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

1. CHAPTER 90:EPIDEMIOLOGY, ETIOLOGY, and PREVENTION of PROSTATE CANCER Campbell’s Urology Review Sundip Patel

2. 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

3. 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

4. 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

5. 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 <55y/o; stronger familial clustering; number of family members and age of onset is most important

6. 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

7. 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

8. 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

9. 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

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. Androgen receptor NKX3-1 PTEN Classical Oncogenes Telomerase Glutathione S-Transferase P27 Vascular Endothelial Growth Factor E-Cadherin Α-Methylacyl-CoA Racemase Etiology and Molecular Genetics Somatic Mutations Associated with Tumor Initiation and Progression

17. Etiology and Molecular Genetics • Prostate Specific Membrane Antigen • Possible immunotherapeutic agent • Epidermal Growth Factor • Associated with prostate cancer • EZH2 • Increase during CaP progression

18. 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

19. 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

20. 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