ORIGINAL CONTRIBUTION

JAMA-EXPRESS

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
Victor G. Vogel, MD, MHS Joseph P. Costantino, DrPH D. Lawrence Wickerham, MD Walter M. Cronin, MPH Reena S. Cecchini, MS James N. Atkins, MD Therese B. Bevers, MD Louis Fehrenbacher, MD Eduardo R. Pajon, Jr, MD James L. Wade III, MD Andre Robidoux, MD ´ Richard G. Margolese, MD, CM Joan James, PA-C Scott M. Lippman, MD Carolyn D. Runowicz, MD Patricia A. Ganz, MD Steven E. Reis, MD Worta McCaskill-Stevens, MD Leslie G. Ford, MD V. Craig Jordan, PhD, DSc Norman Wolmark, MD for the National Surgical Adjuvant Breast and Bowel Project (NSABP)
AMOXIFEN, A SELECTIVE ESTROgen receptor modulator (SERM)1 that has been used to treat both early and advanced breast cancer for more than 3 decades,2 has been thoroughly evaluated for the reduction of the risk of both invasive and noninvasive breast cancer in

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
JAMA. 2006;295:2727-2741 www.jama.com Author Affiliations are listed at the end of this article. A list of the active NSABP STAR P-2 Clinical Centers is at the end of this article. Corresponding Author: Victor G. Vogel, MD, MHS, Magee-Womens Hospital, University of Pittsburgh School of Medicine, 300 Halket St, Room 3524, Pittsburgh, PA 15213-3221 (vvogel@magee.edu).

T

See also pp 2742 and 2784.

women at increased risk.3-9 Raloxifene, a second-generation SERM,1 has been shown to reduce the incidence of mammary malignancy in preclinical models,10-12 and several clinical trials

©2006 American Medical Association. All rights reserved.

(Reprinted) JAMA, June 21, 2006—Vol 295, No. 23 2727

Downloaded From: http://jama.jamanetwork.com/ on 08/14/2012

This trial was a doubleblinded study with neither the participants nor their clinicians aware of which of the 2 treatments they were receiving. A total of 184 460 women were screened using the modified Gail model24. the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2. The objective of STAR is to compare raloxifene with tamoxifen in terms of their relative effects on the risk of invasive breast cancer and numerous other diseases influenced by tamoxifen in the BCPT. Downloaded From: http://jama.13-20 The Multiple Outcomes Raloxifene Evaluation (MORE) study.18 The primary end point was the development of fracture. but raloxifene did not cause an increase in vaginal bleeding. 96 368 had a 5-year risk of at least 1.34. be at least 35 years of age and postmenopausal. 0.83-5. 0. with no apparent decrease in the incidence of estrogen receptor–negative tumors. No increase in the risk of endometrial cancer was observed with raloxifene. 0. menopause was defined as (1) a history of at least 12 months without spontaneous menstrual bleeding or (2) a documented hysterectomy and bilateral salpingo-oophorectomy or (3) age 55 years or older with a hysterectomy with or without oophorectomy. raloxifene increased the risk of thromboembolic disease but did not appear to increase the risk of endometrial cancer. The protocol and consent form were approved by the National Cancer Institute and the institutional review boards of all participating institutions.14 After 4 years of follow-up. 0. or uncontrolled hypertension.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) evaluating it for the prevention and treatment of osteoporosis have suggested that it may also have a role in reducing the risk of invasive breast cancer in postmenopausal women. 0.40). Eligible women had a history of at least 1 vertebral body fracture. Patient Characteristics To be eligible for participation in the STAR trial. 3 The NSABP Study of Tamoxifen and Raloxifene (STAR) trial was launched to directly compare tamoxifen with raloxifene in a population of women at increased risk for breast cancer. or (4) age younger than 55 years.2). was designed to test whether raloxifene. the risk of invasive breast cancer was reduced by 69% (hazard ratio. in the raloxifene group compared with the placebo group. the central review of all protocol events and toxicities was also performed in a blinded fashion. signed a consent form. randomized. For the purposes of this trial.70). or androgens for at least the previous 3 months. From this group. Of this latter group. tamoxifen was approved by the US Food and Drug Administration.5-6.jamanetwork. 1. respectively.22-0. have no uncontrolled atrial fibrillation. All rights reserved. there were 22 cases among 5129 postmenopausal women randomly assigned to raloxifene. 20 168 were found to meet all eligibility criteria of the study. at a daily dose of either 60 mg or 120 mg. 23 (Reprinted) ©2006 American Medical Association. hormone therapy. either with a hysterectomy without oophorectomy or with unknown ovary status. double-blind clinical trial completed in 1999. 19 747 women expressed a desire to go forward with participation in the trial.17 (95% CI.25 to determine their breast cancer risk. not be taking tamoxifen. Like tamoxifen. No. a multicenter. uncontrolled diabetes.20 After 4 years of participation in the CORE trial by 5213 participants. During the CORE trial. 0. the incidence of invasive breast cancer and estrogen receptor–positive invasive breast cancer were reduced by 66% (hazard ratio.71) 2728 in the raloxifene group compared with the placebo group. have no history of stroke. In addition. and with a documented level of follicle-stimulating hormone confirming elevation in the postmenopausal range.15-0.31. a woman had to have at least a 5-year predicted breast cancer risk of 1. Of these. the risk of vertebral fracture was reduced by 30% in the women who received raloxifene. pulmonary embolism. JAMA. The data reported are based on a cutoff date of December 31. the risk of estrogen receptor–positive invasive breast cancer was decreased by 72% during 4 years of raloxifene treatment. METHODS The participants in this study were given a detailed description of the trial and provided written informed consent. reduced the risk of fracture in postmenopausal women with osteoporosis.21-23 Based on our findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) (P-1). A secondary end point in the MORE trial was invasive breast cancer. These women had increased risk of venous thromboembolus when compared with those assigned to placebo (relative risk. At 36 months of follow-up in 6828 women. The Continuing Outcomes Relevant to Evista (CORE) trial examined the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in the MORE trial who agreed to continue therapy.66% based on the Gail model24 .24-0.24.50) and 76% (hazard ratio. During the 8 years of both the MORE and CORE trials.66% (FIGURE 1). oral contraceptives. not currently be taking either warfarin or cholestyramine. compared with 39 cases among 2576 postmenopausal women assigned to placebo.com/ on 08/14/2012 . June 21. and have no psychiatric condition that would interfere with adherence or a performance status that would restrict normal activity for a significant portion of each day. Raloxifene has previously been shown to be less active than tamoxifen in stimulating endometrial cancer growth under laboratory conditions. The MORE trial concluded that among older postmenopausal women with osteoporosis. 20 616 agreed to be screened to determine full eligibility for the trial based on the medical criteria defined below. raloxifene. placebo-controlled. 95% confidence interval [CI]. 2005. Postmenopausal women aged 35 years and older could enter the trial if they had a history of lobular carcinoma in situ (LCIS) treated by local excision alone. 95% CI. 3. 95% CI. or deep vein thrombosis (DVT) and no history of any malignancy diagnosed less than 5 years before randomization except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. 0.1. 2006—Vol 295. 95% CI.

5% for those in the raloxifene group.6) years. and 41. regardless of whether or not they were adherent. transient ischemic attack. 49. cataracts.2% were 60 years or older (TABLE 1). In designing the trial we planned for a nonadherence rate of 9. More than 93% of participants were white.66% 75 752 Did Not Wish to Be Screened Further 20 616 Screened for Medical Eligibility 448 Excluded (Not Medically Eligible) 20 168 Met All Eligibility Criteria 421 Did Not Wish to Participate 19 747 Randomized 9872 Assigned to Receive Tamoxifen 9875 Assigned to Receive Raloxifene 146 Lost to Follow-up 128 Lost to Follow-up 2 Not at Risk for Invasive Breast Cancer∗ 9726 Included in Primary Analysis 9745 Included in Primary Analysis *Both had undergone bilateral mastectomy prior to randomization. and 22.9 (SD.5% were African American. 2. The mean predicted 5-year risk of developing breast cancer among the study population was 4. cardiovascular disease. Those lost to follow-up contributed an average of 24 months of information before becoming lost to follow-up. DVT.2% per year as measured by study dropouts and women who permanently discontinued therapy. and more than 71% reported a history of invasive breast cancer in 1 or more.3% for those in the tamoxifen group and 71.7% had breast biopsy results prior to trial enrollment that showed either atypical ductal or lobular hyperplasia. The observed rate for this parameter is well below the planned rate. 2006—Vol 295.8% were between 50 and 59 years. The mean age of participants at the time of randomization was 58. 1. respectively.66%) 96 368 Had 5-y Breast Cancer Risk ≥1. Participant adherence to protocol therapy was within the levels expected and planned for when designing the trial. severe angina.jamanetwork. and acute ischemic syndrome. in situ breast cancer. this differs from the mean duration of follow-up due to participants’ discontinuing their study drug before the end of the 5-year period.26. Severe angina was defined as angina requiring revascularization by percutaneous coronary intervention (angioplasty or stent) or coronary artery bypass graft surgery.03% (SD. The trial opened for participant entry on July 1.6) years for the tamoxifen and raloxifene groups. the percentage of women persistent with the protocol regimen was 68. Study Flow—NSABP STAR Trial End Points The primary end point was invasive breast cancer. stroke.5 years. pulmonary embolism. 1999. Figure 1. and quality of life. Nine percent were younger than 50 years.27 Eligible women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for a maximum of 5 years. At the time of the cut-off for this analysis. and the remainder were of other racial/ethnic populations. In designing the trial we planned for a loss to follow-up rate of 2% per year of follow-up. (Reprinted) JAMA. Information on all individuals was included up to the time they underwent follow-up. The observed rate is below the planned level. Downloaded From: http://jama. completing accrual on November 4.7) and 3.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) and were randomized to receive either tamoxifen or raloxifene. 2. osteoporotic fracture. NSABP STAR indicates National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene. Vascular-related events included 184 460 Women Screened for Predicted Breast Cancer Risk 88 092 Excluded (5-y Breast Cancer Risk <1. Race information was collected because it is a risk factor for breast cancer and is one of the factors used in the Gail model to determine the predicted risk of breast cancer. The mean time of follow-up was 3.2 (SD. More than 9% reported a personal history of LCIS prior to enrollment in the trial. 1. 1. The mean duration of treatment was 3.com/ on 08/14/2012 . During the course of the study 605 women in the tamoxifen group and 532 in the raloxifene group were lost to follow-up. All rights reserved. 23 2729 ©2006 American Medical Association.1 (SD. Almost 19% reported a family history of breast cancer in 2 or more first-degree relatives. Secondary end points included endometrial cancer. No. Acute ischemic syndrome was defined as the presence of a new Q wave on electrocardiogram or angina requiring hospitalization without surgery.0% were Hispanic. Participants were screened and enrolled through nearly 200 clinical centers throughout North America. June 21. It was collected as self-reported by the participants from options supplied by the investigators. 2.17%). data on all other invasive cancers also were collected prospectively. The cardiac disease end points included fatal and nonfatal myocardial infarction. 2004. death. More than half of the participants reported having undergone a hysterectomy prior to randomization.

