Chemoprevention of Cancer: An Update

WREN Convocation of Practices

May 9, 2009

Howard Bailey, MDUWCCC Chemoprevention Program

Chemoprevention of Cancer

Definition Sporn (1976), use of drugs, biologics, or nutrients to

inhibit carcinogenesis

Rationale A 15% decrease in epithelial cancers would prevent

>100,000 deaths/yr and save $25 billion/yr

Background Epidemiology

Geographic/cultural differences Genetics – 98% malignancies have somatic mutations rather

than germ line mutations association of infections with cancer

Chemoprevention of Cancer The study of carcinogenesis has led to the

current dogma that human carcinogenesis is a multi-year process Boutwell RK, 1976; The biochemistry of pre-neoplasia

in mouse skin Frykberg and Bland, 1993; breast atypical hyperplasia

to DCIS to carcinoma may take 30 years Thus providing an opportunity to intervene

prior to accumulated mutations or phenotypic changes

Basic Progression Model

O’Shaughnessy, et al. - Clin Cancer Res 2002;8:314-46O’Shaughnessy, et al. - Clin Cancer Res 2002;8:314-46

T(0)T(0)

10-30 years10-30 years

Chemoprevention Clinical Trials

Phase IPhase ITrialTrial

Subjects (N)Subjects (N)Duration (months)Duration (months)Primary EndpointsPrimary Endpoints

25-7525-751-121-12pK, pK,

safetysafety

Phase IIPhase IITrial(s)Trial(s)

50-30050-3006-366-36

dose, SEB mod.dose, SEB mod.

Phase IIIPhase IIITrialsTrials

300+300+36-6036-60

cancer inc.cancer inc.

CandidateCandidateAgentAgent

Ris

kR

isk

Cos

tC

ost

Chemoprevention Drug Development How development differs from –

Cancer Therapy Accepted surrogate of tumor/disease regression Primary goal can be determined relatively quickly

Vascular diseases More similar than cancer therapy Accepted surrogates

Hypertension Hyperlipidemia

Chemoprevention Drug Development

Similar to Vascular Health prevention, an accepted surrogate marker/endpoint would make chemoprevention drug development more efficient.

Intraepithelial Neoplasia? Colonic adenomas Cervical Carcinoma in situ Breast ductal carcinoma in situ

Intraepithelial Neoplasia

Cancer and IEN frequently share phenotypic and genotypic changes

IEN is already considered a disease by many and has led to the approval of multiple interventions (celecoxib, diclofenac, topical 5FU, BCG, tamoxifen)

Variability in diagnosis/interpretation Slow and relatively low rate of progression to

cancer Current complexity and limited understanding

Chemoprevention Phenotypic surrogates

Skin – actinic keratoses, dysplastic nevi Oral – leukoplakia, erythroplakia Lung – bronchial dysplasia Esophagus – Barrett’s (dysplasia) Breast – DCIS, LCIS, atypical hyperplasia Colon – adenomas Cervix – cervical intraepithelial neoplasia (CIN) Endometrium – atypical hyperplasia Prostate – prostatic intraepithelial neoplasia (PIN) Bladder – superficial bladder cancer

Chemoprevention Agents – Approved agents

Tamoxifen Selective estrogen receptor modulator (SERM) for breast cancer

prevention NSABP – P1 study (Fischer et al. JNCI 90:1371, 1998), 7000

women in each arm (175 cancers in placebo, 89 cancers in Tam)

Raloxifene Selective estrogen receptor modulator (SERM) for breast cancer

prevention NSABP – P2 (STAR) study,(Vogel et al. JAMA 295:2727, 2006),

approx 4000 post-menopausal women in each arm with an expected BrCa rate of 4% over 5 years, observed only 0.4% in each arm.

