Download Prostate Cancer Prevention - American Institute for Cancer Research

Prostate Cancer Prevention:
Intervention Studies
Steven K. Clinton, M.D., Ph.D.
The Ohio State University
2009 AICR Annual Research Conference on
Food, Nutrition, Physical Activity and Cancer
November 5-6, 2009
Capital Hilton, Washington, DC
Disclosures:
None
But, I am profoundly opinionated.
Objectives
• Basic principles of prostate carcinogenesis
• Etiologic factors
• Strategies for prevention
• Chemoprevention
• Dietary patterns, foods, and nutrients
CAVEAT: Issues related to optimal screening as well as defining “indolent”
vs. clinically significant prostate are important to this discussion but cannot
be fully addressed due to time limitations
Prostate
Carcinogenesis
Prostate Carcinogenesis:
A Long Process
Process
Event
Osteoporosis
Bone Fracture
Atherosclerosis
MI or stroke
Carcinogenesis
Cancer
PCA is a Disease of Aging
1000.0
Mortality
per
100.0
100,000
10.0
Prostate Cancer
US Males
White
1.0
0.1
0
10
20
30
40
50
Age
60
70
80
90
Prostatic Premalignancy
• PIN
• Architecturally normal
glandular elements.
• Epithelial dysplasia
• Value
– Defines “high risk”
•
•
Lower cost trials
Shorter trials
Incidence of High Grade PIN - Autopsy Study
100
High Grade PIN (%)
90
80
70
Afrcian American
Caucasian
60
50
40
30
20
10
0
30's
40's
50's
60's
Age Group
Sakr et al., Rath Res. Pract. 191:838-841, 1995
70's
The essential biological aberrations
during prostate carcinogenesis
Self
Self-sufficiency
sufficiency
in
in growth
growth
signals
signals
Immunologic
tolerance
Insensitivity
to growth
signals
Evading
Evading
apoptosis
apoptosis
Sustained
angiogenesis
∞
Limitless replicative
potential
Tissue
invasion and
metastasis
Adapted from:
Hanahan & Weinberg,
Cell 100:57 (2000)
Progressive Genetic Instability is the
“Enabling Factor”
• Acquired genetic alterations
– Chromosomal
– Mutational
– Epigenetics
•
•
Methylation
Histone acetylation
• Prevention of genetic damage and
the inhibition of their biological
effects are the foundation for
preventive strategies
Etiologic Factors
for
Prostate Cancer
Etiologic Factors (I)
• Aging
• Race / ethnicity
• Endocrine status
– testosterone
• Family history
– mixture of genetics and environment
Etiologic Factors (II)
• Inherited Predisposition
– High risk, high penetrance
genes / polymorphisms are
rare or nonexistent
– Low risk, low penetrance,
genes / polymorphisms are
common
– Future: array based genetic
panels to define risk of
positive diagnosis and
biology.
Etiologic Factors (III)
• Chemical carcinogens
– Tobacco
– Workplace
– Environmental toxins (endocrine disrupters)
• Infectious agents / inflammation
• Diet and nutrition
• Lifestyle (exercise /sexual behavior)
Infection and Inflammation
A) Virochip B) Cluster C) PCR
XMB Nucleic Acid by FISH
Prostate Cancer
Prevention
Strategies
Will screening and therapy eliminate
the role of prevention ?
• Screening
– Improved sensitivity and specificity of PSA / DRE
– Biomarkers of “indolent” vs. clinically significant PCA
• Therapy
– Improved efficacy (treatment of significant cancers)
– Reduced toxicity (sexual dysfunction, incontinence)
Prostate Cancer Prevention Strategies
• Surgical ablation of the prostate
• Reduce exposure to carcinogens
• Treat infections (STDs) / vaccinations
• Chemoprevention
• Diet and Lifestyle
Chemoprevention
Chemoprevention
“Pharmacologic Model”
• Definition:
The administration of specific chemicals to
reverse or suppress carcinogenesis and
prevent the development of invasive cancer.
Chemoprevention: What Chemicals?