To judge impact on osteoporosis.8) 896 (9. 2006—Vol 295.” The findings from the in-depth quality-oflife and symptom assessments are reported in a companion article. follow-up occurred annually. gynecology. regardless of the treatment status at the time of analysis. surgical reports.3) 4732 (48.01 Tamoxifen (n = 9726) 884 (9.0%).0) 206 (2. and bilateral mammograms were to be performed annually.6) 2673 (27.7) 3082 (31.2) 7540 (77. All rights reserved. The rate was defined as the number of observed events divided by the total number of observed event-specific 2730 JAMA. Participant Characteristics—NSABP STAR Trial No. and biostatistics. After 5 years. history of LCIS (yes. Hispanic. and in-depth quality-of-life assessments were performed at selected clinical centers on a subset of 1983 participants using the Medical Outcomes Study Short-Form 36.5) 241 (2. clinical trial methodology. y 49 50-59 60-69 70 Race/ethnicity White African American Hispanic Other First-degree relatives with breast cancer 0 1 2 3 History of hysterectomy No Yes History of lobular carcinoma in situ No Yes History of breast atypical hyperplasia No Yes 5-y predicted breast cancer risk* 2. and 5-year predicted risk of breast cancer ( 2.4) Sexual Functioning Scale.0) 267 (2. 23 (Reprinted) ©2006 American Medical Association.8) 893 (9. Information regarding the occurrence of all protocol-defined end points was ascertained at each follow-up visit and verified by the collection of pathology reports.5%.8) 1532 (15.6) 1559 (16.5%-3.1) 2835 (29. Follow-up occurred at 6 months after treatment initiation and every 6 months thereafter through 5 years.5) 1055 (10.00 2. and 4.com/ on 08/14/2012 .7) 4712 (48.34 Symptoms were self-reported on a 5-point qualitative severity scale ranging from not having the symptom at all to having the symptom with severity that was reported as “extremely bothersome.5) 2186 (22. mammographic reports.” and “bothered quite a bit.2) 7505 (77. and Colles fractures of the wrist.01-3. 50-59.7) 4994 (51.” “moderately bothersome.35 The STAR trial was monitored by an independent data monitoring committee composed of individuals with expertise in research ethics.3) 8833 (90.6) 847 (8.29-32 the Center for Epidemiologic Studies-Depression Scale. 2. the risk ratio (RR) contrasting the rate in the raloxifene group to the rate in the tamoxifen group.24 All analyses were based on the treatment assignment made at the time of randomization. no). Gynecologic examinations.0) 4848 (49.8) 9096 (93. Downloaded From: http://jama.00 3. discharge summaries.1) 5041 (51. and the 95% CIs for the RR. epidemiology. The analyses included all randomized participants with follow-up data who were at risk at baseline for the diagnosis of an incident case of breast cancer. if they really were so. and other medical record documents. Self-reported symptoms were collected at each contact. as well as DVT and pulmonary embolism.2) Raloxifene (n = 9745) 877 (9.28 The women were stratified by age (35-49.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) stroke and transient ischemic attack.8) 318 (3. complete blood cell counts. Statistical Analyses Abbreviation: NSABP STAR. *Determined by the modified Gail model. spine. and routine serum chemistry tests were to be obtained annually. race/ ethnicity (white. we selected 3 fracture sites known to be indicative of this disease: hip.” The 3 intermediate symptom severity levels were “slightly bothersome.2) 859 (8.00 5.6) 5130 (52.5) 233 (2.33 and the Medical Outcomes Study Table 1.8) 2988 (30.0) 2240 (23. the study design provided a 95% probability that we would correctly conclude that the 2 treatments were equivalent. No. With this number of events. African American. The monitoring plan was based on detecting a statistically significant difference between treatment groups in the incidence of invasive breast cancer—the primary end point of the trial—and included 6 interim analyses and a final analysis initiated when at least 327 cases of invasive breast cancer were diagnosed in the entire study cohort.4) 191 (2.6) 8849 (90. (%) Characteristic Age.9%. other).4) 5033 (51.7) 3173 (32.1) 2789 (28.9) 3133 (32.2) 2644 (27.0) 1097 (11. oncology. Randomization and Monitoring Randomization was accomplished using a biased-coin minimization algorithm. Comparison between treatment groups of the study end points was based on the determination of rates per 1000 person-years.01-5.7) 9108 (93. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene. Clinical breast examination was to be per- formed every 6 months. June 21.3) 2893 (29.5) 193 (2. A consumer representative was also included as a member of the committee.0) 203 (2.7) 3039 (31.1) 4850 (49. 60 years). The trial was monitored using a stopping rule based on that proposed by Fleming et al36 using a 2-tailed log-rank test.jamanetwork.

60 −0.34 0.01 No.77 4.72-1. All rights reserved.21 4.05 was used to determine statistical significance. 95% CI.39 0.80-1.81-1. The rate per 1000 was 4.82-1.99 3.68-1.2 (SAS Institute Inc.63) 0. Cary.39 0.16 Rate per 1000 Raloxifene Difference* RR (95% CI)† 2.84 (0.03 5.84 0.69 3. Differences between treatment groups in the distributions of demographic and pathological characteristics were assessed by the 2 test.11) 1. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene.30 in the tamoxifen group and 4.04 (0.21 1.40 (0.08 1.53 −0.09 5.38-1.15 (0.7) 115 (72.38) 0.75-1.94) 0.28) Abbreviations: CI. risk ratio.77) 0.75 (0.98 (0.61 4.29) 1.18 0. Figure 2).5) 38 (24.28) 0.4) 3 51 (31.13 3. ©2006 American Medical Association.55) 1. of Events Participant and Tumor Characteristic at Baseline Age at entry.32 0.28).99 (0.00 0. †RR for women in the raloxifene group compared with those in the tamoxifen group.08 −0.80 1.18 3.16 1.12 (0. RESULTS Invasive Breast Cancer There was no difference between the effect of tamoxifen and the effect of raloxifene on the incidence of invasive breast cancer (TABLE 2 and FIGURE 2).52) 1.78-1.05 3.03 (0.8) 2 133 (80.88-1.83 4.74) 1.09 1.99 (0.38 4. respectively (P = .58 −0.8) 15 (9.07 4.58-1.8) 13 (7.82-1.22 0.83 3.70-1. y 49 50-59 60 History of LCIS No Yes History of atypical hyperplasia No Yes 5-y predicted breast cancer risk 3.7) 96 (60.0 3.83.06 5.62 5.11 (0.46) 0.40 0.11 1.53 0. All P values reported are 2-sided.74) 0. confidence interval.39 4.00 5.30 −0.13 0.com/ on 08/14/2012 . NSABP STAR.96) 0.1 Unknown Nodal status Negative Positive Unknown Estrogen receptor status Negative Positive Unknown Total Tamoxifen Raloxifene Tamoxifen By Participant Characteristics 7 83 73 130 33 122 41 32 61 70 52 72 39 8 78 82 135 33 121 47 44 47 77 53 78 37 2.24 2. *Rate in the tamoxifen group minus rate in the raloxifene group.19 −0.14 0.1-3.63 2.0 1.18 −0. lobular carcinoma in situ. RR. ‡Values in parentheses in first 2 columns indicate percentage of women with known information.16 0.03 −0.06 0.41 −0.01-5. Plots comparing the treatment groups in terms of the cumulative incidence over time were also developed for several end points.40 0.8 per 1000 for the tamoxifen and raloxifene groups. (Reprinted) JAMA.04 0.16 3.27) 0.89 9. 23 2731 Downloaded From: http://jama. When the treatment groups Table 2.3) 91 (54.94 (0.75-1.43) 1.56) By Tumor Characteristics‡ 47 (29.86 (0.81 2.53-9.35 5.1 and 24.11 4. The cumulative incidence was determined accounting for the competing risk due to death.00 −0.69-1.00 3.60-1. 0.87-2.6) 32 (19. of first-degree relatives with breast cancer 0 1 2 Tumor size.72-1.97 (0.04-2.49 0.93 (0.50-1.21 2.1) 8 168 1. LCIS. cm 1. conditioning on the total number of events and person-years at risk.93 (0.02) 1.18 6.24) 1.76-1.31 (0. NC). The cumulative incidence through 72 months for the 2 treatment groups was 25.15 (0.41 in the raloxifene group (RR.96.47) 0.5) 8 44 (27.81 5.37 (0.86 0.22 3.9) 109 (68.02.05 (0. The CI for each RR was determined assuming that the event followed a Poisson distribution.76 9.30 1.29 −0.88 7.5) 5 117 (75.28) 1.13 (0. No.34 2.37 P values to assess statistically significant differences between cumulative incidence curves were determined by the log-rank test.10 −0.09 (0. Rates of Invasive Breast Cancer by Patient and Tumor Characteristics—NSABP STAR Trial No.02 (0.40 (0.jamanetwork.19 0. there were 163 cases of invasive breast cancer in the women assigned to ta- moxifen and 168 cases in those assigned to raloxifene.3) 4 163 62 (37.51-1. June 21. 1. P .55) 1.33) 0.03 5.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) person-years at risk.06-1.55) 1.87-1.37-3. 2006—Vol 295.13 −0. Analyses were performed using SAS version 8. The P value testing the difference between treatment groups in invasive breast cancer incidence determined from the log-rank test and including the stratification factors as covariates was .

98-2. there were no differences between the treatment groups in regard to distributions by tumor size.18 (0.25 0.) Cumulative incidence through 6 years was 8.76 0.com/ on 08/14/2012 . risk ratio. tumor size. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene. at Risk Raloxifene Tamoxifen Time Since Randomization.04 Difference* −0.18) 1. 2006—Vol 295. †RR for women in the raloxifene group compared with those in the tamoxifen group.62 (0. §Among women not diagnosed with uterine cancer. 95% CI.20 −0.60 0.62 7.44 (0. Histological characteristics.37 (0. 1.69 4. history of LCIS.67 13.76 0.29) 0.052 60 66 72 Tamoxifen Noninvasive Breast Cancer Time Since Randomization. mo 9745 9726 8916 8931 6701 6653 4323 4254 833 809 9745 9726 8885 8909 6667 6633 4291 4243 828 805 Table 3. confidence interval.00) 0. (Rate for noninvasive breast cancer.37 −0.90-2. There were 57 incident cases of noninvasive breast cancer among the women who took tamoxifen and 80 among the women who took raloxifene.55) 0.6 in the raloxifene group (P = . Uterine Hyperplasia.33-4.02 0.51 per 1000 women assigned to tamoxifen and 2.56 7 80 0. mo No. nodal status.76-2.51 Rate per 1000 Raloxifene 1. No.11 per 1000 women assigned to raloxifene [RR. lobular carcinoma in situ.35-0. *Rate in the tamoxifen group minus rate in the raloxifene group.1 per 1000 in the tamoxifen group and 11.56) Uterine Disease and Hysterectomy‡ 23 2. 1. 0. ductal carcinoma in situ. Cumulative Incidence of Invasive and Noninvasive Breast Cancer Invasive Breast Cancer Cumulative Incidence.16 (0. Figure 2). and Hysterectomy There was a trend toward a decreased incidence of uterine cancer in the ral- Figure 2.93 3. and nodal status were derived from submitted pathology reports.53 RR (95% CI)† 1.jamanetwork.052.16 1. NSABP STAR. Uterine Cancer. per 1000 Cumulative Incidence.08 (0-0. there were fewer noninvasive breast cancers in the tamoxifen group than in the raloxifene group (TABLE 3. 23 (Reprinted) ©2006 American Medical Association.98-2.09-0.75 3. When we assessed the pathological characteristics of the tumors in these patients. ‡Women at risk were those with an intact uterus at entry. with the balance being mixed types.09-0.32) 0.79 29 0. and the number of relatives with a history of breast cancer.54) 1. Downloaded From: http://jama. although this difference did not reach statistical significance. The pattern of fewer cases among the tamoxifen group was evident for both LCIS and DCIS. history of atypical hyperplasia. 2732 JAMA.40 (0.31 0.16 (0.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) are compared by baseline categories of age.40.41) 1.46 (0. or estrogen receptor level (Table 2). June 21. All rights reserved.00]. per 1000 30 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 P = .11 1.08) 0. Figure 2). DCIS.16 0. RR. Noninvasive Breast Cancer In contrast to the findings for invasive breast cancer.71 0. the pattern of no differential effect by treatment assignment is consistent.83 54 60 66 72 30 Raloxifene 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 P = .02 −0. of Events Disease/Uterine Event Type DCIS LCIS Mixed Total Invasive cancer Hyperplasia§ Without atypia§ With atypia§ Hysterectomy during follow-up§ Tamoxifen 30 21 6 57 36 84 72 12 244 Raloxifene Tamoxifen Noninvasive Breast Cancer 44 0.35-1. Gail model–derived 5-year predicted risk of breast cancer. and none of the RRs in these subsets are statistically significant (Table 2). LCIS. Rates of Noninvasive Breast Cancer and Uterine Disease/Hysterectomy—NSABP STAR Trial No. there was no central review of pathology slides.18 2. About 36% of the cases were LCIS and 54% were ductal carcinoma in situ (DCIS).00 14 13 1 111 4.57 Abbreviations: CI.05 6.

