ware J.E.Jr.,et al.  THE MOS 36- ITEM SHORT FORM HEALTH SURVEY (SF- 36) CONCEPTUAL FRAMEWORK AND ITEM SELECTION , 1992 .

[54]  E L Korn,et al.  Applications of crude incidence curves. , 1992, Statistics in medicine.

[55]  V. Jordan,et al.  Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. , 1990, Cancer research.

[56]  M. Gail,et al.  Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. , 1989, Journal of the National Cancer Institute.

[57]  V. Jordan,et al.  Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. , 1987, Cancer research.

[58]  T R Fleming,et al.  Designs for group sequential tests. , 1984, Controlled clinical trials.

[59]  L. Freedman,et al.  Allocation of patients to treatment groups in a controlled clinical study. , 1978, British Journal of Cancer.