Chemoprevention Agents – Approved agents

Tamoxifen P1 study

Fisher JNCI 1998

Chemoprevention Agents – Approved agents

Tamoxifen P1 study

Chemoprevention Agents – Approved Agents

Tamoxifen and Raloxifene are approved for women at “high risk” High risk is a women with a 1.66% chance of developing

invasive breast cancer in the next 5 years All women > 60 yo Younger women with some number of the following risk

factors: early menarche (<12 yo) , late menopause (>55 yo), nulliparity or >30 yo at first full term pregnancy, first degree family relative with breast cancer, prior breast biopsies especially with atypical ductal hyperplasia, …

Chemoprevention Agents – Approved agents

Celocoxib Specific COX-2 inhibitor approved for adenoma

prevention in FAP (Steinbach et al. NEJM 342:1946, 2000)

Prevention of sporadic polyps (Bertagnolli et al. NEJM 355:873, 2006)

Increased cardiac risks (Solomon et al. NEJM 352:1071, 2005)

Sporadic AdenomasPhase III Trials

APC Trial• Sporadic CRN (n=2,035)• 91 participating sites• Celecoxib 200 mg bid or

400 mg bid vs. placebo• Rec. adenomas at 3 years

CelecoxibCelecoxib200 mg bid200 mg bidPlacebo bidPlacebo bid CelecoxibCelecoxib400 mg bid400 mg bidCelecoxibCelecoxib200 mg bid200 mg bidPlacebo bidPlacebo bid CelecoxibCelecoxib400 mg bid400 mg bid

**p<0.0001 vs. placebo; Bertagnolli – NEJM 2006;355:873-84p<0.0001 vs. placebo; Bertagnolli – NEJM 2006;355:873-84

Recurrent AdenomasRecurrent AdenomasAdvanced AdenomasAdvanced Adenomas

Chemoprevention Agents – Approved Agents

Quadravalent HPV vaccine for cervical cancer VLP vaccine against HPV 6, 11, 16, 18 Initial Pilot study of monovalent (Koutsky et al.

NEJM 347:1645-51, 2002) Initial phase 2 quadravalent (Villa et al. Lancet

6:271-78, 2005) approved for females 9-26 yo FUTURE I an II studies (NEJM 356: 1915,

2007)

Chemoprevention Agents

VLP vaccine, bivalent 16/18 Harper et al. Lancet 367, 2006

Further f/u on women who received all 3 doses Seropositivity/immunogenicity maintained for

≥ 5 yrs Protection beyond 16/18, also decreased 45/31

Chemoprevention Agents – Approved Agents

Are they being used? Infrequently at best Reasons are many starting with limited interest from

Primary Providers and Lay Public’s negative views

Assessment of Dane County Providers M Jensen et al. survey of healthcare providers for

adolescents opinions regarding the HPV vaccine. O Olaigbe et al. survey of healthcare providers for

women regarding tamoxifen for breast cancer prevention

Prostate Cancer Prevention Trial (PCPT): Specific Rationale

Link between androgens and CaP T DHT AR Epidemiology Finasteride inhibits 5-alpha-reductase Safety profile from BPH studies

5-alpha-reductase

1993-96

2000-03

18,882 Men> 55 yrs, < 3

PSA, normal DRE

Endpoint: 7-year period prevalence of prostate cancer

Primary Endpoint:Seven-Year Period Prevalence

Placebo Finasteride

Known prostate cancer status

4692 4368

Prostate cancer 1,147 (24.4%) 803 (18.4%)

Relative Risk Reduction 24.8% (18.6% - 30.6%), P < 0.001

Thompson, et al NEJM 2003

PCPT Conclusions

• Misclassification rates on biopsy were higher in the placebo arm and high grade rate on prostatectomies were not higher on finasteride arm

• True risk of 8-10 is unknown• Estimates based on PCPT data including possibility of

more high grade disease still show significant overall health benefit (person-years saved) to society with finasteride

• Use of 5α reductase inhibitors probably won’t evolve unless another study is positive

Unger et al. Cancer 2005

Reduction by Dutasteride of Prostate Cancer Events

(REDUCE)• Dutasteride

– dual inhibitor of type 1 and 2 5α reductase– BPH studies suggested decreased Pr CA incidence– Serum DHT levels further reduced by dutasteride