0. 1. 2.29). per 1000 Cumulative Incidence.16. There were 14 cases of skin cancer in the tamoxifen group and 12 in the raloxifene group (RR. 12 cases of ovarian cancer in the tamoxifen group and 18 in the raloxifene group (RR. The majority of the others who developed uterine cancer (56 [91%]) were diagnosed with stage I disease. and leukemia/hematopoieticcancerswerethe most frequently diagnosed sites of other primary tumors. Of the remaining cases.98). 95% CI.36-1. Annual incidence rates were 2. 95% CI. 95% CI.48. lung. 95% CI. mo 4712 4732 4304 4291 3219 3106 2094 1971 408 367 9745 9726 8962 8948 6764 6682 4362 4286 836 813 ©2006 American Medical Association.56). 0.com/ on 08/14/2012 .09-0.88-3. No.77.00 per 1000 (tamoxifen) and 1. 1. 2006—Vol 295. 0. Colorectal. 30 raloxifene) and for leukemia/hematopoietic The findings for the 3 types of ischemic heart disease events in the study are shown in TABLE 5. There also was a statistically significant difference between the treatment groups in the number of hysterectomies performed during the course of follow-up.85-1.48-1. 95% CI. mo No. FIGURE 3). there were 28 cases of lung cancer in the tamoxifen groupand39intheraloxifenegroup(RR. 2 with stage III disease in the raloxifene group. Only 1 case of uterine cancer occurred among women younger than 50 years.23. 0. 0. Cumulative Incidence of Invasive Uterine Cancer and Thromboembolic Events Invasive Uterine Cancer Cumulative Incidence. In addition. 0. For the tamoxifen and raloxifene groups. Cumulative incidence rates through 7 years were 14.50).84-1.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) oxifene group.44. 0. 0. The difference between the treatment groups was larger for lung cancer but not statistically significant. in a participant in the tamoxifen group.07 60 66 72 30 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 P = . 95% CI. Differences between treatment groups were small for colorectal cancer (31 tamoxifen. 1. While there were no significant differences with respect to risk of uterine cancer.7 per 1000 (tamoxifen) and 8.32).20). 0. Other Invasive Malignancies cancers (32 tamoxifen. Ischemic Heart Disease TABLE 4 shows the site-specific incidence of invasive cancers other than breast and uterine malignancy.95). and thyroid. 0.1 per 1000 (raloxifene) (P=. 0.09-0. (Reprinted) JAMA. clinicopathological stage was unknown for 3 cases (1 in the tamoxifen group. The rates were 84% less in the raloxifene- treated group (14 cases) than in the tamoxifen-treated group (84 cases) (RR. there was a statistically significant difference between the groups in the incidence of uterine hyperplasia.07. but the difference was not statistically significant—36 cases (tamoxifen) vs 23 (raloxifene) (Table 3. 0. 1. there were 114 events in those assigned to tamoxifen and 126 in those assigned to raloxifene. there were 244 hysterectomies performed in those assigned to tamoxifen compared with 111 in those assigned to raloxifene (RR. Two of these cases were mixed Mullerian cell type. June 21.68-3. both were in the tamoxifen group. 1. Among women who were not diagnosed with endometrial cancer.00-0. ovary. in total or by specific site of diagnosis. 95% CI. 0.83-2. This magnitude of difference between treatment groups was evident for hyperplasia both with and without atypia.01 60 66 72 Raloxifene Tamoxifen Thromboembolic Events Time Since Randomization.38.38). 2 in the raloxifene group). 95% CI. 0. respectively. there were 11 fewer myocardial infarctions (RR. The next most frequently diagnosed sites of cancer included skin. and 8 cases of thyroid cancer in the tamoxifen group and 18 in the raloxifene group (RR. per 1000 30 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 P = . we found no significant differences between the treatment groups when we inspected the separate types of events. At the time of analysis.25 per 1000 women (raloxifene) (RR. Among those who did not have a diagnosis of uterine cancer.93-5. 0. 0.62. and 11 more cases of acute ischemic syndrome (RR. at Risk Raloxifene Tamoxifen Time Since Randomization. there was 1 case of stage II disease in each of the treatment groups.34).10.18. This difference was not statistically significant (RR. there were 12 cases and 1 case with atypia (RR.08). 23 2733 Downloaded From: http://jama. 95% CI.43). 0.85. Figure 3). and 1 with stage IV disease in the raloxifene group. 95% CI. There were no statistically significant differences between the treatment groups in regard to the number of women who developed any other cancer. All rights reserved.35-1.81).24. there were differences between the treatment groups indicating that the effect of raloxifene on the uterus is less than that of tamoxifen. 95% CI.jamanetwork. Figure 3.08. 0.72.55) and 72 and 13 cases without atypia (RR. 12 more cases of severe angina (RR.35-0. 28 raloxifene). 95% CI. Overall. 0. 0. In women assigned to raloxifene. 95% CI.

707 developed cataracts during the course of follow-up.49) 1.66 (0.13 0.51) NA 0.41-1.08 0 0. RR.10 0 0. Fractures ifen group and 96 in the raloxifene group experienced 1 of these fractures (RR. 0. there were 26 and 23 hip fractures (RR. 0. 0. Figure 3).03 −0.11 −0.28 0. 0. 2734 JAMA. No.03 0.54-6. Of those assigned to tamoxifen.64.01. and Colles fractures of the wrist.56-1.54- 0.10 Rate per 1000 Raloxifene 0. Cataracts Although all fracture sites were recorded. The difference in total number of strokes was small.81 0. 0. Pulmonary embolism and DVT occurred in 54 vs 35 women (RR. there was a statistically significant difference between the treatment groups for the incidence of thromboembolic events.99 (0.95) 0.99 (0. Overall.83 (0.68 0.44 (0.05 RR (95% CI)† 0.05 Difference* 0.24 (0.93-5.10-117. NSABP STAR.87 (0.05 0. 0.03) 1. 0. 0.00) and in 87 vs 65 women (RR.81) NA 1.23 0.03 0.18 0. 95% CI. All rights reserved.91). 95% CI.53).36-1.23 −0. 95% CI. There was no difference between treatment groups in the total number of these fractures or in the number for any of the specific types of fracture (Table 5).98) NA 1. and only data for clinically apparent vertebral fractures were captured. the prespecified fracture sites of interest in the trial were the hip.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) Stroke and Thromboembolic Events The findings for strokes and thromboembolic events are shown in Table 5. 394 Table 4. 1.69-1.01-4. 95% CI.25 (0.com/ on 08/14/2012 .26) 0.18 0.26 0.74. 0.22).20-3.85 (0.68-3.03 −0. with the number of events occurring in women assigned to tamoxifen being only 2 more than in those assigned to raloxifene (53 vs 51).01-78. 0.34) 0.16 0.83-2. One hundred four women in the tamox- At the time of randomization. respectively (P=.33 (0.85 (0.11-4. Among those who were cataract-free at baseline.0 per 1000 for the tamoxifen and raloxifene groups. June 21.16 0. and 27 and 23 Colles fractures (RR. The differences between treatment groups for the incidence of cataracts and cataract surgery were statistically significant.03 0.46). risk ratio.03 0.08 0. with occurrence for both being less in the raloxifene group.01 0.03 0.47 0.38) 1.41) NA 0.64) 0.10 −0.18) 2.70.78 0.47) Abbreviations: CI.01-2.21.45 0.03 0.96) 1. there were 141 events with tamoxifen and 100 with raloxifene. respectively.46-1. However.0 per 1000 and 16.73 0. 23 (Reprinted) ©2006 American Medical Association.13 0. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene. 53 and 52 spine fractures (RR. FIGURE 4).50 (0.25 (0.08 0. 0. not available because not calculated. 95% CI.98.03) assigned to tamoxifen and raloxifene. The cumulative incidence at 6 years was 21.07 0 0. There was no statistically significant difference between tamoxifen and raloxifene in the number of transient ischemic attacks that occurred (41 in the tamoxifen group vs 50 in the raloxifene group.10 0.13) 0.03 0. 0. †RR for women in the raloxifene group compared with those in the tamoxifen group.03 0 −0.38 (0. Downloaded From: http://jama. With regard to the specific types of fracture for the tamoxifen and raloxifene groups.16 0. 0.84 0.75 (0.24-2.33) 0. of Events Site of Cancer Buccal cavity and pharynx Esophagus Stomach Colorectal Liver Gallbladder Pancreas Retroperitoneum Spleen Nasal/middle ear/sinuses Lung.03 0.78) 0.48 (0.65-1.79 (0.51) 0.96 (0. 0.01-78.88.01-2.48-1.88). 95% CI.73 0.57-3.85.60).07 −0. 0. respectively.03 1. 95% CI.10 0. 2006—Vol 295.79-1.03 0.05 0.02 −0.03 0. NA.24 0 0.06-5.03 0.31 0 0.99 (0.03 0. confidence interval.37 0.34 0.33-4.jamanetwork.04-3.16 (0. spine. Annual Rates of Site-Specific Invasive Cancer Cases Other Than Breast and Uterine Cancer—NSABP STAR Trial No.10 0. No screening was performed for vertebral fractures. *Rate in the tamoxifen group minus rate in the raloxifene group. bronchus Bone/cartilage/connective tissue Skin Gynecologic Cervix Ovary Other Urinary bladder Kidney Eye Nervous system Thyroid gland Leukemia or other lymphatic/hematopoietic Site unspecified Secondary/uncertain Tamoxifen 4 1 3 31 4 1 6 4 0 1 28 3 14 1 12 1 7 9 0 6 8 32 5 4 Raloxifene 3 0 1 30 1 1 5 1 1 1 39 2 12 0 18 2 6 13 1 7 18 28 9 2 Tamoxifen 0.02 −0. 2808 participants reported a history of cataracts (Table 5.02 0.92.21 0. with the raloxifene group experiencing fewer cases of pulmonary embolism and DVT.02 0. indicating that the risk was 30% less in the raloxifene group (RR.03 0.50-1.05 0. trachea. RR.03 0.03) 0.80) 0.06 0.53-1.03 0. 95% CI.