• Pharmaceuticals (synthetic agents)
• “Nutrients” at pharmacologic doses
• Natural compounds (bioactives)
The Prostate Cancer Prevention Trial
(PCPT)
PCPT Design
•• Phase
Phase III
III
•• Randomized
Randomized double
double blinded
blinded prospective
prospective trial
trial
•• Finasteride
Finasteride (Proscar™
(Proscar™ // Propecia™
Propecia™ MERCK
MERCK ))
••
55 -reductase
-reductase inhibiter
inhibiter
•• Accrual
Accrual 1994-1997
1994-1997 of
of 18,000
18,000 men
men
••
>> 55
55 yr
yr age
age
••
Normal
Normal DRE
DRE
••
PSA
PSA << 33 mg/ml
mg/ml
PCPT Design
• Annual evaluation by DRE and PSA
• End of study biopsy at 7 years
• Power:
– 90% for detecting a 25% decrease in cancer
• Study terminated 15 months early
– primary objective being achieved
– conclusions were unlikely to change
– 81 % had completed 7 yr evaluation
NEJM 2003;349:215-24
PCPT: Prostate Cancer Diagnosis
Finasteride
Placebo
N = 4368
N = 4692
1200
Prostate Cancers
1100
1000
900
800
700
600
500
400
300
200
100
803 1147
0
Total PCA
435
571
For Cause
PCA
368 576
End-of-Study
PCA
End of Study Results
•
Cancer.
– 803 / 4368 = 18 % in finasteride group
– 1147 / 4692 = 24 % in placebo group
•
Relative risk
– reduction of 24.8 %
– 95 % CI = 18.6 to 30.6 %
– P<0.001
Finasteride (Risk / Benefit)
• BPH symptoms decreased
• Symptoms of prostatitis / infections decreased
• Sexual dysfunction increased
– reduced volume of ejaculate
– erectile dysfunction
– loss of libido
– gynecomastia
Finasteride: Risk of Higher Grade Cancer
•
•
•
•
Gleason Grade
Glandular architecture
Sum of the two scores
Associated with
– Risk of metastasis
– Time to metastasis
– Risk of death
Finasteride: Risk of Higher Grade Cancer
• Finasteride
•
37 % ( 280 / 757 ) had Gleason scores >7.
• Placebo
•
22 % ( 237 / 1068) had Gleason scores >7.
• Relative Risk of Higher Grade Tumor
•
1.67 [ 95% CI, 1.44 to 1.93 ], P<0.001,
• Similar rates of localized disease
– T1-T2:
97.7 % (finasteride) vs. 98.4 % (placebo)
Estimated fractions of total subjects with
low-grade or high-grade PCA at PTX.
PCPT: Current Conclusion
• Effects of finasteride on prostate volume and
selective inhibition of low-grade cancer, rather than
effects on tumor morphology, may have contributed
to the “relative” increase in high-grade cancers with
finasteride in the PCPT
• The results suggest that high-grade cancer was
detected earlier and was less extensive in the
finasteride group than in the placebo group
REDUCE
Reduction by Dutasteride
of Prostate Cancer Events
REDUCE
•
•
•
•
•
•
Randomized prospective trial
8,200 men, negative biopsy, PSA 2.5-10
Dutasteride (Avodart™, GlaxoSmithKline)
Biopsy at 2 and 4 years
Early results reported - 2009 AUA meeting
23% reduction in cancer risk
SELECT
SELECT
Selenium
Selenium and
and Vitamin
Vitamin EE
Cancer
Cancer Prevention
Prevention Trial
Trial
SELECT
Selenium and Vitamin E Cancer Prevention Trial
•
•
•
•
•
•
Randomized prospective trial
Factorial design (2x2)
12 years in duration
Selenium (200 µg/d, L-selenomethionine)
Vitamin E (400 IU/d all rac--tocopheryl acetate)
Accrual started in 2001 with 35,534 enrolled
SELECT
Vitamin E (400 mg)
Selenium
200 mcg
-
+
Placebo
Placebo
+
Placebo
-tocpherol
Placebo
-tocpherol
Selenium
Selenium
PCPT,
PCPT, REDUCE,
REDUCE,
and
and SELECT:
SELECT:
The
The Legacy
Legacy
Legacy (short term)
• Implementation is very modest.
