Cancer Prevention Clinical Trials in America

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

• ? cost/tax
• Smoke-free environment
• Youth
• Cessation in adults
• Anti-nicotine vaccine

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Lung Cancer PreventionPhase IIb Trial of
Anethole Dithiolethioneon Bronchial Dysplasia (
sites/grade)
Current/Former Smokers with Bronchial
Dysplasia N112
Anethole Dithiolethione 25 mg TID
Placebo
Repeat Bronchoscopy at 6 months
Results ? New lesions No regression of
old lesions
Lam et al., 2002
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BREAST CANCER PREVENTION
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Breast Cancer PreventionOutline

• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority

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Breast Cancer PreventionRisk Factors for Breast
Cancer

• Weight Gain as an adult/obesity
• Estrogen Progestin use
• Alcohol use

Lubet,2000
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Breast Cancer PreventionOutline

• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority

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Breast Cancer Prevention Breast Cancer
Prevention Trial (BCPT)Recruitment
13,388
Tamoxifen
Placebo
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Breast Cancer Prevention Breast Cancer
Prevention Trial (BCPT)Events Among Participants
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Breast Cancer Prevention Multiple Outcomes of
Raloxifene Evaluation (MORE) TrialRecruitment
Postmenopausal Women With Osteoporosis (n7,705)
Raloxifene 120 mg/d (n2,572)
Raloxifene 60 mg/d (n2,557)
Placebo (n2,576)
3-Year Intervention
Primary Endpoint Fractures Secondary Endpoint
Breast Cancer
Cummings et al., 1999
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Breast Cancer Prevention MORE 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
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Breast Cancer Prevention Study of Tamoxifen and
Raloxifene (STAR) TrialRecruitment
Risk-Eligible Postmenopausal Women (n19,000)
Tamoxifen 20 mg/d X 5 years
Raloxifene 60 mg/d X 5 years
NSABP, 1999
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Breast Cancer Prevention Third Generation
Aromatase Inhibitors/Inactivators
N
N
Nonsteroidal Inhibitors
N
NC
CN
Anastrozole
Letrozole
Androgen substrate
Steroidal Inactivator
Androstenedione
Exemestane
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Breast Cancer Prevention ATAC (ARIMIDEX,
TAMOXIFEN, ALONE OR IN COMBINATION) Trial
Postmenopausal women with invasive breast cancer
Stage I II
Surgery ? radiotherapy ? chemotherapy
Anastrozole 1 mg/dTamoxifen Placebo 3125
Anastrozole Placebo Tamoxifen 20 mg/d 3116
Anastrozole 1 mg/d Tamoxifen 20 mg/d 3125
58 ? compared to tamoxifen, p0.007
ATAC trialists, 2002
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Breast Cancer PreventionOutline

• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority

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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
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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
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Prostate Cancer Prevention
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Prostate Cancer PreventionFinasterideMechanism
of Action
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Prostate Cancer PreventionPCPT Schema
Men 55 yr PSA 3 ng/ml N18,882
Randomization
Follow-up every 3 months for 7 years
Finasteride
Placebo
End of Study Biopsy
End of Study Biopsy
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Prostate Cancer PreventionProstate Cancers
Detected
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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
20
100
0
Total Cancers
2 - 4
5 - 6
7 - 10
Gleason

Score
Not graded Finasteride n46, Placebo n79
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Simulated needle biopsies in 3-dimensional
reconstruction of radical prostatectomy specimen
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PSA
PSA
Placebo
PSA
Finasteride
PSA
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Prostate Cancer PreventionU.S. Finland Lung
CancerIntervention Trial
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ATBC StudyCumulative Lung Cancer Incidence
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ATBC StudyCancers According to Vitamin
ETreatment Status
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Skin Cancer Prevention TrialDesignSelenium (200
?g) in Brewers Yeast vs. Placebo
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Skin Cancer Prevention TrialEnd PointsSelenium
(200 ?g) in Brewers Yeast vs. Placebo
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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
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Prostate Cancer Prevention Plasma 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
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Prostate Cancer PreventionSelenium and Vitamin
ECancer Prevention Trial (SELECT)
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Prostate Cancer PreventionSelenomethionine and
Prostate CancerRecruitment of Presurgical
Patients
68 Presurgical prostate cancer patients
SeMet 200 ?g/d
Observation
2-3 weeks

• Results
• ? Prostate tissue Selenium levels
• Pre Post-study PSA unchanged

Sabichi et al, SWOG, 2002
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Pre-Prostatectomy Model

• Selenium/VitaminE
• Sulindac sulfone
• Celecoxib
• Genistein/Soy isoflavones
• Toremifene
• Hectorol
• Lycopene
• Bicalutamide DFMO