04 0.30 −0. Osteoporotic Fractures.22 RR (95% CI)† 1.43) 1.85-1.00 37 1. NA. Two women had both a hip and a spine fracture. NSABP STAR.74 (0.71 96 2.64 and 2. 0.82 (0.65-1.30 215 8.002).41 65 2. Deaths A total of 197 deaths occurred among the study participants.51 9.46-1.92) 0.10 (0. *Rate in the tamoxifen group minus rate in the raloxifene group. 313.10 0.43) 0.64 0.33 1. Of these women. and Cataracts—NSABP STAR Trial No.34 26 0.68-0.30 −0. There were 101 deaths in those assigned to tamoxifen and 96 in those assigned to raloxifene. per 1000 Cumulative Incidence. confidence interval.50) 0. 2006—Vol 295.46) 0.03 60 66 72 Raloxifene Tamoxifen Cataract Surgery Time Since Randomization. 23 2735 Downloaded From: http://jama. the distribution of these fatalities by cause of death is shown in TABLE 6.96 (0.60 2.64-1.30 2. RR.54-0.77 (0.94.71-1.9 and 56. §Diagnosis based on new Q wave on electrocardiogram without angina or angina requiring hospitalization without surgery.41 Abbreviations: CI.50 0.22 1.23 (0. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene.39 23 0.79 (0. Distribution by cause of death did not differ by treat- Table 5. The RR for cataract surgery was 0.49.88-3.21 (0. 0.69-1.92).20) 1.96 1.29 Osteoporotic Fractures 23 0. Figure 4.81) 1.00) 0.69 0. The RR for cataract incidence was 0. (Reprinted) JAMA.73 Cataracts and Cataract Surgery 8329 313 12.06 −0. per 1000 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 P = . †RR for women in the raloxifene group compared with those in the tamoxifen group.60 1.72 (0.48-1.88 (0.29 0.03 3.29 0. 0.60 0.11 0.68-0.jamanetwork. of Events Type of Event Ischemic heart disease Myocardial infarction Severe angina‡ Acute ischemic syndrome§ Stroke Transient ischemic attack Thromboembolic events Pulmonary embolism Deep vein thrombosis Hip Spine Colles Total Without cataracts at randomization Developed cataracts during follow-up Developed cataracts and had cataract surgery Rate per 1000 Difference* −0.35 0.88) 0.03) 0.26).85 (0.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) were diagnosed with cataracts and of those assigned to raloxifene.002 60 66 72 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 P = . Cumulative incidence at 6 years for tamoxifen and raloxifene was 77. respectively (P=.68-0.72 6.71 35 1.39 50 1. All rights reserved. Cumulative Incidence of Cataracts and Cataract Surgery Cataracts Cumulative Incidence.08 0.53) 0.98 (0.68 52 1. respectively (RR.58 1. June 21.79 (95% CI. No. mo No.22) NA 0.64 (0. resulting in a rate per 1000 of 2.08 100 3.99) Tamoxifen Raloxifene Tamoxifen Raloxifene Ischemic Heart Disease and Vascular-Related Events 114 48 51 15 53 41 141 54 87 26 53 27 104 8334 394 260 126 3.91) 0. risk ratio.29 0.92 (0. Annual Rates of Ischemic Heart Disease and Vascular-Related Events.70 (0. 260 in the tamoxifen group and 215 in the raloxifene group had cataract surgery. 0. Mortality in the treatment groups was similar.68 1.41-1. 95% CI.26 63 1.99).39 51 1.60) 0.62 2. ‡Diagnosis based on angina requiring either percutaneous coronary intervention or coronary artery bypass graft surgery.91 1.com/ on 08/14/2012 .3 per 1000.68-0.48-1. not available because not calculated.82 (95% CI.61 0. mo 8329 8334 7594 7622 5662 5600 3567 3532 673 638 8329 8334 7638 7672 5727 5686 3632 3605 690 657 ©2006 American Medical Association.79-1.84-1. at Risk Raloxifene Tamoxifen Time Since Randomization.53-1.

95% confidence interval. these results demonstrate that raloxifene is an alternative for lowering risk of invasive breast cancer in postmenopausal women with higher Gail risk scores and in those with LCIS for whom the Gail model does not apply. 23 (Reprinted) ©2006 American Medical Association. There were 30 lung cancer deaths.8 per 1000 (tamoxifen) (P=.17. and 33 and 29. 22 and 20.26.72.49) to tamoxifen than in those assigned to raloxifene.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) ment group. 2736 JAMA.94. The proportion of smokers was the same in the tamoxifen and raloxifene treatment groups. 0. risk ratio.1 per 1000 women (raloxifene) vs 24. *Risk ratio.78-3. The mean baseline 5-year breast cancer risk of STAR participants was 4%. All rights reserved.71-1. Downloaded From: http://jama. Distribution of Deaths—NSABP STAR Trial No. COMMENT In this initial report of the STAR trial. died of other causes. The cumulative incidence rates were 25. with 2 more occurring in women assigned Table 6.com/ on 08/14/2012 . 0. 11 in the tamoxifen group and 19 in the raloxifene group.83). 1. Atypical hyperplasia or LCIS and a family history of breast cancer in a firstdegree relative increase the likelihood of developing breast cancer and account for the overrepresentation of women with these characteristics in the study popu- Abbreviations: CI. No. 2006—Vol 295. raloxifene does not reduce the risk of noninvasive breast cancer. National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene. RR. Raloxifene also was associated with significantly less risk of thromboembolic events and cataracts. this difference was not statistically significant (RR. Forty-six and 47 women in the tamoxifen and raloxifene groups. In contrast to tamoxifen.64) Raloxifene 47 1 1 2 2 1 0 1 19 6 1 3 3 1 1 0 1 4 20 2 1 2 5 5 4 1 29 0 1 4 1 0 2 0 1 1 0 3 2 0 1 1 12 96 (2. although not statistically significant. Consistent with preclinical findings and with results from other large-scale studies showing that. respectively. respectively. respectively. More than 70% of participants had a history of invasive breast cancer in a firstdegree maternal relative. and more than 9% reported a history of LCIS. 95% CI. raloxifene and tamoxifen were equivalent in efficacy for lowering the risk of invasive breast cancer. of Deaths Cause of Death Cancer Bladder Bone and articular cartilage Brain Breast Colon Kidney Liver Lung Lymphatic/hematopoietic Oral Ovary Pancreas Spleen Stomach Thyroid Uterus Other and unspecified sites Circulatory/vascular disease Aortic Atherosclerosis Hypertensive disease Ischemic heart disease Other heart disease Stroke Pulmonary embolism Other Alcohol dependence syndrome Aplastic anemia Auto crash Complications of surgery Disorders of metabolism Intracranial injury Other conditions of the brain Other diseases of intestine Other diseases of digestive system Other diseases of urinary system Other respiratory tract diseases Pneumonia Poisoning Septicemia Ill-defined conditions Unknown Total deaths. died of cancer.38 More than 20% of participants reported a history of atypical lobular or ductal hyperplasia on breast biopsy prior to entry into the trial. an important component of a woman’s perceived risk of breast cancer.20 the rate of endometrial cancer in the STAR trial.99). There were only 10 deaths from stroke. The most frequent cause of death was lung cancer. compared with placebo. raloxifene does not increase endometrial cancer risk. rate per 1000* Tamoxifen 46 0 0 5 4 3 1 2 11 5 2 4 4 0 0 1 2 2 22 0 1 0 9 5 6 1 33 1 0 1 0 1 1 1 1 1 1 7 2 1 3 2 10 101 (2. 0.jamanetwork. died as a result of cardio- vascular disease. Combined. June 21. confidence interval. was 38% lower in the raloxifene group than in the tamoxifen group. NSABP STAR.

endometrial hyperplasia. 95% CI. 23 2737 Downloaded From: http://jama. 95% CI. All rights reserved. and continuing follow-up of the women who participated in the STAR trial plus data from other studies involving raloxifene will shed more light on whether raloxifene is associated with other cancer risks. suggesting that raloxifene is not associated with increased risks of these diseases. there have been isolated case reports of this tumor associated with raloxifene. but. 0.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) lation. No. the 10year rate of ipsilateral invasive breast tumors was only 6%. although the number of events in those studies was very small. However.4 per 1000 per year). 95% CI.jamanetwork. RR. The annual rates of invasive breast cancer among women aged 50 years or older (baseline) with no history of LCIS were similar in our 2 prevention studies (3.14. June 21. More cancers of the lung. 2006—Vol 295. In the NSABP DCIS trial B-24. but the RRs were small and CIs were large (Table 4).56).17.5 times higher than those for women who participated in the study and had no history of LCIS (3. We found no statistically significant difference between raloxifene and tamoxifen in the risk of noninvasive disease (LCIS and DCIS) (incidence. only 59 invasive uterine cancers were diagnosed in both study groups during more than 76 000 woman-years of follow-up.83 (tamoxifen) and 9. The greater mean age at entry and the higher 5-year risk of breast cancer in STAR participants may be the explanation for these differences. a risk factor for endometrial cancer. or both appeared in the literature during the STAR trial. the noninvasive cancers occurring in these individuals in either treatment group appear to be similar to noninvasive cancers occurring in the general population. More data are needed to confirm this observation. this study may have been underpowered to detect such a differ- ence.982. The number of participants undergoing a hysterectomy for non–cancerrelated reasons was significantly reduced in the raloxifene group (RR. 0.35-1. Therefore.29).20 in which raloxifene did not reduce the risk of noninvasive breast cancer.8.com/ on 08/14/2012 . (Reprinted) JAMA. and thyroid gland were seen with raloxifene.41 The CORE results through 8 years of follow-up show that raloxifene continues to offer a significant reduction in invasive disease. who had the highest annual rates of invasive breast cancer (Table 2). tamoxifen and raloxifene had equivalent effects in reducing risk of invasive breast cancer in all examined subgroups. 0. 1.16. Most of the STAR cases were diagnosed as a result of mammograms demonstrating increasing calcifications. including women with a history of atypical hyperplasia or LCIS.43 but no such association was causally linked to an increased risk of cardiovascular events. The individuals were undergoing careful follow-up and as a result their cancers were small.6%) of women in STAR who had already undergone hysterectomy is likely attributable to the fact that such women had no risk for uterine malignancy.44. We did see impor- ©2006 American Medical Association. All of these results taken together suggest that different SERMs have unique and specific mixes of benefits and risks and that neither a benefit nor a risk seen with one SERM can be generalized across the entire class. The difference between the tamoxifen.61 (raloxifene) per 1000 women are about 2. Previous studies have shown that raloxifene does not increase the risk of uterine malignancy when compared with placebo.42 The rates of uterine cancer were 2.and the raloxifene-treated individuals with DCIS was quite small (0.7 times higher in the STAR trial than in the tamoxifen group of the BCPT.39.00). 0. 0.86 [raloxifene] per 1000). kidney. similar results were seen in the MORE and CORE studies. Similar patterns emerged when we compared the STAR trial and the BCPT in terms of breast cancer results in women with or without a baseline history of atypical hyperplasia. which was associated with tamoxifen in the BCPT. However. There were no differences in the rates of myocardial infarction.30 per 1000 in the BCPT).20 In the STAR trial. Approximately 36% of the cases were LCIS and 64% were DCIS or mixed LCIS and DCIS.00 per 1000 (tamoxifen) and 1.08). Anecdotal reports of an association between raloxifene and elevated levels of serum cholesterol. the rates in women with an LCIS history were about 1. It is important to note that the difference between the treatment groups in non–cancer-related hysterectomies has likely caused an underestimate of the true magnitude of endometrial cancer risk associated with tamoxifen and an underestimate of the true magnitude of difference between the 2 treatment groups for this end point. the clinical impact of this finding remains to be seen.76 [tamoxifen] and 3. the status of the axillary lymph nodes or presence of estrogen receptor protein was not significantly different between the groups. triglycerides.11 per 1000 per year. The LCIS subgroup rates of 9. In the STAR trial. 95% CI.40. 0.090. However. or acute ischemic syndrome between the tamoxifen and raloxifene groups in our study. This difference did not reach statistical significance (RR. 1.51 vs 2.40 We are in the process of obtaining further data on all of the cases of in situ breast cancer. and most were treated surgically with lumpectomy.25 per 1000 (raloxifene). Although uterine cancer of the mixed Mullerian type occurred in only 2 cases in the tamoxifen group of the STAR trial. was far more common in the tamoxifen-treated group than in the raloxifene group (RR. Several nonsignificant differences in rates of invasive cancers other than breast or uterine cancer occurred between the 2 groups in the STAR trial. The mechanism that would allow for a decrease in invasive breast cancers but a lesser impact on noninvasive disease is unknown. Approximately 25% fewer cases of uterine cancer were diagnosed in the raloxifene than in the tamoxifen group (Table 3). Pathological size of incident invasive breast cancers was similar between study groups. suggesting that raloxifene has a durable benefit despite this lesser impact on noninvasive disease. ovary. The large benefit of tamoxifen that was demonstrated in the BCPT in women with atypical hyperplasia or LCIS may explain the large numbers of women with atypical hyperplasia or LCIS willing to participate in the STAR trial.35-0. to date.62. However. 0. The large proportion (51. severe angina.