• Education is necessary
– primary care physicians
– urologists
– the “at risk” population
• Research
–
–
–
–
who should be treated
at what age
for how long
optimal screening
Targeting Androgen Signaling
• Obstacles to future “anti-androgen” development
– Sexual dysfunction
– Concerns regarding “grade” of cancer
– Developing standards for screening
• Approaches
– Intermittent therapy / target critical periods
– Tissue specific targeting / gene therapy
– Timing in life cycle
Novel
Novel Agents
Agents
for
for
Prostate
Prostate Cancer
Cancer
Chemopevention
Chemopevention
Agents Under Development
• NSAIDS
• Celecoxib derivatives
– PI3K-AKT signaling inhibitors (OSU 03012)
• Histone modification / epigenetics
– Histone deacetylase inhibitors (OSU HDAC-42)
• Natural compounds
–
–
–
–
Indol-3 carbinol (broccoli) and derivatives (OSU A9)
Isoflavones (soy)
Lycopene (tomatoes)
ECGC (green tea)
Dietary Patterns,
Foods, and Nutrients
Dietary Patterns, Foods, and
Nutrients in Prostate Cancer
Prevention
• There are no large scale randomized controlled
clinical trials of dietary patterns, foods, or
bioactive phytochemicals for prostate cancer
prevention.
Speculative Relationships to PCA
• Energy Balance / body composition Obesity
• Phytochemical rich food products
– Tomatoes, soy, broccoli, teas, mushrooms, herbals,
flaxseed, pomegranate, etc.
• Nutrients
– Vitamin D / Calcium, selenium, vitamin E.
– Bioactive lipids (omega-3)
Strategies for Food /Nutrient Based Prevention
• Nutrients
•
Study using pharmaceutical model
• Dietary Change
•
Design and compliance challenges
• Novel food products
•
Standardization of dose and quality
• Combinations
•
•
Foods and chemoprevention
Multiple targets, non-overlapping toxicity
Design Novel Foods to
Target
Specific Cancers
Combining Food Components
Reductionist Thinking vs. Food Systems
Boileau et al.
Prostate carcinogenesis in
N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato
powder, lycopene, or energy-restricted diets.
JNCI 93:1578-1686, 2003
Normal Rat
Prostate
Prostate Cancer
Prostate Carcinogenesis Protocol
Testosterone implants
Hormone
regimen
Testosterone injections
Cyproterone acetate
Control (0.0 g/kg)
Diets
Lycopene Beadlet (0.161 g/kg)
ToTomato Powder (0.013 g/kg)
Age
(weeks) 5
6
8
10
12
14
16
Begin 20% food
Randomize
restriction
NMU
to diets
administration
i.v. (50 mg / kg)
58
60
62
64
Design and Results
Dietary
Treatment
Group
Lycopene
N
Control
0
68
Lycopene
0.25%
161 mg/kg
68
Tomato
Powder
10%
13 mg/kg
68
Incidence
(%)
Hazard
Analysis
Design and Results
Dietary
Treatment
Group
Lycopene
N
Incidence
(%)
Control
0
68
80
0.25%
161 mg/kg
68
72
Lycopene
Tomato
Powder
10%
13 mg/kg
68
62
Hazard
Analysis
P < 0.017
HR=0.63
(0.43-0.92)
Novel Foods for PCA
• Tomatoes
• Soy
– Epidemiology suggestive
– Multiple bioactives
– Active in rodents
– Epidemiology suggestive
– Multiple bioactives
– Active in rodents
Tomato-based food products
for cancer prevention studies
Department of Horticulture
Selection of Tomato Cultivar
Phytochemical content
Growth characteristics
Disease resistance
Processing issues
OSU Farms
11 can
can == 150
150 ml
ml juice
juice (6
(6 oz)
oz)
22.5
mg
lycopene
