Cancer Prevention Clinical Trials in

America

Peter Greenwald, M.D., Dr. P.H.Division of Cancer Prevention

National Cancer Institute

NIH, DHHS

Lung Cancer PreventionPublic Health Approaches

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

Current/Former Smokers with Bronchial Dysplasia

N=112

Anethole Dithiolethione25 mg TID

Results: New lesions No regression of old lesions

Lung Cancer PreventionPhase IIb Trial of Anethole Dithiolethioneon Bronchial Dysplasia (# sites/grade)

Lam et al., 2002

Placebo

Repeat Bronchoscopy at 6 months

BREAST CANCER PREVENTION

Breast Cancer PreventionOutline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority

Lubet,2000

Breast Cancer PreventionRisk Factors for Breast Cancer

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

Breast Cancer PreventionOutline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority

13,388

Tamoxifen Placebo

Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Recruitment

Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Events Among Participants

Postmenopausal WomenWith Osteoporosis

(n=7,705)

Placebo(n=2,576)

Raloxifene60 mg/d

(n=2,557)

Raloxifene120 mg/d(n=2,572)

3-Year Intervention

Primary Endpoint: FracturesSecondary Endpoint: Breast Cancer

Cummings et al., 1999

Breast Cancer Prevention Multiple Outcomes of Raloxifene Evaluation (MORE) TrialRecruitment

Placebo RaloxifeneRelative Risk

(Confidence Interval)

Breast CancerRate 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 TrialResults: Invasive Breast Cancer

Risk-EligiblePostmenopausal Women

(n=19,000)

Tamoxifen20 mg/d

X 5 years

Raloxifene60 mg/d

X 5 years

NSABP, 1999

Breast Cancer Prevention Study of Tamoxifen and Raloxifene (STAR) TrialRecruitment

Breast Cancer Prevention Third Generation Aromatase Inhibitors/Inactivators

AnastrozoleLetrozole

NC CN

AndrostenedioneO

O

Exemestane

Nonsteroidal Inhibitors

OCH2

O

CNNCCH3 CH3

CH3 CH3

N

N N

Steroidal Inactivator

Androgen substrate

N N

N

1414** 3333 2828Results:Results: Contralateral Contralateral Breast CancerBreast Cancer

Postmenopausal women with invasive breast cancer Stage I & IIPostmenopausal women with invasive breast cancer Stage I & II

Surgery Surgery radiotherapy radiotherapy chemotherapy chemotherapy

AnastrozoleAnastrozole 1 mg/d 1 mg/d++

TamoxifenTamoxifen Placebo Placebo31253125

AnastrozoleAnastrozole Placebo Placebo++

TamoxifenTamoxifen 20 mg/d 20 mg/d31163116

AnastrozoleAnastrozole 1 mg/d 1 mg/d++

TamoxifenTamoxifen 20 mg/d 20 mg/d31253125

Breast Cancer Prevention ATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION) Trial

* 58% * 58% compared to tamoxifen, p=0.007 compared to tamoxifen, p=0.007ATAC trialists, 2002ATAC trialists, 2002

Breast Cancer PreventionOutline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority

Brown, Elledge et al, Texas Cancer Genetics Consortium, 2002

Breast Cancer PreventionBreast Biomarker Modulation Trial

Bexarotene (Targretin) 200 mg/d x 4 wks

Placebo

High Risk Women N = 100

BRCA 1, 2 TestingPre-treatment Biopsy

Post-treatment BiopsyEnd-points: Biomarker modulation, proliferation, apoptosis, retinoid regulated genes; BRCA mutation status

Lubet,2000

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

Prostate Cancer Prevention

Prostate Cancer PreventionFinasterideMechanism of Action

Follow-up every 3 months

for 7 years

End of Study Biopsy

End of Study Biopsy

Men 55+ yr

PSA ≤ 3 ng/ml

N=18,882

Placebo Finasteride

Randomization

Prostate Cancer PreventionPCPT Schema

803

435368

1147

571 576

0100200300400500600700800900

100011001200

Total Cancers For Cause Cancers End-of-StudyCancers

Num

ber

of C

ance

rs

FinasteridePlacebo

Not graded: Finasteride n=46, Placebo n=79

N = 4368N = 4692

Prostate Cancer PreventionProstate Cancers Detected

Not graded: Finasteride n=46, Placebo n=79

N = 4368N = 4692

803

20

457

280

1147

55

776

237

0100200300400500600700800900

100011001200

Total Cancers 2 - 4 5 - 6 7 - 10Gleason Score

Num

ber o

f Can

cers

FinasteridePlacebo

Prostate Cancer PreventionGleason ScoreTotal Number of Cancers

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

PSA

PSA

PSA

PSA

Placebo

Finasteride

Prostate Cancer PreventionU.S. –Finland Lung CancerIntervention Trial

ATBC StudyCumulative Lung Cancer Incidence

ATBC StudyCancers According to Vitamin ETreatment Status

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

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

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 SeleniumLevels, ppm 0.66 0.76 0.82 0.88 1.14

Multivariant Odds Ratiofor Prostate cancer 1.00 0.59 0.35 0.76 0.35

p trend = 0.03

Yoshizawa et al., 1998

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

Prostate Cancer PreventionSelenium and Vitamin ECancer Prevention Trial (SELECT)

Prostate Cancer PreventionSelenomethionine and Prostate CancerRecruitment of Presurgical Patients

SeMet 200 g/d

68 Presurgicalprostate cancer patients

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

Observation

Sabichi et al, SWOG, 2002

2-3 weeks

Pre-Prostatectomy Model

Selenium/VitaminESulindac sulfoneCelecoxib Genistein/Soy isoflavones Toremifene HectorolLycopeneBicalutamide + DFMO