54-0. Tamoxifen was well known to oncologists who had used it extensively in the treatment of receptor-positive breast cancer. 2. there was a statistically significant 30% reduction in the risk of thromboembolic events in the raloxifene group vs the tamoxifen group (RR. in part because the drug has been characterized as too toxic. Uncertainty over duration. In contrast. MD. JAMA. April 18.7 per 1000) was substantially lower than this rate in the women in the BCPT who took placebo (21. Tamoxifen was viewed as a cancer drug. Its risk-benefit advantages over tamoxifen in postmenopausal women notwithstanding.07-1. Similar questions about the duration of tamoxifen therapy for breast cancer persists 25 years after that drug’s initial approval for treating the disease and have not impeded either its widespread use or its benefit. A single small (fewer than 30 participants) trial examining short-term raloxifene therapy in premenopausal women found an increased incidence of ovarian cysts. 0.85) for stroke. but we did not achieve our goal of fully proportional minority participation relative to the North American population of women at increased risk.45. 0. 1. there were no significant differences between tamoxifen and raloxifene in participant-reported outcomes for physical and mental health. the majority of whom are older and at lower risk of breast cancer than are the women in the STAR trial. 95% CI. No. Although women may not perceive cataracts to be as serious as certain other STAR end points (such as uterine malignancy or venous thromboembolic events).87) for DVT. the lower frequency of cataract development/cataract surgery in the women who took raloxifene is an impor2738 tant consideration in weighing its relative merits (vs tamoxifen) for reducing the risk of breast cancer.46 The Women’s Health Initiative trial indicated that estrogen plus progestin hormone therapy had hazard ratios of 1. primary care physicians have not broadly accepted the idea of tamoxifen use for breast cancer chemoprevention. The rate of cataract development in the women who took tamoxifen was lower in the STAR trial than in the BCPT (12.86). 23 (Reprinted) ©2006 American Medical Association. 3. who likely are representative of North American minority women at increased risk for breast cancer.39-3. Detailed data about symptoms and quality of life outcomes are presented in the article by Land and her colleagues in this issue of JAMA.18 Tamoxifen is known to increase rates of both cataracts and cataract surgery. The initial NSABP P-1 trial demonstrated that tamoxifen could reduce the risk of invasive breast cancer by 49% and established proof of principle that the chemoprevention of breast cancer is possible.com/ on 08/14/2012 . 95% CI.3.3) and a 60% increased risk of DVT (RR. 95% CI. For pulmonary embolism. Raloxifene demonstrated a positive riskbenefit ratio among STAR minority participants.13 (95% CI. All rights reserved.25) for pulmonary embolism compared with placebo in postmenopausal women.0 vs 4. Although incidence of stroke or transient ischemic attack did not differ statistically significantly between groups. raloxifene is not a substitute for tamoxifen in premenopausal women. however.6.3. raloxifene should not be prescribed for these women. this follow-up should help answer questions about the duration of raloxifene treatment for breast cancer risk reduction. and the news reports highlighting its toxicity may have hampered primary care physicians in exploring its use as a preventive agent. Downloaded From: http://jama.0. Continued follow-up is both required and ongoing among STAR participants. Nevertheless. and 2. 1.8 per 1000).3 vs 24.49-2.35 In summary. when we compared the rates of thromboembolic vascular events reported with the 2 agents. 26%. The rate of cataract development among women in the STAR trial who took raloxifene (9.7 per 1000). Compared with placebo in the MORE trial.47. 0. We made special efforts in the STAR trial to recruit women from racial and ethnic groups in proportion to their numbers in the North American population. This was confirmed in the STAR trial. SERMs generally are known to reduce the risk of fracture in postmenopausal women. June 21. but the rate of cataract surgery was higher (8.91).48 Venous thromboembolic events occurred at similar rates among the postmenopausal women who took hormone therapy in the Women’s Health Initiative study and the postmenopausal women who took raloxifene in the STAR trial.44 raloxifene demonstrated a 3-fold increase in the risk of pulmonary embolism (RR.13. should not be a barrier to use of the drug. 1.91-2. the reduction in risk was 36% and for DVT. almost double the number of minority participants enrolled in the BCPT.NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) tant differences. There is an important distinction to be made between tamoxifen and raloxifene relative to the latter’s potential use for breast cancer chemoprevention. 1.07 (95% CI. 2006).41 (95% CI. These data indicate that both tamoxifen and raloxifene increase the risk of thromboembolic events but raloxifene less so.49 In the STAR trial. raloxifene is well known to the primary care community and is widely prescribed for the prevention and treatment of osteoporosis in postmenopausal women. raloxifene was associated with a 21% lower rate of cataract development and an 18% lower rate of cataract surgery.7 per 1000). who agreed to undergo follow-up indefinitely after unblinding. however. Eli Lilly and Co. compared with tamoxifen.29. but the drug was not commonly prescribed by primary care physicians. 1. More than 500 000 women in the United States are currently taking raloxifene (John Mershon. Additional educational and recruitment efforts will be required in future clinical trials of risk reduction to achieve this goal. oral communication. Rates of fracture were virtually identical in the raloxifene and tamoxifen groups and were similar to previously reported rates for both agents.50 Without larger studies to further examine the efficacy and safety of raloxifene for breast cancer risk reduction in premenopausal women.jamanetwork. who are the most involved in preventive care. 2006—Vol 295. The trial enrolled more than 6% racial/ethnic minority women. The question of how long to use raloxifene to achieve optimal benefit remains unanswered by the STAR trial and other relevant published data.70.