• GSK sponsored study, 650 centers, 8000 subjects

• Men 50-75 yo, PSA 2.5-3.0 to 10 ng/ml, must have a neg. prostate bx within 6 mos (no HGPIN or ASAP), prostate volume ≤80 cc

Andriole et al. J Urology 2004

The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

• NCI sponsored prostate chemoprevention trial opened 2001– 32,000 men, ≥ 50-55 yo, PSA ≤4.0 ng/ml, DRE-

negative

– Selenomethionine 200 µg, α tocopherol 400 IU

– Followup every 6 mos

– Primary endpoints – Prostate Ca incidence• Factorial design with 5 comparisons

• Each agent vs placebo, the combination vs placebo, combination vs each agent

Lippman et al. JNCI 2005

SELECT

• Preliminary Results• Neither Selenium or Vitamin E alone or

together prevented prostate cancer• Uncertain findings –an increase in

prostate cancers in men taking Vit E alone; and small increase in the number of cases of adult onset diabetes in men taking selenium

Chemoprevention Agents/Issues with Micronutrients

CARET, ATBC, and NPC Results Concerning negative results

Micronutrients assumed not to be harmful Replacement doses vs supraphysiologic (pro-

oxidant effects?) Regular dietary consumption vs

supplementation Smokers and gender differences in metabolism

Nutrients and Cancer

Dietary Nutrients Polyphenols (primarily green tea)

Strong epidemiologic data Important constituents are catechins (specifically

epigallocatechin gallate/EGCG) Cup of green tea contains 3-400 mg of polyphenols (10-30

mg EGCG) Encouraging clinical research at 400-800 mg of EGCG/day

Isoflavones/Soy Phytoestrogen Genistein – UW bladder prevention study

Genistein inhibits growth of carcinoma cells of multiple tumor types in vitro.

It is a potent inhibitor of tyrosine kinase, a key enzyme in signal transduction.

Glycoside conjugates account for more than 2/3 of the total isoflavone content of soybeans.

Chemoprevention Agents - Genistein

Nutrients and Cancer Dietary Nutrients (cont.)

Carotenoids carotene Lycopene

– Polyphenolic constituent of tomatoes and some fruits– How tomatoes are cooked/processed influences amount of

lycopene– Epidemiologic studies– Positive in vitro/in vivo effects– Ongoing chemoprevention studies

Lutein Organosulfurs/seleniums

Anethole dithiolethione (ADT) Flavanoids

Quercetin

Nutrients and Cancer

Dietary Nutrients (cont.) Curcumin Perillyl alcohol Resveratrol Isothiocyanates/indoles

Indole-3-carbinol/Diindolymethane (DIM) UW prostate study

Phenylethyl isothiocyanate (PEITC)

Bjelakovic et al. Lancet 364:1219, 2004

Meta-analysis of Antioxidants for GI Cancer Prevention

Chemoprevention Development: Directions?

Better risk stratification Genomics, unbiased pursuit e.g. quantitative trait

loci Proteomics, a less invasive way to assess

intervention Non-invasive imaging of preneoplasia/intraepithelial

neoplasia Cross-disciplinary studies of health

maintenance, e.g. WHI WREN Wisconsin Network for Health Research (WiNHR)

Cancer Chemoprevention

• Possible study idea

• Green tea polyphenols in patients with or at risk of metabolic syndrome– Compelling data for beneficial effects of green

tea polyphenols in Cancer, CardioVascular and Neurodegenerative disease and Insulin resistance.

Chemoprevention of Cancer Clinical trials pose both new and old

issues for cancer-related drug development

We should look to other disciplines for advice, e.g. renal or vascular preventive health

We need to “understand our audience better”

Thank you.

Chemoprevention Agents Selenium Clinical studies

NPC Trial 1300 subj (Eastern U.S.) with skin CA hx

randomized to 200 g/d of selenized brewer’s yeast or placebo (Duffield-Lillico et al. JNCI, 2003)

Effects on skin cancer contradictory Significant decrease in prostate CA (Clark et al.

Br J Urol 89:730, 1998), but other cancer incidence was examined also.

