Risk Benefit and Conclusions

1. George Sledge, MDIndiana University School of Medicine Risk Benefit and Conclusions

2. Do We Need a New Chemoprevention Agent? • Breast cancer continues to represent a major cause of morbidity and mortality • Few women actually receive tamoxifen as chemoprevention for breast cancer • Real toxicities (VTE, uterine cancer) limit its use • Perception that it is a “cancer drug” with poor risk/benefit ratio

3. Raloxifene Demonstrates Efficacyin Postmenopausal WomenAcross a Spectrum of Breast Cancer Risk 56% RR 1.02 71% 44%

4. Confirmation of Raloxifene’s Effectiveness Relative to Tamoxifen in STAR STAR Primary Analysis RR (95% CI) = 1.02 (0.82, 1.27) STAR Non-inferiority Analysis Proportion retention of tamoxifen’s effect* (95% CI) = 97% (65%, 128%) * Tamoxifen’s effect based on women 50 years or older in P-1

5. Raloxifene as an Alternative to Tamoxifen: Benefit • Similar efficacy with regard to prevention of invasive breast cancer • Less effect on noninvasive cancers

6. Non-Invasive Breast Cancerin Placebo-Controlled StudiesMORE, CORE, RUTH SEER 5/2576 3/2557 2/1274 5/2716 5/5057 11/5044 (N=5133) (N=3990) (N=10,101) SEER annual US incidence rate per 1,000 in white women ≥50 (2000 data)

7. Efficacy and Important Safety Outcomes STAR FAVORS TAMOXIFEN FAVORS RALOXIFENE P=0.057 * P=0.055 * * * *P < 0.05 vs. tamoxifen Difference in Number of Events (95% CI) per 1000 Women/Yr

8. Differences in Outcomes forRaloxifene versus TamoxifenSTAR Difference in # of events per 1000treated per 5 years (RALOXIFENE VS. TAMOXIFEN) Outcome Non-invasive breast cancer 3 more DCIS only 2 more Hysterectomy 40 fewer† Hyperplasia 20 fewer† Uterine cancer 4 fewer Venous thromboembolism 6 fewer† Deep vein thrombosis 3 fewer Pulmonary embolism 3 fewer Cataracts 10 fewer† Cataract surgery 9 fewer† †P < 0.05

9. Invasive Breast Cancer Risk Reduction Compares Favorablywith Other Prevention Therapies *NNT = number of patients needed to treat for 1 year to prevent 1 outcome 1Sever PS et al., Lancet. 2003 Apr 5;361(9364):1149-58 2MRC Working Party Br Med J 1992;304:405-412 3Berger JS et al. JAMA 2006;295:306-313 4Fisher B et al., J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88.

10. Postmenopausal women at high risk for breast cancer should now have a choice

11. Raloxifene and Postmenopausal Women with Osteoporosis • Well established, FDA approved agent for prevention and treatment of osteoporosis • Reduced risk of invasive breast cancer observed in MORE has been confirmed in RUTH and STAR • Clinically important benefit for these women

12. P-1 (age≥50) Placebo MORE Placebo Invasive Breast Cancer and Vertebral Fracture MORE and P-1 12 10 8 Invasive Breast Cancer (No. per 1000/yr) 6 4 2 0 0 2 4 6 8 10 12 Clinical Vertebral Fracture (No. per 1000/yr)

13. P-1 (age≥50) Placebo MORE 3.6 fewer Placebo Tamoxifen 3.1 fewer Raloxifene Invasive Breast Cancer and Vertebral Fracture MORE and P-1 12 10 8 Invasive Breast Cancer (No. per 1000/yr) 6 4 2 0 0 2 4 6 8 10 12 Clinical Vertebral Fracture (No. per 1000/yr)

14. Invasive Breast Cancer and Vertebral Fracture MORE and P-1 12 10 P-1 (age≥50) 8 Invasive Breast Cancer (No. per 1000/yr) Placebo MORE 6 3.6 fewer Placebo 4 Tamoxifen 3.1 fewer 5.2 fewer 0.5 fewer 2 Raloxifene 0 0 2 4 6 8 10 12 Clinical Vertebral Fracture (No. per 1000/yr)

15. Postmenopausal women considering raloxifene for treatment of osteoporosis should be informed about the potential additional benefit on their risk of invasive breast cancer Slide Modified: Memo:

16. Conclusion • Since 1998 an estimated 22 million postmenopausal women worldwide have received raloxifene to prevent or treat osteoporosis. • Clinical trials involving more than 37,000 postmenopausal women now provide information on the benefits and risks of the use of raloxifene to reduce the risk of invasive breast cancer. • The benefit-risk is favorable in postmenopausal women at high risk for breast cancer and in postmenopausal women taking raloxifene for osteoporosis.