University of Texas M. Pajon. Sinclair (PC). Philadelphia. Joan Westendorp (PC). CCOP Alton Ochsner Medical Foundation. and having received honoraria from. Del: Timothy Francis Wozniak (PI). Analysis and interpretation of data: Vogel. Boca Raton Community Hospital. McCaskill-Stevens. Miami Beach: Rogerio C. Classen (PI). Drafting of the manuscript: Vogel. Frazier (PI). CCOP Santa Rosa Memorial Hospital. Eastern Cooperative Onc Group/ National Medical Association. Ind: Anna Maria V. CCOP Duluth Cancer Center. CCOP Southeast Cancer Control Consortium Inc. Claudette Phinney (PC). CCOP Nevada Cancer Research Foundation. Md (Drs McCaskill-Stevens and Ford). Fleming (PC). Md: John L. Atkins (PI). St Louis. Portland. Pa: Thomas G. Stella (PI). Eli Lilly and Astra- Zeneca. All rights reserved. Mich: Raymond S. Huntsville. Critical revision of the manuscript for important intellectual content: Vogel. Wolmark. CCOP Metro-Minnesota. Morton (PI). Mo: Rakesh Gaur (PI). Dakhil (PI). Ford. Syracuse. Bronx. Marge J. Robidoux. Kayleen R. given their experience with raloxifene. Jordan. Wade. Denver (Dr Pajon). Decatur (Dr Wade). Cecchini. Pittsburgh (Dr Reis). CCOP Hematology-Oncology Associates of CNY. Farmington (Dr Runowicz). Lord III (PI). Mon´ ´ treal. Wickerham. Allegheny General Hospital. Mary Klaus-Clark (PC). NY: Lora R. Aultman Hospital. Houston. Filiz Gokce (PC). Alvin J. Fla: Louise E. Baptist Hospital East/CBC. Author Contributions: Dr Costantino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Calif: Ian C. Springfield. Nafziger (PI). Antinora (PC). Heidi Fritz (PC). Iowa: Abby R. Rebecca L. Cancer Research Network Inc. Eppes (PC). Robidoux. Costantino. Kathy A. Jones (PC). Augusta Kosowicz (PC). Becky Buchanan (PC). Kardinal (PI). St Louis. Flynn (PC). Wolmark. CCOP Northern Indiana Research Consortium. Lippman. NY: Victor R. Kaiser Permanente Northern California. PC. Connecticut BCPT Task Force. Ihde (PI). Marcom (PI). ND: Ralph Levitt (PI). Andrea B. Louisville. Decatur. Ariz: David K. Palm Springs. Bevers. Wendall Goodwin (PI). King (PI). Karen E. Noreen (PC). Storniolo (PI). Wash: Andrew D. Omaha. CCOP Marshfield Clinic. Margolese. Ganz. NY: Joseph Sparano (Principal Investigator [PI]). Mass: Nadine Tung (PI). CCOP Sioux Community Cancer Consortium/SDHRF. Baltimore. Fox ´ Chase Cancer Center. Capko (PI). Lange (PI). Joyce (PC). Mo: Alan P. Des Moines: Roscoe F. Shelly B. Statistical analysis: Costantino. Cooperstown. National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers. Good (PC). Karyn Hart (PC). Winston-Salem. Ann Deshler (PC). Ford. Scottsdale. Judy Norman (PC). Brown (PC). La: Carl G. Kuross (PI). Duarte. Ga: Janice Galleshaw (PI). Wolmark. CCOP Western Regional. Ohio: John Philip Kuebler (PI). University of Pittsburgh. CCOP Dayton.1001/jama . Urbana. AstraZeneca. St Louis Park. Friday (PC). Rena Leib (PC). Pajon. Connie M. Boston. Dana-Farber Cancer Institute. Acquisition of data: Vogel. Rossy Sandoval (PC). Houston (Drs Bevers and Lippman).NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) This trial confirms the previously reported benefit of raloxifene in reducing the risk of invasive breast cancer and indicates that raloxifene is as active as tamoxifen in this regard. Ganz. NC (Dr Atkins). Beth Israel Deaconess Medical Center. Philadelphia. CCOP Columbus. Ohio: Howard M. Tucson: David S. Indianapolis. Gregory S. Doreen Mayberry (PC). CCOP Benaroya Research Institute at Virginia Mason. BaylorSammons Cancer Center. Reis. Baptist Cancer Institute. Deborah S. Study supervision: Vogel. Harper (PC). Margolese. Ariz: Tom R. Merrill Garrett (PI). Central Illinois CCOP. Bryn Mawr. Gish (PC). Mich: Marianne K. Lilenbaum (PI). Gross (PI). Denver: Eduardo R. Una Hopkins (Project Coordinator [PC]). Minn: Steven A. East Carolina University. Donna Hewitt (PC). Dallas. Hackensack: Deborah M. and National Cancer Institute/ National Institutes of Health. Southeast Cancer Control Consortium. Ohio: Eleftherios Paul Mamounas (PI). Don and Sybil Harrington Cancer Center. Neb: Gamini Soori (PI). Calif (Dr Ganz). Ky: Daniel C. Charleston. Clarian Health Partners Inc. Fox Chase Cancer Center. Carol J. CCOP Mayo Clinic Scottsdale. Dr Wolmark reports having received honoraria from Eli Lilly. CCOP St Louis-Cape Girardeau. Ganz. Kirshner (PI). Cronin. Brown (PI). Ford. Dr Cronin reports having served on the Adherence Advisory Board for AstraZeneca. Judy E. Melinda F. primary care physicians may be more willing. Robidoux. Fargo. Costantino. CCOP Wichita. Wash: Lauren K. D. Dr Wickerham reports having served on the speaker’s bureau for. Bernadette L. Fla: Charles L. Morrell (PI). Cronin. Desai (PI). Wade. Philadelphia.51 If raloxifene is approved by the Food and Drug Administration for the prevention of breast cancer. CCOP South Florida STAR Group. Camille Alyce Servodidio (PC). Billings: David B. Tschetter (PI). Costantino. Ellis Fischel Cancer Center. Bethesda. Davison (PC). Financial Disclosures: Dr Vogel reports having served on the speaker’s bureau and as a consultant for. Cronin. 2006: United States: Albert Einstein Comprehensive Cancer Center of Montefiore Medical Center. Pittsburgh (Drs Costantino.joc60074). Ganz. Patricia M. Robidoux. NY: Jeffrey J. Pa (Ms James and Dr Jordan). University of Pittsburgh School of Medicine (Dr Vogel) and Graduate School of Public Health (Dr Costantino). Alice Somich (PC). Cecchini. Duluth. Thrower (PI). Maria Schwieter (PC). Kortni R. Alberts (PI). CCOP Heartland Cancer Research: St Louis. St Cloud. Myers (PI). No other authors reported disclosures. Pa. Garber (PI). Mich: David A. CCOP Grand Rapids Clinical Oncology Program. CCOP Cancer Research for the Ozarks. Mo: Antonella L. Lyss (PI). Comprehensive Cancer Institute. Vogel (PI). Canto (PC). Jubelirer (PI). CCOP Oklahoma. Pajon. Pittsburgh. Seattle. Cronin. Study concept and design: Vogel. SD: Loren K. No. Wolmark. Robidoux.23. City of Hope National Medical Center. Sally Brown (PC). Susan C. Verrill (PC). Jackson (PC). McCaskill-Stevens. Merkel (PI). Baylor College of Medicine. Neag Comprehensive Cancer Center. June 21. Eastern Maine Medical Center. University of Pittsburgh. Jacobs (PI). Peggy S. Fehrenbacher. CAMC Health Education and Research Institute Center for Cancer Research. Packard (PC). Cleveland Clinic Health System Star BCPT. Wis: James L. Robin Szekely (PC). Tex: Kathy Kimmey (PI). Cronin. Fitch (PI). Denver Veterans Medical Center. Ceglio (PC). Rowland (PI). Pittsburgh. CCOP Upstate Carolina. Pajon. to prescribe it for breast cancer chemoprevention than they have been to prescribe tamoxifen. Allegheny Cancer Center Protocol Office. Gero (PC). Wickerham. Calif: Janet K. CCOP William Beaumont Hospital. Zapas (PI). Philadelphia. CCOP Kalamazoo. CCOP Northwest. Windschitl (PI). Author Affiliations: Magee-Womens Hospital. Fla: Neil Abramson (PI). University of Connecticut Health Center. Fuemmeler (PC). Greenville. Lockhart (PI). Tackett (PC). Reis. Costantino. 2006 (doi:10. Mass: Judy E. Jewish General Hospi´ tal. Ill: James Lloyd Wade III (PI). James. Lanier (PI). Desert Regional Medical Center. Pa: Ajit M. Nancy J. WVa: Steven J. SC: Jeffrey K. Ford. CCOP Central Illinois. Pa: Norman Wolmark (PI). UCLA Schools of Public Health and Medicine and Jonsson Comprehensive Cancer Center. Kelly J. Jennifer Thibodeau (PC). Decker (PI). Marshfield. CCOP Missouri Valley Cancer Consortium. Loots (PC). Jenny L. Dr Margolese reports having served on the speaker’s bureau for AstraZeneca. Jacksonville. Anderson Cancer Center. Durham. Atkins. Schaefer (PI). Pickett (PC). Tex: Brian Pruitt (PI). CCOP Northern New Jersey/Hackensack University Medical Center. Spartanburg. Robidoux. Mary Beth Wilwerding (PC). NC: James N. Giguere (PI). Active NSABP STAR P-2 Clinical Centers as of May 3. Julie O’Brian (PC). Siteman Cancer Center at Barnes-Jewish Hospital & Washington University School of Medicine. Royal Oak. technical. Greenville. Deborah A. Sauter (PI). Cedar Rapids. Ford. Bassett Healthcare. Daly ©2006 American Medical Association. Boston. Sisk (PC). Duke University Medical Center. Mary P. BaltimoreWashington Regional STAR Center. Hon (PI). DeFusco (PI). and having received honoraria from. 23 2739 Downloaded From: http://jama. Kathy Morris (PC). Ala: Jeremy K. and Wolmark and Mr Cronin and Ms Cecchini). CCOP Montana Cancer Consortium. Mary L. Dayton. Jan P. Grann (PI). Pa: Edith P. Cronin. Boca Raton. Colman (PI). Fehrenbacher. Atkins. Manhasset. Pamela G. Jordan. Columbus. Jordan. Hoehn (PI). Berkshire Hematology Oncology. Plantation. DeKorne (PC). Ellerton (PI). Zon (PI). Costantino. New Orleans. James. Linda Meehl (PC). Marta L. Nancy E. Lippman. James. NY: Anne N. Colorado CCOP. Memphis. Rosemary Wiggins (PC). Szczepanek (PC). Pittsburgh (Drs Wickerham and Wolmark). Murphy (PC). Sue Averson (PC). Baptist Clinical Research Center. Montreal (Dr Margolese). Francine Mineau (PC). Hartford: Patricia A. Calif: Lawrence D. Cathleen Goetsch (PC). Fehrenbacher. Mass: Harvey Zimbler (PI). Minn: Patrick James Flynn (PI). Corso (PI). Cane (PC). Kathy V. Runowicz. CCOP Michigan Cancer Research Consortium Community Clinical Onc Program. Ill: Kendrith M. Cronin. CCOP Atlanta Regional. Ann Arbor: Philip J. Pa: Mary B. Ohio: Paul L. Hansen (PC). Wichita. Valorie Steichen (PC). Administrative. Mo: Bethany Graham Sleckman (PI). CCOP Christiana Care Health Services. Los Angeles. Centre hospitalier de l’Universite de Montreal. Kathleen Laico (PC). Wade. Phoenix. Amarillo. or material support: Vogel. McCaskill (PC). Ore: Keith S. Annette S. Highland Park. Toni E. (Reprinted) JAMA.jamanetwork. Donna C. Bensman (PC). Jeanne Archer (PC). CCOP North Shore University Hospital. Tenn: Lee S. Santa Rosa. Quebec (Dr Robidoux). CCOP Iowa Oncology Research Association. Schwartzberg (PI). Gloria F. Newark. Jr (PI). Kan: Shaker R. Coborn Cancer Center. McCaskillStevens. CCOP Greenville. Charmaine Green (PC). Weiselberg (PI). Jane V. Tex: Powel H. Albert Einstein Healthcare Network. 2006—Vol 295. Published Online: June 5. Wickerham. CCOP Main Line Health. Kansas City. Wagman (PI). Costantino. Wickerham. Kathleen Van Wagenen (PC). Arizona Cancer Center. Berby-Todd (PC). Jeanette M. Bevers. Sioux Falls. Laurie Lewis (PC). Bangor: A. Marianne Dias (PC). Lippman. Scullin. Warrensville Heights. Columbia University Medical Center. Ohio: Roger F. Ill: Douglas E. Columbia. Minn: Harold E. Tulsa: James B. Mo: J. Mo: Edward R. Kate Rodger (PC). Lippman. Vallejo (Dr Fehrenbacher). Grant (PI). Susan Colvin (PC). Shirley Hall (PC). Wolmark. Reis. Canton. Jr (PI). Grand Rapids. McGill University. Anderson (PI). Elaine Lagow (PC). Cronin. Margolese. Haefling (PC). Victory (PC). CCOP Columbia River Oncology Program. Costantino. CCOP Carle Cancer Center. Toledo. CCOP MeritCare Hospital. Robin Burgess (PC). South Bend: Robin T. Runowicz. Tex: Michael D. Gwendolyn Randall (PC). Mitchell (PI). Bevers. Meyer (PC). Pittsfield. Atlanta. Las Vegas: John A. Kalamazoo. CCOP Colorado Cancer Research Program. New York. Jennifer M. Bevers. SC: Steven W. Obtained funding: Costantino. NC: Paul K. CCOP Cedar Rapids Oncology Project-Mercy Medical Center. Mabel Goodpaster (PC). Winston-Salem. CCOP Evanston/Highland Park Hospital. Atkins. NC: Rosa Cuenca (PI).com/ on 08/14/2012 . CCOP Toledo Community Hospital Oncology Program. Cecchini. CCOP Kansas City Clinical Oncology Program.295. CCOP Scott and White Hospital. Rastelli (PI). Tacoma. Temple.

