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

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

CLINICAL PRESENTATION

The Prostate

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

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

DESCRIPTIVE EPIDEMIOLOGY

The burden of prostate cancer

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:

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

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

RISK FACTORS

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

Race/Ethnicity as a risk factor SEER Registry, 2.4x greater mortality for blacks vs. whites

Family history as a risk factor Hemminki CEBP 2002

GWAS and prostate cancer Thomas G, Nature Genetics 2008

Risk factors for prostate cancer in HPFS ( ) Giovannucci, Int J Cancer 2007

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

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

OBESITY AND PHYSICAL ACTIVITY

Obesity and weight change

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

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

Insulin, obesity and lethal prostate cancer

Weight change and risk of cancer recurrence

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

INFECTIONS

Local Inflammation Infections PROSTATE CANCER PROGRESSION

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

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

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

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

COFFEE

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

All prostate cancer Lethal cancerNonlethal cancer p trend =0.10p trend =0.004 p trend =0.77 RR=0.40 ( ) RR=0.93 ( ) RR=0.82 ( ) Coffee and prostate cancer risk Wilson et al, JNCI 2011

Regular vs. Decaf Lethal cancer Regular Coffee RR=0.56 ( ) Decaf Coffee RR=0.59 ( )

VITAMIN D

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

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

SUMMARY

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