and
33
mg
isoflavones
22.5 mg lycopene and 33 mg isoflavones
Plant and harvest
Department of Food
Science and Technology
Process into paste
Phytochemical analysis
Reconstitution
Reconstitution
and
and
Formulation
Formulation
Commercial Sources
Soy protein and extracts
Phytochemical analysis
Solubility
Solubility
Taste
Taste
Texture
Texture
Taste
Taste Panel
Panel
Changes in PSA
All
n = 41
% with rising PSA prior at
enrollment
41 / 41 (100%)
% showing same or lower PSA at
end of study
15 / 41 (37%)
% showing slower doubling time
compared with pre-enrollment
23 / 40 (58%)
PSA Velocity
50
Percent of Men
40
30
Before
Intervention
20
After
10
Intervention
0
<4
4 to 9
PSA Doubling time
>9
(months)
Tomato based foods for phase III long
term cancer prevention trials
•
•
•
Tomato products are popular
Tomato flavors dominate in “mixed” foods
Advantages of juice
– Easily incorporated into usual diets
– Adjustable dose based upon can size
– Stability
– Consistency
– Portable
• Easily modified to enhance bioactivity
• Additional anti-cancer components could be added
Nutrients and
Prostate Cancer:
Vitamin D
Prostate Cancer (PCa) Mortality is Associated
with Low UV Exposure
Low UV
PCa Rate
Low
High UV
High
Hanchette 2000, Cancer 70:2861
Schwartz, 2006, Cancer Causes Control 17:1091
Vitamin D and PCA: A hypothesis
Cell Biology:
Phenomenon = strong
Doses = pharmacologic
Targets = many
Epidemiological:
Animal Models:
UV to PCa = suggestive
Analogs = possible
VD status to PCa = suggestive
VD status = unproven
Clinical:
Analogs = unproven
VD status = unproven
TRAMP or APT121/Rbf Model
Murine prostate
Normal
mPIN
Human prostate
Androgens
DNA
rPB
SV40 large T antigen
SV40 Lg T mRNA
Cancer
The interactions between
vitamin D and calcium on
prostate carcinogenesis in the
APT121/RBf model
Invasive PCa (%)
Vitamin D Reduces Invasive PCa
100
80
60
40
20
0
Die
t
90
80
70
60
0.2
0.5
1.5
% Diet Ca
25
1.5
Ca
0.5
0.2
lci
um
(%
)
150
1000 D3
V
t
e
Di
/k
U
I
(
g)
Invasive PCa (%)
%)
Invasive PCa (
120
Ca Only
100
VD Only
100
90
80
70
60
25
150
1000
Diet Vitamin D3
THE VITAMIN D AND OMEGA-3 TRIAL
(VITAL)
• The VITamin D and OmegA-3 TriaL
• National Institutes of Health funding
• Run from Harvard Medical School
– Drs JoAnn Manson and Julie Buring
•
•
•
•
20,000 participants
Woman aged >65 or older \ man aged >60
Vitamin D (placebo vs. 2000 IU)
Omega-3 (placebo vs. 1 gm fish oil)
Prostate Cancer Prevention:
Intervention Trials
Protstate Cancer Prevention Trials
• Challenges
– Screening, diagnosis, personalized therapy
•
•
•
Trails are feasible
Trials can be completed in 5-7 yrs
High-risk cohorts can be defined
– Family history
– Ethnicity
– Elevated PSA and negative biopsy
– PIN coupled with above conditions
– BPH that requires intervention
Prostate Cancer Prevention Trials
• Build upon the finasteride foundation
– Duration, timing, intermittent
• Combination agent rational
– Non-overlapping toxicity
– Multiple targets
• Combinations
– Nutrients
– Phytochemicals
– Foods
– Diet and lifestyle
1000
Current Rates
100
Rates with
Prevention
10
Mortality
Mortality
1
per
per
100,000
100,000
0.1
0.01
0
10
20
30
40
50
60 70
Age
80
90 100 110 120
Questions