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Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H.

Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H. Division of Cancer Prevention National Cancer Institute NIH, DHHS. Lung Cancer Prevention Public Health Approaches.  cost/tax Smoke-free environment Youth Cessation in adults

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Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H.

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  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 PreventionPublic Health Approaches •  cost/tax • Smoke-free environment • Youth • Cessation in adults • Anti-nicotine vaccine

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

  4. BREAST CANCER PREVENTION

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

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

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

  8. Breast Cancer PreventionBreast Cancer Prevention Trial (BCPT)Recruitment 13,388 Tamoxifen Placebo

  9. Breast Cancer PreventionBreast Cancer Prevention Trial (BCPT)Events Among Participants

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

  11. Breast Cancer PreventionMORE TrialResults: Invasive Breast Cancer Relative Risk (Confidence Interval) Placebo Raloxifene 27 3.6 13 0.9 0.24 (0.13-0.44) Breast Cancer Rate per 1,000 Women-Years Cummings et al., 1999

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

  13. N N N CH3 CH3 NC CN CH3 CH3 O O O O CH2 Breast Cancer PreventionThird Generation Aromatase Inhibitors/Inactivators N N Nonsteroidal Inhibitors N NC CN Letrozole Anastrozole Androgen substrate Steroidal Inactivator Exemestane Androstenedione

  14. Breast Cancer PreventionATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION) Trial Results: Contralateral Breast Cancer 14* 33 28 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 * 58%  compared to tamoxifen, p=0.007 ATAC trialists, 2002

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

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

  17. Breast Cancer PreventionAgents 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 Lubet,2000

  18. ProstateCancer Prevention

  19. Prostate Cancer PreventionFinasterideMechanism of Action

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

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

  22. N = 4368 N = 4692 Prostate Cancer PreventionGleason ScoreTotal Number of Cancers 1147 1200 Finasteride 1100 Placebo 1000 900 803 776 800 700 600 Number of Cancers 457 500 400 280 237 300 200 55 100 20 0 Total Cancers 2 - 4 5 - 6 7 - 10 Gleason Score Not graded: Finasteride n=46, Placebo n=79

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

  24. PSA PSA Placebo PSA Finasteride PSA

  25. Prostate Cancer PreventionU.S. –Finland Lung CancerIntervention Trial

  26. ATBC StudyCumulative Lung Cancer Incidence

  27. ATBC StudyCancers According to Vitamin ETreatment Status

  28. Skin Cancer Prevention TrialDesignSelenium (200 g) in Brewers Yeast vs. Placebo

  29. Skin Cancer Prevention TrialEnd PointsSelenium (200 g) in Brewers Yeast vs. Placebo

  30. Prostate Cancer Prevention Selenium Level in Toenails and RiskHealth Professional Follow-up Study 181 Prostate Cancers Among 33,737 Cohort Members Quintile of Selenium Level1 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 PreventionPlasma Selenium and Later Prostate CancerBaltimore 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 PreventionSelenium and Vitamin ECancer Prevention Trial (SELECT)

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

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

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