analysis. Alene: Haluk Tezcan (PI). NY: Jayne R. Judith Murray (PC). Stanford University. Loma Linda University Cancer Institute. Zera (PI). Le Groupe Hospitalier de l’Universite de Montre Mon´al. Maria Serrano (PC). Indianapolis: William M. Norris Cotton Cancer Center at the Dartmouth-Hitchcock Medical Center. Vancouver. University of Cincinnati. Marie Lamey (PC). Valorie A. Resurrection Medical Center. Rosalia Santos (PC). Vassar Brothers Hospital. Director of Scientific Publications for the NSABP. Vermont Cancer Center University of Vermont. Parker (PC).NSABP STUDY OF TAMOXIFEN AND RALOXIFENE (STAR) (PI). Fiske (PI). Kimmel Cancer Center at Thomas Jefferson University. Wash: Richard B. University Hospital & Medical Center at Stony Brook. Naval Medical Center San Diego. Sheffield (PC). Wake Forest University School of Medicine. Schwarzenberger (PI). Ann M. Plant (PC). Seattle. University of California San Diego Cancer Center: Anne M. Iowa City: Neal Walter Wilkinson (PI). Scranton. Calif: Patricia A. Wilson (PC). Pensacola: Mark S. NH: Bradley A. Lexington: Edward H. St Luke’s Breast Care Center. Sponzo (PI). North Idaho Cancer Risk Assessment Clinic–NICRAC Coeur D. UCLA-Center for Health Sciences. Louisville. Oregon Health and Science University. Camille Finkle (PC). for her valuable assistance in the conduct of the study. Elizabeth Broome (PC). Loyola-Cardinal Bernardin Cancer Center. Los Angeles. Costin (PC). Lickley (PI). Calif: Deanna Attai (PI). Harper (PI). Smith (PC). Providence Hospital Cancer Center. Bevers (PI). Fla: Darrell N. Doris Cuadrado (PC). Ann W. Sponzo (PC). Lisa Quirk (PC). 23 (Reprinted) ©2006 American Medical Association. Owens (PC). Ill: Adrian Bianco (PI). Colleen M. Mich: Michael Simon (PI). Montre Que´al. Lemon (PI). Pa: Ronald E. Conn: Donald R. Woo (PI). Pa: James F. Tait (PC). De Haas (PC). Michigan State University. Neb: Stephen J. Pasadena. St Michael’s Hospital Breast Centre. Montgomery (PI). New York. Ontario: H. Thompson Cancer Survival Center. Morrow (PI). Julie Fries (PC). Cleveland. Mary M. Jackie H. Sutter Health Cancer Research Group-Eastern Division. Sarah Ord (PC). Oklahoma City: Karl K. MBCCOP Howard University Cancer Center. Anderson Cancer Center. Bement-Stump (PC). Hendrick Cancer Center. Acknowledgment: We thank Barbara C. NY: Stefan Madajewicz (PI). Carol P. Joelle Machia (PC). Nicole Trem´ blay (PC). Ill: Janet M. in the collection. Beth A. Edmonton. Josie B. Ohio: Ralph Douglas Trochelman (PI). Lackland AFB. Lubbock: Everardo Cobos (PI). Pedro Bernal (PC). USC/Norris Cancer Center. Cooper (PC). Roswell Park/WNY STAR Consortium. Bethany S. Omaha. Christine Schurman (PC). Honolulu: Nancy L. LeMarbre (PI). St Vincent’s HospitalManhattan. Stewart (PI). Carr (PC). Bronx. Joan Pearson (PC). Lehigh Valley Hospital. Boatman (PI). Tex: Allyson Lynn Harroff (PI). Elliott (PC). Cooks (PC). University of Texas M. Laura Getty Gibson (PC). Cheryl Hopkins (PC). Hempling (PI). Thirlwell (PI). 2006—Vol 295. Baltimore. Houston: Therese B. Ill: Nora T. Dastur (PC). Nancy J. Winnipeg: Andrew L. Cooke (PI). Stuart. Calif: Joel I. DC: Claudine Isaacs (PI). Rush University Medical Center. Lubbock. PhD. Hamm (PI). John and Dorothy Morgan Cancer Center. University of Texas Southwestern Medical Center at Dallas: Ann Marilyn Leitch (PI). Isabel Rodrigues-Fong (PC). Marsha MacIntyre (PC). Ill: Kathy Albain (PI). URCC Cancer Prevention Network. Linda Ellinwood (PC).com/ on 08/14/2012 . Bernik (PI). Rapid City. Downloaded From: http://jama. Romond (PI). Ala: Paul O. Portland: Rodney F. New Orleans: Julia A. Tom Baker Cancer Centre. Tarolli (PC). Ohio: Rosemary A. Albuquerque: Aroop Mangalik (PI). Oakland: Louis Fehrenbacher (PI). York Cancer Center. Oklahoma NSABP Consortium. University of Wisconsin Comprehensive Cancer Center. Kaplan Comprehensive Cancer Center at NYU Medical Center. Birhiray (PI). Lombardi Cancer Center. Tenn: Mark Kelley (PI). Yakima Valley Memorial Hospital/North Star Lodge Cancer Center. Baltimore. Putz (PC). Roberta Gross (PC). SUNY Upstate Medical University. Dugan. Women’s College Campus. Rochester. Krause (PI). Radiant Research. Blanca N. Calif: Carlos A Garberoglio (PI). British Columbia: Urve Kuusk (PI). Wis: Paul J. Green (PI). Centre Hospitalier Affilie Universitaire de Quebec. the manuscript was submitted to AstraZeneca and Eli Lilly before submission. Holcombe (PI). Peggy Blize (PC). NY: Janice Dutcher (PI). Quebec: Richard ´ Gordon Margolese (PI). Toppmeyer (PI). Jewish General Hospital. June 21. Tasha N. Klass (PC). Cincinnati. Ridgewood. San Diego. Kelminski (PC). Michele D. Betty Razvillas (PC). Lynn Fearn (PC). Catherine Meaney (PC). Lannin (PI). Caggiano (PI). Maria Francisco-Arriola (PC). Paula Fry (PC). Yolanda M. Chicago. Parsons (PC). Mobile. Winston Salem. Funding/Support: This study was supported by Public Health Service grants U10-CA-37377. Melissa F. Yale University School of Medicine-Yale Cancer Center. Jann E. Lavina A. Quebec: Henry Ryu´ suke Shibata (PI). Jensen (PC). Montreal. University of Tennessee Medical Center. NY: Stephanie F. MBCCOP Louisiana State University Health Sciences Center. Carolyn A. treal. Fla: Susan Minton (PI). MBCCOP University of New Mexico Cancer Research and Treatment Center. Pa: Martin Hyzinski (PI). Cheryl B. Minn: Sandhya Pruthi (PI). AdamsCampbell (PI). Kansas City: William R. Angelina G. Mayo Clinic Rochester. Paterson (PI). York. Anderson (PI). Glens Falls. Moore (PC). Stanga (PC). Ottawa Hospital Regional Cancer Centre. Kelly A. Montreal. MBCCOP Virginia Commonwealth University. Kahlenberg (PI). Mary E. U10-CA69974. Steele (PC). Pa: Roy E. Linda Robitaille (PC). Geisinger Breast Clinic. Calif: Darcy V. MBCCOP San Juan. Hirsch (PI). Glenda J. Valley Hospital. Robinson (PC). Memorial Sloan-Kettering Cancer Center. Debbie A. Pittsburgh. St Vincent Hospitals and Health Services. Mercy Cancer Center. Toronto. University of Pittsburgh Medical Center Health Systems. MBCCOP University of Hawaii. Slomski (PI). Ohio: Elizabeth A. Kosic (PC). UBC-Vancouver Hospital & Health Science Center. Cleveland. Ky: John T. Syracuse. Susan G. New Brunswick: Deborah L. Yong Anna Park (PC). Miss: Nathaniel Brown (PI). Akron. Stony Brook. Calif: Robert W. Krajcovic (PI). Pruitt (PC). Bernard (PI). National Institutes of Health. Biostatistical Center. and interpretation of data. Calif: Preston S. Barbara Kahn (PC). Smith (PI). Burlington: Seth P. Milwaukee Prevention Trial Sinai Samaritan Medical Center MIL. Gwendolyn G. Vickie Reynolds (PC). Yelizaveta Yanovskaya (PC). Barb Gore-Hickman (PC). NY: Gary R. Cross Cancer Institute. Jr (PI). or in the development of the manuscript. Brandy Fitzhenry (PC). Thunder Bay. Royal Victoria Hospital. Mehta (PI). Summa Health System. Salt Lake City: John Harris Ward (PI). Guylaine Julien (PC). Lech (PI). Chicago. NSABP. Jo Ann Jameson (PC). Ill: Seema A. Ireland Cancer Center at Case Western Reserve University. Pa: Bruce M. Department of Health and Human Services. Sales (PC). University of Kentucky Medical Center. The Cancer Institute of New Jersey. Furumoto (PI). Toronto. Pa: Victor G. Boyd (PI). NJ: Harold Bruck (PI). New York. Karen Carapetyan (PC). Indiana Community Cancer Care. Tampa. Eichenhofer (PC). University of North Carolina at Chapel Hill. University of Louisville/Brown Cancer Center. Mid-Delta Family Practice Clinic II Inc. University of Iowa Hospitals and Clinics. Calgary. San Juan. Wash: Thomas E. Per contractual arrangement. Buaiz (PC). Wolter (PI). West Florida Cancer Institute. Alguard (PC). NY: Stephen B. Goodman (PI). NY: Leslie Montgomery (PI). Jaswinder Grewal (PC). Jewell (PI). Quebec: Andre Robidoux (PI). NY: Carol S. Vanderbilt Cancer Center. San Gabriel Clinical Oncology Research Program. University of Chicago. Barbara A. Mich: Judie R. Maria Oldfield (PC). St Mary Medical Center/ Pacific Shores Medical Group. Ruth L. San Diego. Tamara D. The Regional Cancer Center. Lebanon. Joy Dritschilo (PC). Waukesha. Diane Andersen (PC). Kita (PC). Loma Linda. The Johns Hopkins Oncology Center. Calif: Vincent A. Role of the Sponsor: The study sponsors had no role in any aspect of study design. Tenn: Daniel Mark Ibach (PI). Good. Ontario: Jarley Koo (PI). Nancy Pope (PC). Quebec: Louise Provencher (PI). Joe Arrington Cancer Research and Treatment Center. Abilene. Thuy Pham (PC). Bernstein (PI). Tex: Mark W. Poughkeepsie. Sacramento. Meisenberg (PI). Jeannette Kostenuik (PC). Indianapolis. Bell (PC). Karen M. Alberta: Barbara E. Allentown. Linda M. Danville. University of Arkansas for Medical Sciences/Arkansas Cancer Res Center: Little Rock: V. Jo A. Wendy A. Malek (PC). Suzanne Klimberg (PI). Stafford (PI). Pommier (PI). Ann Arbor: Sofia Merajver (PI). Glendale Memorial Hospital Comprehensive Cancer Center. Velazquez (PC). Irvine Medical Center. Madison: James A. Palo Alto. Mary E. Wood (PC). Charlamb (PI). Edge (PI). Debi Oxenberg (PC). Ganz (PI). Wayne State University Karmanos Cancer Institute. Redrow (PI). Mary Ann J. Ottawa. NJ: Frederick B. Washington. Scripps-Stevens Cancer Center. Texas Tech University Health Sciences Center Southwest Cancer Center. Shaughnessy (PI). Ontario: Margaret Lyn Anthes (PI). Minneapolis. New Haven. Long Beach. Kane (PC). Md: Kala Visvanathan (PI). Melba Nelson (PC). Gourley (PC). Tex: Paul J. Wallace (PI). JAMA. Philadelphia. Joan James (PC). Calif: Benjamin T. Pamela Dawson (PC). Greenebaum Cancer Center. University of Texas Health Science Center at San Antonio: Morton S. Thunder Bay Regional Health Sciences Centre. Smith (PC). bec: Michael P. Knoxville. Margaret A. Chapel Hill: Stephen A. Los Angeles. Rinella (PC). Chesterfield. SD: Richard Charles Tenglin (PI). NortonHealthcare Inc. Ohio State University/James CHRI. NY: Robert W. Henkin (PC). Tupelo: Charles W. No. Mary Hamielec (PC). Vogel (PI). Columbus: William B. Chicago. Yakima. East Lansing: Carol A. Erie. University of Kansas Medical Center. Northern California Kaiser Permanente Divison of Research. San Diego. Biggs (PC). Kathy Christiansen (PC). Saint Barnabas Health Care System Consortium. Cohick (PC). Rapid City Regional Oncology Group. Md: Barry R. G. Jaskowiak (PI). U10CA-12027. MBCCOP University of Illinois at Chicago (UIC): Divyesh G. Montreal General Hospital. University of Michigan University Hospital. Calif: Jonathan Polikoff (PI). Schmidt (PC). Ky: Jeffrey B. Puerto Rico: William Caceres (PI). Davis (PC). Harris Methodist Fort Worth. Methodist Cancer Center Omaha. Maywood. Jean M. Evans (PI). Nashville. Beth A. Southfield. Luzminda B. Carolyn Rhoton (PC). Richmond: Mary Helen Hackney (PI). Hennepin County Medical Center. Pa: Gregory R. University of California. Boatright (PI). Tolli J. Alberta: Alexander H. Khan (PI). Lawrence (PI). Mary Akagi (PC). Vacek (PC). Washington. Ind: Ruemu E. Tex: Victor J. Valerie Sepeda (PC). Ontario: Shailendra Verma (PI). Orange: Randall F. Pittsburgh: John A. Michelle Arnold (PC). Pauli (PC). Janet H. New York. Knoxville: Daniel M. Gray (PC). Cindy Sinnott (PC). Willhite (PC). Rachel Cohn (PC). Rochester. Newark. Kaiser Permanente San Diego. Gerty Fortune (PC). D. Carlson (PI). Mary Amy Waddell (PC). Deborah R. The Cancer Center at Glens Falls Hospital. Glendale. Mo: David P. NC: Edward A. Laura J. Peggy Florack (PC). Lisa B. and by AstraZeneca Pharmaceuticals and Eli Lilly and Co. Farrar (PI). Detroit. Elizabeth M. Chaunda L. Sarah L. Harlow (PI). Louisville. Gable (PI). Strohbehn (PC). Buffalo. Cheryl Robins (PC). Boman (PI). North Mississippi Medical Center. and U10CA-69651 from the National Cancer Institute. Clarfeld (PI). Fred Hutchinson Cancer Research Center. for editorial assistance and Lynne Anderson. NY: Anna Pavlick (PI). 2740 Northwestern Memorial Hospital. Huntsman Cancer Institute at the University of Utah. Nancy S. Vee A. The Western Pennsylvania Hospital. Spicer (PI). All rights reserved. Donovan (PC). Cohen (PI). Holly J. MBCCOP Our Lady of Mercy Medical Center. Leeming (PI). Chicago. MBCCOP Gulf Coast. Hopital du St-Sacrement. DC: Lucile L. Fort Worth.jamanetwork. Kathy O’Day (PC). Levine (PI). Roof (PC). Wilford Hall Medical Center. Belma Kantardzic (PC). Carol A. H. Daisy J. Maureen A. Lee Moffitt Cancer Center and Research Institute. Calif: Nerses Simon Tchekmedyian (PI). Hargis (PI). Minn: Richard T. Canada: CancerCare Manitoba. Arrick (PI).

