1. Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H. Division of Cancer Prevention National Cancer Institute NIH, DHHS

2. Lung Cancer Prevention Public Health Approaches  cost/tax Smoke-free environment Youth Cessation in adults Anti-nicotine vaccine

3. Current/Former Smokers with Bronchial Dysplasia N=112 Anethole Dithiolethione 25 mg TID Results:  New lesions No regression of old lesions Lung Cancer Prevention Phase IIb Trial of Anethole Dithiolethione on Bronchial Dysplasia (# sites/grade) Lam et al., 2002 Placebo Repeat Bronchoscopy at 6 months

4. BREAST CANCER PREVENTION

5. Breast Cancer Prevention Outline Lifestyle Risk Factors Prevention Trials Biomarker End-point/ER Negative Priority

6. Lubet,2000 Breast Cancer Prevention Risk Factors for Breast Cancer Weight Gain as an adult/obesity Estrogen & Progestin use Alcohol use

7. Breast Cancer Prevention Outline Lifestyle Risk Factors Prevention Trials Biomarker End-point/ER Negative Priority

8. 13,388 TamoxifenPlacebo Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT) Recruitment

9. Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT) E vents Among Participants

10. Postmenopausal Women With Osteoporosis (n=7,705) Placebo (n=2,576) Raloxifene 60 mg/d (n=2,557) Raloxifene 120 mg/d (n=2,572) 3-Year Intervention Primary Endpoint: Fractures Secondary Endpoint: Breast Cancer Cummings et al., 1999 Breast Cancer Prevention Multiple Outcomes of Raloxifene Evaluation (MORE) Trial Recruitment

11. PlaceboRaloxifene Relative Risk (Confidence Interval) Breast Cancer Rate per 1,000 Women-Years 27 3.6 13 0.9 0.24 (0.13-0.44) Cummings et al., 1999 Breast Cancer Prevention MORE Trial Results: Invasive Breast Cancer

12. Risk-Eligible Postmenopausal Women (n=19,000) Tamoxifen 20 mg/d X 5 years Raloxifene 60 mg/d X 5 years NSABP, 1999 Breast Cancer Prevention Study of Tamoxifen and Raloxifene (STAR) Trial Recruitment

13. Breast Cancer Prevention Third Generation Aromatase Inhibitors/Inactivators AnastrozoleLetrozole NCCN Androstenedione O O Exemestane Nonsteroidal Inhibitors O CH 2 O CN NC CH 3 N N N Steroidal Inactivator Androgen substrate NN N

14. 14* 3328 Results: Contralateral Breast Cancer Postmenopausal women with invasive breast cancer Stage I & II Surgery  radiotherapy  chemotherapy Anastrozole 1 mg/d + Tamoxifen Placebo 3125 Anastrozole Placebo + Tamoxifen 20 mg/d 3116 Anastrozole 1 mg/d + Tamoxifen 20 mg/d 3125 Breast Cancer Prevention ATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION ) Trial * 58%  compared to tamoxifen, p=0.007 ATAC trialists, 2002

15. Breast Cancer Prevention Outline Lifestyle Risk Factors Prevention Trials Biomarker End-point/ER Negative Priority

16. Brown, Elledge et al, Texas Cancer Genetics Consortium, 2002 Breast Cancer Prevention Breast Biomarker Modulation Trial Bexarotene (Targretin) 200 mg/d x 4 wks Placebo High Risk Women N = 100 BRCA 1, 2 Testing Pre-treatment Biopsy Post-treatment Biopsy End-points: Biomarker modulation, proliferation, apoptosis, retinoid regulated genes; BRCA mutation status

17. Lubet,2000 Breast Cancer Prevention Agents With Promise Against ER Negative Tumors Tyrosine Kinase Inhibitors – Specific (EGFR family) – Non-specific (Genistein) Bexarotene & retinoid-like compounds COX-2 Inhibitors Farnesyl transferase inhibitors Statins Doublets

18. Prostate Cancer Prevention

19. Prostate Cancer Prevention Finasteride Mechanism of Action

20. Follow-up every 3 months for 7 years End of Study Biopsy Men 55+ yr PSA ≤ 3 ng/ml N=18,882 Placebo Finasteride Randomization Prostate Cancer Prevention PCPT Schema

21. Not graded: Finasteride n=46, Placebo n=79 N = 4368 N = 4692 Prostate Cancer Prevention Prostate Cancers Detected

22. Not graded: Finasteride n=46, Placebo n=79 N = 4368 N = 4692 803 20 457 280 1147 55 776 237 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 Total Cancers2 - 45 - 67 - 10 Gleason Score Number of Cancers Finasteride Placebo Prostate Cancer Prevention Gleason Score Total Number of Cancers

23. Simulated needle biopsies in 3-dimensional reconstruction of radical prostatectomy specimen

24. PSA Placebo Finasteride

25. Prostate Cancer Prevention U.S. –Finland Lung Cancer Intervention Trial

26. ATBC Study Cumulative Lung Cancer Incidence

27. ATBC Study Cancers According to Vitamin E Treatment Status

28. Skin Cancer Prevention Trial Design Selenium (200  g) in Brewers Yeast vs. Placebo

29. Skin Cancer Prevention Trial End Points Selenium (200  g) in Brewers Yeast vs. Placebo

30. Prostate Cancer Prevention Selenium Level in Toenails and Risk Health Professional Follow-up Study 181 Prostate Cancers Among 33,737 Cohort Members Quintile of Selenium Level 1 2 3 4 5 Median Selenium Levels, ppm 0.66 0.76 0.82 0.88 1.14 Multivariant Odds Ratio for Prostate cancer 1.00 0.59 0.35 0.76 0.35 p trend = 0.03 Yoshizawa et al., 1998

31. Prostate Cancer Prevention Plasma Selenium and Later Prostate Cancer Baltimore Longitudinal Study of Aging Quartile of Selenium Level 1 2 3 4 Se (µg/dl) (8.2-10.7) (10.8-11.8) (11.9-13.2) (13.3-18.2) Cases (%) 20 ( 39 ) 9 ( 17 ) 10 ( 19 ) 13 ( 25 ) Controls (%) 18 ( 19 ) 28 ( 29 ) 26 ( 27 ) 24 ( 25 ) Odds Ratio 1.00 0.15 0.21 0.24 Brooks et al., 2001

32. Prostate Cancer Prevention Selenium and Vitamin E Cancer Prevention Trial (SELECT)

33. Prostate Cancer Prevention Selenomethionine and Prostate Cancer Recruitment of Presurgical Patients SeMet 200  g/d 68 Presurgical prostate cancer patients Results:  Prostate tissue Selenium levels Pre & Post-study PSA unchanged Observation Sabichi et al, SWOG, 2002 2-3 weeks

34. Pre-Prostatectomy Model  Selenium/VitaminE  Sulindac sulfone  Celecoxib  Genistein/Soy isoflavones  Toremifene  Hectorol  Lycopene  Bicalutamide + DFMO