1. 1 Study of Tamoxifen and Raloxifene STAR Larry Wickerham, MD NSABP STAR Project Officer

2. 2 # Events Placebo93 Tamoxifen60 50 40 30 20 10 0 # Events Placebo250 Tamoxifen145 50 40 30 20 10 0 Cumulative Rate/1000 Invasive Breast Cancer Noninvasive Breast Cancer Time to Breast Cancer (Years) P < 0.0001 P= 0.008 NSABP P1 Study

3. 3 STRATIFICATION Age Gail Model Risk Race History of LCIS Hysterectomy Tamoxifen 20 mg/day x 5 years Study Design STAR Raloxifene 60 mg/day x 5 years Risk-Eligible Postmenopausal Women

4. 4 Inclusion and Exclusion Criteria STAR Inclusion –At least 35 years of age –Postmenopausal –Risk eligible Lobular carcinoma in situ or 5-year Gail risk of breast cancer >1.66% Exclusion History of: –Invasive breast cancer –Ductal carcinoma in situ –DVT, PE –CVA, TIA –Uncontrolled diabetes, hypertension or atrial fibrillation

5. 5 Primary Aims STAR The primary aim of the study was to determine which of the following three statements is true: –Compared to tamoxifen, raloxifene significantly reduces the incidence rate of IBC –Compared to raloxifene, tamoxifen significantly reduces the incidence rate of IBC –The statistical superiority of one of the treatments cannot be demonstrated and the choice of therapy should be based on benefit/risk considerations

6. 6 Primary Objective STAR Evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women who are at increased risk.

7. 7 Secondary Objectives STAR Non-invasive breast cancer Endometrial cancer Ischemic heart disease Fractures of the hip, spine or wrist Toxicity and side effects

8. 8 Screening, Accrual and Follow-up STAR Screened184,460 Eligible96,368 Randomized19,747 Woman-years of follow-up79,173 Average follow-up (years) 4.06

9. 9 Baseline Characteristics STAR Age (mean)58.5 Caucasian93% Hysterectomy51% First degree relative(s) with breast cancer71% History of Lobular carcinoma in situ9% Atypical hyperplasia23% 5-year predicted Gail risk of invasive breast cancer (mean)4.03%

10. 10 Effects on Invasive Breast Cancer STAR RR (95% CI) = 1.02 (0.82, 1.27)

11. 11 Invasive Breast Cancer STAR 168 173 325

12. 12 Invasive Breast Cancer by 5-year Predicted Risk STAR 33 63 72 44 49 80

13. 13 Invasive Breast Cancer Tumor Characteristics STAR Tamoxifen n=168 Raloxifene n=173 Estrogen Receptor Status +72%69% -28%31% Tumor Size <129%39% 1.1-361%54% >3.110%8% Nodal Status -74%80% +26%20%

14. 14 34 35 47 41 Invasive Breast Cancer in Women with a History of LCIS or Atypical Hyperplasia STAR

15. 15 Non-Invasive Breast Cancer STAR

16. 16 Non-Invasive Breast Cancer STAR Tamoxifen (n) Raloxifene (n) RR (95%CI) DCIS32471.46 (0.91-2.37) LCIS23291.26 (0.70-2.27) Mixed571.39 (0.38-5.57)

17. 17 Uterine Cancer STAR

18. 18 Tamoxifen (n) Raloxifene (n) RR (95% CI) Hysterectomy during study 246920.37 (0.28, 0.47) Hyperplasia100170.17 (0.09, 0.28) with atypia1520.13 (0.01, 0.56) w/o atypia85150.17 (0.09, 0.30) Uterine Hyperplasia and Hysterectomy STAR

19. 19 Ischemic Heart Disease STAR Tamoxifen (n) Raloxifene (n) RR (95% CI) Myocardial infarction 53390.73 (0.47-1.13) Severe angina55711.28 (0.89-1.86) Acute ischemic syndrome 17281.64 (0.87-3.19) Total1251381.10 (0.86-1.41)

20. 20 Osteoporotic Fractures STAR Tamoxifen (n) Raloxifene (n) RR (95% CI) Hip28260.92 (0.52-1.63) Spine58 0.99 (0.68-1.46) Wrist27 0.99 (0.56-1.76) Total*1111080.97 (0.73-1.27) *Columns not additive because one patient may have had fractures at multiple sites.

21. 21 Mortality STAR Tamoxifen (n) Raloxifene (n) Cancer52 Breast cancer52 Circulatory/vascular2521 Other3231 Any cause109104 RR (95% CI) 0.95 (0.72-1.25)

22. 22 Venous Thromboembolic Events STAR

23. 23 Cataracts and Cataract Surgery During Follow-up STAR 435 295 343 240 RR = 0.78 (95% CI = 0.68–0.91) RR = 0.81 (95% CI = 0.68–0.96)

24. 24 Summary STAR Compared with tamoxifen, raloxifene was: similar in decreasing the risk of invasive breast cancer not as effective at decreasing the risk of non-invasive breast cancer associated with fewer: –adverse events related to uterus –VTEs –cataracts and cataract surgery