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in the “Invasive Breast Cancer” panel of Figure 2 on page 2732. December 27.faseb. the term “risk” was incorrectly used in Table 2 on page 1360. It will take such initiatives by scientists. receiving compensation as chair of the board of University of Minnesota Physicians. “Boston Medical Center. DMMT LLC. MD. Dr Furcht reports having equity or royalty relationships with Apollo Diamond. The Table 2 title should have read “Crude and Adjusted Odds Ratios [rather than risk] for Death as a Function of Preeclampsia.org/pdf/LeoFurchtPresident7.” In Reply: It is very encouraging to know that a prestigious organization such as FASEB has developed principles and standards for conduct and management of academia- 2926 JAMA. 3.org/pdf/FASEB_COI_paper . 2006. JAMA Chicago. and in Table 5 on page 2735. Catherine D. Liz Pottier (PC). Ill Financial Disclosures: None reported. Md Leo T.296: 996-998.295:2727-2741).94. 1. Failure of authors to disclose as required indeed “does not automatically translate to the article being flawed. incorrect data were reported. not 6701. 2006.06. PhD lbrockway@faseb. Also. journals. http://opa. CORRECTIONS Incorrect Data and Omission of Trial Site and Personnel: In the Original Contribution entitled “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” published in the June 21. the cut-in headings in the table should have read simply “Crude” and “Adjusted. ASF LLC. Boston.30. issue of JAMA (2006. industry interactions from the scientists’ perspective.pdf.14. The Federation of American Societies for Experimental Biology (FASEB). Prout (PI). Athersys Inc. Downloaded From: http://jama. 2006. 2006. All rights reserved. DeAngelis. not −0. JAMA. MCL LLC. 24 (Reprinted) ©2006 American Medical Association. not 0. Accessed October 24. Mentor Inc. and the difference between the rates by treatment group should have been reported as −0.faseb.jamanetwork. DeAngelis CD. and MGI Pharma. 2. 2006—Vol 296. The Federation of American Societies for Experimental Biology (FASEB).99.93. Shared responsibility.296:1357-1362).”1 Nevertheless. http://opa. the number at risk in the raloxifene group at 36 months should have been reported as 6702. and all others involved in discovery and dissemination to assure public trust in biomedical science. issue of JAMA (2006.” Similarly. The influence of money on medical science.LETTERS public. Brockway. 2006. a trial site and its personnel were inadvertently omitted: in the list of active NSABP STAR P-2 clinical centers appearing on page 2739. News FASEB: July 14. industry. it does create the perception that the authors had something to hide and decreases public trust in medical research. and serving as a board member for University of Minnesota Assurance Company. Incorrect Terminology: In the Original Contribution entitled “Trends in Fetal and Infant Survival Following Preeclampsia” published in the September 20. No.pdf. 2006.” should have appeared between the entries for Boca Raton Community Hospital and CAMC Health Education and Research Center. Furcht. the risk ratio (RR) for estrogen receptor–positive patients should have been reported as 0. Laura M. individual integrity: scientists addressing conflicts of interest in biomedical research: July 14. Accessed October 24. Mass: Marianne N. the rate per 1000 for ischemic heart disease in the tamoxifen group should have been reported as 2. MD Department of Laboratory Medicine and Pathology University of Minnesota Medical School Minneapolis Financial Disclosures: Dr Brockway reports being a recipient of a grant from the AAMC-ORI (Association of American Medical Colleges–Office of Research Integrity) Responsible Conduct of Research Program for Academic Societies.org Office of Public Affairs Federation of American Societies for Experimental Biology Bethesda. by Birth Period.00. MPH Editor in Chief. 2006.com/ on 08/14/2012 . In Table 2 on page 2731.29. not 3.

Determining this would require another large randomized clinical trial with mortality outcomes. Robert A.edu Harmony R. numbers at risk in the raloxifene group at 18. North Carolina Judith S. (Reprinted) JAMA. respectively. et al. 2000. Dzavik. Milo O.14 and for the SF-36 Physical Component Summary. Circulation. the difference per 1000 as 7. the gene symbol LPA. Harrington.jamanetwork. Involvement of inducible nitric oxide synthase in the inflammatory process of myocardial infarction.” Also. 2007.” Incorrect Data in Tables: In the Original Contribution entitled “Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study” published in the April 11. perhaps taking into consideration baseline renal function.50]). the rate per 1000 for tamoxifen as 12. the mean age for men with acute coronary syndrome (ACS) should be 60. Kaluski E. especially since it is believed that iNOS is the important target in patients with cardiogenic shock. should have been identified as LPL and in Table 3. 9 973 Downloaded From: http://jama.14.39 [0. Ontario.1 per 1000 women (tamoxifen) vs 24.” Also.39 (0.7 years and for the controls. Blatt A. Van de Werf.8%) in the raloxifene groups” should have read “Forms were not expected from the 207 women (1. In the “invasive cancer” row of Table 3 on page 2732. On page 2733. Liz Pottier (PC). On the same page the P values should have been reported similarly in text: “(P=. at the dose and duration studied in TRIUMPH. In the “Invasive Uterine Cancer” panel of Figure 3 on page 2733. New York Vladimir Dzavik. and 371. Cotter G. All rights reserved.hochman@med. Wildhirt SM. 60. and the RR as 0.com/ on 08/14/2012 . Dr Hochman reported receiving honoraria from ArgiNOx and Procter and Gamble and performed consulting for Datascope. Eur Heart J.0 years. 3233.50). Dr Dzavik reported receiving honoraria from Datascope.52.83). and the RR (95% CI) as 0. Prout (PI). the rate per 1000 for tamoxifen should have been reported as 1. and Hochman) reported receiving institutional research support from ArgiNOx Pharmaceuticals for their work on TRIUMPH. September 5. MD New York University New York.0%) who died or from the 1352 women (6. It is possible that other dosing strategies. In the “Invasive Breast Cancer” panel of Figure 2 on page 2732. issue of JAMA (2007. Alexander.5 Effects of NOS inhibition in patients with cardiogenic shock should differ from normal volunteers. 2003. which occurred at some point during follow-up for 197 women (1. 2003. Also in Table 3. issue of JAMA (2006.30-0. Boston. on the same page. the number of events for tamoxifen should have been reported as 221 and for raloxifene as 87. 3. respectively. Circulation. However. et al. it is not clear that L-NAME is more potent in vivo. 295[23]:2742-2751) reported incorrect data and included incorrect wording. MD University of Toronto Toronto. 50(3):253-261. the annual incidence rate for tamoxifen should have been reported as 1. 1. 2103. the text that read “Forms were not expected after death or consent withdrawal. Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study. MCS and P=.297[14]: 1551-1561). and 72 months should have been reported as 4311. Reynolds. Also on page 2733. the difference in rate per 1000 as 0.74. 2007. the numbers at risk at these same points should have been reported as 4301.24 and for raloxifene as 4. Canada Frans J. Van de Werf. Dudek RR. Reynolds HR.1 We believe our conclusion is valid: L-NMMA. incorrect data were reported in 3 tables. Incorrect Data and Wording: The Original Contribution entitled “PatientReported 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” published in the June 21. the P value for the SF-36 Mental Component Summary should have been . No.24(14):1287-1295. Cotter G.63. 2.107(24):2998-3002. Hochman JS. and the RR (95% confidence interval [CI]) as 0. Dzavik V.63.0%) in the tamoxifen and 1352 (6. 2007—Vol 298. CORRECTIONS Incorrect Data and Omission of Trial Site and Personnel: In the Original Contribution entitled “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” published in the June 21. 54.4 Refractory shock is characterized by lower-thanexpected systemic vascular resistance and hypotension.30-0. both potential effects of excess NO.94.101(12):13581361. MD John H. Harrington. In the first paragraph of the Comment section on page 2736. 4. 2006. 28(9):1109-1116. had no effect on mortality. end of first paragraph in column 2.6. L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock. and 409.72. 2006.8%) who withdrew consent at some point during follow-up. the terms “raloxifene” and “tamoxifen” were reversed in the second sentence.LETTERS ent effects at the cellular level. et al. the number of hysterectomies performed in those assigned to tamoxifen should have been reported as 221 and in those assigned to raloxifene as 87.” should have appeared between the entries for Boca Raton Community Hospital and CAMC Health Education and Research Center. issue of JAMA (2006. Belgium Financial Disclosures: All members of the writing committee (Drs Alexander. “Boston Medical Center. Reynolds.23. the P value should have been .295(23):2727-2741). and the cumulative incidence rate through 7 years for tamoxifen as 14. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. et al.nyu. L-NAME is relatively nNOS and eNOS selective.99. In Tables 1 and 2. the sentence should have read “The cumulative incidence rates were 25. In Table 5 on page 2735. Cotter G. the RR for raloxifene as 0. PCS). the number at risk in the raloxifene group at 36 months should have been reported as 6702. in the tamoxifen group. Importantly. Mass: Marianne N. in Figure 1. 1984. Kaluski E. 36. 5. MD judith.99. 3120. the risk ratio (RR) for estrogen receptor–positive patients should have been reported as 0. ©2007 American Medical Association. or other NOS inhibitors might have a different effect. a trial site and its personnel were inadvertently omitted: in the list of active NSABP STAR P-2 clinical centers appearing on page 2739. Suzuki H. the rate per 1000 for ischemic heart disease in the tamoxifen group should have been reported as 2. In Table 2 on page 2731. incorrect data were reported. MD University Hospital of Gasthuisberg Leuven. top of column 1. Int J Cardiol. 1995.30. Eur Heart J. MD Duke University Durham.8 per 1000 (raloxifene) (P = .23. One page 2746.99 and the difference per 1000 as −0. in the “hysterectomy during follow-up” row. Hochman. LINCS: L-NAME (a NO synthase inhibitor) in the treatment of refractory cardiogenic shock: a prospective randomized study. the initial positive singlecenter experience with NOS inhibition in patients with cardiogenic shock used L-NMMA.

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