NPC Trial: Incidence and Relative Risk of non-melanoma skin cancer

Baseline Se level RR P value<105 ng/ml 0.87 .42105-122 1.49 .03>122 1.59 .01

Duffield-Lillico, JNCI, 2003

Chemoprevention / Development Clinical Testing

Phase I testing normal volunteers vs increased risk population dose de-escalation or escalation randomization to one of multiple dose levels (for de-

escalation studies) or placebo

Examples Phase I de-escalation study of DFMO, Love et al.

JNCI 85:732, 1993 Phase I escalation study of UAB30, J. Kolesar et al. Phase Ib study of diindolymethane in subjects

undergoing prostatectomy, J Gee et al.

Chemoprevention / Development Clinical Testing

Phase 2 testing 2a – shorter duration (days to weeks) biomarker

studies 2b – randomized, double-blinded, placebo-

controlled longer duration (>3 mos) biomarker studies

Provide rationale for the design of a phase 3 study Examples

Phase 2a study of genistein in subjects with superficial bladder cancer, E Messing, & J. Gee

Phase 2b study of DFMO in Organ Transplant Recipients at risk of skin cancer,

Chemoprevention/Development Clinical Testing (cont.)

Phase 3 – randomized, double-blinded, placebo controlled studies Demonstrate a significant decrease in cancer

incidence or mortality or an accepted surrogate Validate surrogate markers Hopefully lead to improved population health

Examples Phase 3 Study of DFMO in subjects with a history

of skin cancer Phase 3 Study of Tamoxifen in women at risk of

breast cancer

Phase III TrialsPreSAP Trial (n=1,561)• 107 participating sites• Celecoxib 400 mg qd vs.

placebo• Rec. adenomas at 3 years

RR=0.64 (0.56-0.75); any

RR=0.49 (0.33-0.73); adv.

APPROVe Trial (n=2,587)• 108 participating sites• Rofecoxib 25 mg qd vs.

placebo• Rec. adenomas at 3 years

RR=0.76 (0.69-0.83); any

RR=0.70 (0.57-0.73); adv.

N Engl J Med 2006;355:885-95 and Gastroenterol 2006; epubN Engl J Med 2006;355:885-95 and Gastroenterol 2006; epub

Cardiovascular Toxicity

Rofecoxib

• APPROVe Trial

• N=2,586 subjects

• Follow-up = 3,327 pt-years

• CV Adverse events (%):–Placebo (2%); RR=1.0

–25 mg QD (3.6%); RR=1.9

N Engl J Med. 2005;352:1071-80 and 1092-102N Engl J Med. 2005;352:1071-80 and 1092-102

Celecoxib

• APC Trial

• N=2,035 subjects

• Follow-up = 2.8-3.1 years

• CV deaths (%):–Placebo (1%); RR=1.0

–200 mg BID (2.3%); RR=2.3

–400 mg BID (3.4%); RR=3.4

www.washingtonpost.com; 4/7/05www.theoaklandpress.com; 12/18/04

Celecoxib and Colon Cancer Prevention

• Psaty and Potter (NEJM 355:950, 2006)– Reviewed APC and PreSAP trials and concluded the

following

– Celecoxib decreases adenoma formation

– Celecoxib increases the risk of cardiovascular adverse events

– The potential increase in CV event/mortality outweighs the projected decrease in colon cancer incidence

• Could Celecoxib be an option in people with low cardiac risk?

Gleason Score: Percent of Men Evaluated

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

0.5%

10.5%6.4%

1.2%

16.5%

5.1%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2 - 4 5 - 6 7 - 10Gleason Score

Per

cen

t o

f M

en E

valu

ated

Finasteride

Placebo

N = 4368

N = 4692

1.25 RR

PCPT: Increased rate of High Grade Cancers, Detection-bias?

