1. Epidemiology of prostate cancer Epidemiology and Molecular Pathology of Cancer: Bootcamp course Tuesday, 3 January 2012

2. Learning Objectives  To describe clinical presentation of prostate cancer  To present descriptive epidemiology of prostate cancer  To give overview of risk factors for prostate cancer and opportunities for prevention of lethal disease

3. CLINICAL PRESENTATION

4. The Prostate

5. Clinical synopsis  99% of cancers are epithelial adenocarcinoma  Symptoms Urinary frequency, urgency, nocturia, bone pain Majority of cancers diagnosed now have no symptoms  Diagnosis Digital rectal exam Prostate specific antigen (PSA) screening/testing Biopsy of prostate  Treatment Radical prostatectomy Radiation Watchful waiting Hormonal therapy either as primary or adjuvant treatment

6. Stage and Grade Gleason Grade (2-10)TNM*-stage * T=tumor, N=node, M=metastases

7. DESCRIPTIVE EPIDEMIOLOGY

8. The burden of prostate cancer

10. Latent prostate cancer Prostate cancer reservoir in men dying from causes other than prostate cancer and who were not known to have prostate cancer during life Welch, JNCI J Natl Cancer Inst 2010;102:605-613

11. Trends in prostate cancer incidence over time IARC, 2008 USA Sweden Italy Japan

12. Trends in prostate cancer mortality over time USA Sweden Italy Japan IARC, 2008 Greece

13. RISK FACTORS

14. Older age as a risk factor IARC, Cancer Mondial, CI5plus

15. Race/Ethnicity as a risk factor SEER Registry, http://seer.cancer.gov/statfacts/html/prost.html 2.4x greater mortality for blacks vs. whites

16. Family history as a risk factor Hemminki CEBP 2002

17. GWAS and prostate cancer Thomas G, Nature Genetics 2008

18. Risk factors for prostate cancer in HPFS (1986-2002) Giovannucci, Int J Cancer 2007

19. Model of prostate cancer development and progression RISK OF AGGRESSIVE PROSTATE CANCER LETHAL PROSTATE CANCER Pathways: Energy Balance/Insulin * Inflammation * Vitamin D signaling Factors: Obesity * Physical inactivity * Infection * Coffee * Low vitamin D

20. Overview of factors Current Hypotheses 1. Obesity and weight change 2. Physical activity Novel hypotheses 1. Infections 2. Coffee 3. Vitamin D

21. OBESITY AND PHYSICAL ACTIVITY

22. Obesity and weight change

25. Obesity is associated with: Higher levels of insulin Lower levels of adiponectin Lower levels of testosterone Higher levels of inflammatory cytokines

26. Obesity and prostate cancer survival Physicians’ Health Study 2,500 men with prostate cancer Obesity at baseline Followed for up to 28 years Excess body weight could account for 33.7% of PCa death

27. Insulin, obesity and lethal prostate cancer

28. Weight change and risk of cancer recurrence

29. Does walking lower risk of PCa progression?  Prostate cancer progression Richman E, 2011 Cancer Res Relative risk of prostate cancer progression associated with walking pace and duration among 1275 men with cancer < 3 mph ≥ 3 mph

30. INFECTIONS

31. Local Inflammation Infections PROSTATE CANCER PROGRESSION

32. Trichomonas vaginalis and prostate cancer  Common non-viral sexually transmitted infection  Mostly asymptomatic in men  Infections can reach prostate  Repeated infections do not confer immunity

33. Study design Physicians’ Health Study 1982 Blood samples from 14,916 participants 2000 1,116 men diagnosed with prostate cancer 2008 673 cancer cases 673 controls Follow-up for metastases & mortality

34. T vaginalis and risk of advanced prostate cancer Relative risk : 2.2 (95% CI: 1.1, 4.4) % T. vaginalis seropositive Stark et al, JNCI 2009

35. T vaginalis and risk of lethal disease Relative risk: 2.7 (95% CI: 1.4, 5.3) % T. vaginalis seropositive Stark et al, JNCI 2009

36. COFFEE

37. Coffee and prostate cancer risk  Insulin  Inflammation  Antioxidants Coffee  Prostate cancer progression

38. All prostate cancer Lethal cancerNonlethal cancer p trend =0.10p trend =0.004 p trend =0.77 RR=0.40 (0.28-0.77) RR=0.93 (0.74-1.16) RR=0.82 (0.68-0.98) Coffee and prostate cancer risk Wilson et al, JNCI 2011

39. Regular vs. Decaf Lethal cancer Regular Coffee RR=0.56 (0.28-1.11) Decaf Coffee RR=0.59 (0.36-0.96)

40. VITAMIN D

41. 41 The Vitamin D pathway CYP27A1 CYP27B1 VDR Differentiation Apoptosis Cell-cycle Anti-angiogenesis CYP24A1

42. Vitamin D and lethal prostate cancer  Circulating levels of vitamin D: High vitamin D  40 percent lower risk of lethal prostate cancer  Vitamin D in tumors: High expression of receptor in tumor  70 percent lower risk of lethal prostate cancer  Genetic variants in vitamin D pathway Significantly associated with lethal prostate cancer

43. SUMMARY

44. Prevention of lethal prostate cancer Risk factorAssociationPrevention Obesity  Weight loss Physical activity  Walking Infections  Treatment; anti- inflammatory Coffee  Vitamin D  Supplements; Sun