Transcript Campbell`s Chapter 90

CHAPTER 90:
EPIDEMIOLOGY,
ETIOLOGY, and
PREVENTION of
PROSTATE CANCER
Campbell’s Urology Review
Sundip Patel
EPIDEMIOLOGY
• Most common visceral malignant neoplasm
in US men.
• Lifetime risk
– 17.6% WHITES
2.8% DEATHS
– 20.6% AFRICAN AMERICANS 4.7% DEATHS
Annual Death rates 30/100,000
EPIDEMIOLOGY
• Worldwide , prostate cancer is 4th
most common male malignant
neoplasm
• Lowest rate is in Asia (1.9/100,000)
• Highest in North America and
Scandinavia, esp AA (272/100,000)
• CaP rarely diagnosed in men <50.
• Peak incidence b/w 70-74 years
• 85% diagnosed after age 65 years
EPIDEMIOLOGY
• Now, a more favorable stage at
presentation
• Incidence of local regional disease is
increased, metastatic disease
incidence is decreased.
• Non-palpable cancers account for
75% of newly diagnosed disease
• Thus, 5/10 year survival rates
improved
• Effects on mortality - controversial
RISK
FACTORSinfluences
• Genetic
and environmental
• GENETIC INFLUENCES
– Risk increased according to number of
affected family members, relatedness, age
of infliction
– Hereditary FORM
• If dx at <55y/o; stronger familial clustering;
number of family members and age of onset is
most important
EPIDEMIOLOGY
– GENES
• HPC1 best cited; RNase L enzyme; Type I
interferons, 2-5A synthetases, R462Q, Arginine
to Glutamine substitution
• HPC1 autosomal dominant with high penetrance
• SR-A/MSR MIC1 --- MEDIATORS OF
InflamaTION
• PON1
• CHEK2/BRCA2/OGG1 --- DNA REPAIR
Inflammation, infection,
genetic susceptibility
• Prostate cancer may be associated
with hx of STD or prostatitis
• Proliferative inflammatory atrophy
are frequent in prostate specimens
• Compromised cellular defenses
against inflammatory oxidants may
initiate and perpetuate prostatic
carcinogenesis
Molecular Epidemiology
• Androgens
– Affects proliferation and
differentiation of luminal epithelium
– Long term ABSENCE of androgens are
protective
• Estrogens
– Could be protective or teratogenic
– Phytoestrogens may be beneficial
Molecular Epidemiology
• Insulin – Like Growth Factor Axis
– IGF-1 inhibits apoptosis in normal
prostate
– Its protein, IGFBP-3 can be cleaved by
PSA, reducing its pro-apoptic activity
• Leptin
Produced by adipocytes
Stimulates DU145 and PC3 prostate
cancer cell lines
Molecular Epidemiology
• Vitamin D in relation to cancer risk
(protective)
– Higher CaP mortality rate in men living in
northern latitudes
– Occurs more frequently in older men
– African Americans have the highest worldwide
incidence
– Increased dairy intake assoicted with prostate
cancer
– Native Japanese – high vit D diet- have low
incidence of prostate cancer
Epidemiology
• Sexual Activity
– Unknown effect
• Vasectomy
– Predispostion to cancer
• Smoking
– Risk factor for prostate cancer
• Diet
– Strong effect on CaP
Epidemiology
• Dietary Fat
– Polyunsaturated fat consumption
correlated highly with prostate cancer
• Obesity
– INC BMI demonstrate oxidative stress
– Lower PSA concentrations in higher BMI
patients
• Alcohol
– 1-3 glasses of red wine may be
protective
Etiology and Molecular
Genetics
• CaP exists in 2 forms
– Histologic – similar prevalence worldwide
– Clinically Evident Form – prevalence variable
• Androgen Influence
– 1o androgen is DIHYDROTESTOSTERONE
– Testosterone  [type 2] 5α-Reductase 
Dihydrotestosterone
– Insufficient exposure to DIHYDROTESTOSTERONE is protective
Etiology and Molecular
Genetics
• Stem Cells
– Likely exist and are being researched
for both prevention and therapeutic
purposes
• Epigenetic change
– Involves a change in expression without
altering the actual DNA
• Methylation, chromatin remodeling, histone
modification, RNA interference
Etiology and Molecular
Genetics
• Cyclooxygenase [Cox-2]
– Enzymes that help produce
prostaglandin, which is used during an
inflammatory response
– Prostate cancers express more Cox-2
– NSAIDS inhibit COX-2 expression and
may be protective
Etiology and Molecular Genetics
Somatic Mutations Associated with Tumor Initiation and Progression
– Androgen receptor
– Glutathione STransferase
– NKX3-1
– P27
– PTEN
– Classical Oncogenes
– Vascular Endothelial
Growth Factor
– Telomerase
– E-Cadherin
– Α-Methylacyl-CoA
Racemase
Etiology and Molecular
Genetics
• Prostate Specific Membrane Antigen
– Possible immunotherapeutic agent
• Epidermal Growth Factor
– Associated with prostate cancer
• EZH2
– Increase during CaP progression
CHEMOPREVENTION
• Prostate Cancer Prevention Trial
– Tested hypothesis that treatment with
finasteride prevents prostate cancer
– 19000 men with normal DRE and PSA were
randomly assigned to daily medication vs
placebo
– Trial stopped 15 months early
– Risk reduction of 25% reached in medication
arm
CHEMOPREVENTION
• Antioxidants and Selenium and Vitamin E
– Selenium can decrease the risk of prostate
cancer
• Vitamin E [α-tocopherol]
– Major lipid-soluble antioxidant in cell membranes
– Proposed to induce cell cycle arrest and direct
antiandrogen activity
CHEMOPREVENTION
• Soy
– Have isoflavones which inhibit prostatic
epithelial cell growth, downregulate androgen
genes, and reduce tumor growth
• Lycopene
– Potent antioxidant activity
• Mixed evidence of lowering risk of prostate cancer
• Green Tea
– Inferred to help prevent prostate cancer
based on low incidence among asian men with
higher intake of green tea