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% WHITES2.8% DEATHS –20.6% AFRICAN AMERICANS 4.7% DEATHS Annual Death rates 30/100,000

3. EPIDEMIOLOGY Worldwide, prostate cancer is 4 th 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 –1 o 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. Etiology and Molecular Genetics –Androgen receptor –NKX3-1 –PTEN –Classical Oncogenes –Telomerase –Glutathione S- Transferase –P27 –Vascular Endothelial Growth Factor –E-Cadherin –Α-Methylacyl-CoA Racemase 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