• The increase in HG was based on biopsies

• RP is the gold-standard for determining GS

• HG was not significantly increased at RP

• Detection bias– Increased PSA sensitivity

– Increased biopsy sensitivityLucia, et al JNCI September 2007

PlacebPlaceboo

FinasterideFinasteride

Median Prostate Volume:

38.8 cc

vs

24.4 cc

(p = 0.001)

SIMULATED BIOPSY: Sampling Bias

Lucia, et al, JNCI, 2007; 1375-83

Detection-bias: The Evidence

Finasteride(n=98)

mean sd med

38 20 33

4.9 2.9 4.4

9.3 10.6 6.2

% cores pos

Greatest lin extent (mm)

43 25 40

5.4 3.7 4.4

12.9 16.0 7.0

Placebo(n=61)

mean sd med

Aggregate lin ext (mm)

Bilateral disease 26.5% 44.3%

Perineural invasion 9.2% 16.4%

(p=0.02)

Lucia, et al JNCI September 2007

Bx findings in GS 8-10 tumors

Does Finasteride Make the Grade?

803

20

457

19090

1147

55

776

184

53

0100200300400500600700800900

100011001200

TotalCancers

2 - 4 5 - 6 7 8 - 10

Gleason Score

Num

ber

of C

ance

rs

Finasteride = 4368

Placebo - 4692

SELECT• Selenium

– Essential cofactor for enzymatic processes, e.g. redox

– Derived from diet, dietary levels related to soil content

– Epidemiologic studies correlating low selenium levels to increased prostate cancer incidence

– Typical US diet contains 80-160 ug/d, Recommended daily amount 55 ug/d

– Issues with form and optimum dose

DN Syed et al. Ca Epid Biom Prev 2007

Chemoprevention Agents Selenium Clinical studies

NPC Trial 1300 subj (Eastern U.S.) with skin CA hx

randomized to 200 g/d of selenized brewer’s yeast or placebo (Duffield-Lillico et al. JNCI, 2003)

Effects on skin cancer contradictory Significant decrease in prostate CA (Clark

et al. Br J Urol 89:730, 1998), other cancer incidence also reduced.

NPC Trial: Incidence and Relative Risk of non-melanoma skin cancer

Baseline Se level RR P value<105 ng/ml 0.87 .42105-122 1.49 .03>122 1.59 .01

Duffield-Lillico, JNCI, 2003

SELECT

• Vitamin E– Naturally occuring compounds (tocopherols,

tocotrienes)– Co-factor to many cellular functions, anti-

oxidant effects– Epidemiologic studies– Typical US intake 10 mg/d, recommended is

15 mg/d– Issues with form / dose

SELECT

• ATBC study– Finnish study of 30,000 smokers randomized to α

tocopherol (50 mg), β carotene (20 mg)– 30-40% decrease in prostate Ca, but 19% increase

in Lung Ca (more from β carotene)

• Prospective study from China of Vit E, Sel, β carotene decreased prostate Ca

• Recent meta-analysis raised concerns for increased CV events with vit E doses > 400-1,000 IU/day

Chemoprevention Agents under study at UW

• DFMO• Vitamin D

– Because of use/indications outside of cancer prevention, more extensively studied

• Others– Genistein, Diindolymethane, Polyphenon E, Vitamin E

metabolites,

Examples by Target Organ

Kelloff, et al. - Cancer Epidemiol Biomarkers & Prev 2000;9:127-37Kelloff, et al. - Cancer Epidemiol Biomarkers & Prev 2000;9:127-37

Chemoprevention AgentsO Olaigbe et al.

152 respondents out of approx 500 mailed 85% Physicians / 15% NP or PA 51% Fam Med, 26% Int Med, 14% Gyn Knowledge of Tam and Breast Ca Prev

7% very much, 75% basic, 18% very little Ever recommended Tam as preventive

Yes 20%, No 80% Reasons for not recommending

Hi risk/benefit ratio 23%, questionable effectiveness 20%, unpleasant side effects 10%, other 40%

Cancer ChemopreventionFuture Directions

• Better assessment of an individual’s risk (via genomics or proteomics) will likely lead to greater interest/willingness to employ chemoprevention

• Consideration of more global health issues; use of low risk/small gain agents which modify risk of numerous serious illnesses