1 Risk Benefit and Conclusions George Sledge, MD Indiana University School of Medicine

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 Efficacy in Postmenopausal Women Across a Spectrum of Breast Cancer Risk 71% 56% 44% RR 1.02

4 Confirmation of Raloxifene’s Effectiveness Relative to Tamoxifen in STAR STAR Non-inferiority Analysis Proportion retention of tamoxifen’s effect* (95% CI) = 97% (65%, 128%) STAR Primary Analysis RR (95% CI) = 1.02 (0.82, 1.27) * 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 Cancer in Placebo-Controlled Studies MORE, CORE, RUTH 11/50445/50572/12745/2716 (N=5133)(N=3990)(N=10,101) 5/25763/2557 SEER SEER annual US incidence rate per 1,000 in white women ≥50 (2000 data)

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

8 Difference in # of events per 1000 treated per 5 years (RALOXIFENE VS. TAMOXIFEN) Non-invasive breast cancer3 more DCIS only2 more Hysterectomy40 fewer † Hyperplasia20 fewer † Uterine cancer4 fewer Venous thromboembolism6 fewer † Deep vein thrombosis3 fewer Pulmonary embolism3 fewer Cataracts10 fewer † Cataract surgery9 fewer † Outcome †P < 0.05 Differences in Outcomes for Raloxifene versus Tamoxifen STAR

9 1 Sever PS et al., Lancet Apr 5;361(9364): MRC Working Party Br Med J 1992;304: Berger JS et al. JAMA 2006;295: Fisher B et al., J Natl Cancer Inst Sep 16;90(18): Invasive Breast Cancer Risk Reduction Compares Favorably with Other Prevention Therapies TherapyEventNNT* Atorvastatin 1 MI/CHD death294 Antihypertensives 2 Strokes370 Coronary event417 Aspirin 3 MI753 Tamoxifen 4 Invasive BrCa303 Raloxifene (MORE)Invasive BrCa323 Raloxifene (CORE)Invasive BrCa335 Raloxifene (RUTH)Invasive BrCa862 *NNT = number of patients needed to treat for 1 year to prevent 1 outcome

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

11 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 Raloxifene and Postmenopausal Women with Osteoporosis

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

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

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

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.