CHAPTER 90: EPIDEMIOLOGY, ETIOLOGY, and PREVENTION of PROSTATE CANCER

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CHAPTER 90EPIDEMIOLOGY, ETIOLOGY, and
PREVENTION of PROSTATE CANCER

• Campbells Urology Review
• Sundip Patel

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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

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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 lt50.
• Peak incidence b/w 70-74 years
• 85 diagnosed after age 65 years

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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

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RISK FACTORS

• Genetic and environmental influences
• GENETIC INFLUENCES
• Risk increased according to number of affected
  family members, relatedness, age of infliction
• Hereditary FORM
• If dx at lt55y/o stronger familial clustering
  number of family members and age of onset is most
  important

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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

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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

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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

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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

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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

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Epidemiology

• Sexual Activity
• Unknown effect
• Vasectomy
• Predispostion to cancer
• Smoking
• Risk factor for prostate cancer
• Diet
• Strong effect on CaP

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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

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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 5a-Reductase ?
  Dihydrotestosterone
• Insufficient exposure to DIHYDROTESTOSTERONE is
  protective

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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

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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

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Etiology and Molecular Genetics
Somatic Mutations Associated with Tumor
Initiation and Progression

• Androgen receptor
• NKX3-1
• PTEN
• Classical Oncogenes
• Telomerase

• Glutathione S-Transferase
• P27
• Vascular Endothelial Growth Factor
• E-Cadherin
• ?-Methylacyl-CoA Racemase

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Etiology and Molecular Genetics

• Prostate Specific Membrane Antigen
• Possible immunotherapeutic agent
• Epidermal Growth Factor
• Associated with prostate cancer
• EZH2
• Increase during CaP progression

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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

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CHEMOPREVENTION

• Antioxidants and Selenium and Vitamin E
• Selenium can decrease the risk of prostate cancer
• Vitamin E a-tocopherol
• Major lipid-soluble antioxidant in cell membranes
• Proposed to induce cell cycle arrest and direct
  antiandrogen activity

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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