Fellow GU Lecture Series, Prostate Cancer. Asit Paul, MD, PhD 02/20/2018

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1 Fellow GU Lecture Series, 2018 Prostate Cancer Asit Paul, MD, PhD 02/20/2018

2 Disease Burden Screening Risk assessment Treatment

3 Global Burden of Prostate Cancer Prostate cancer ranked 13 th among cancer related mortality in global scale Global Cancer Statistics, CA Cancer J Clin 2005 Global Burden Disease Center Collaboration, JAMA 2015

4 Prostate Cancer in USA 9.6 % all new cancer cases 4.4 % of all cancer deaths 5 year survival rate 99% Life-time risk of prostate cancer in US men: 1 in 8 Leading cause of new cancer (19%) & 3 rd most common cause of cancer death (8%) in US men in 2017 Median age of diagnosis 66 y Life-time risk of death from prostate cancer is 3.4% (1 in 30) New diagnosis & death both are decreasing each year. 5 y survival rate has improved from 66% in 1975 to 99% in 2008 SEER & American Cancer Society

5 New Cases Per 100,000 persons Death SEER

6 Prostate cancer is a disease of elderly Age & older Lung, male 0.2 ( 1 in 608) 0.7 ( 1 in 145) 2 ( 1 in 51) 6.4 ( 1 in 16) Prostate, male 0.3 ( 1 in 325) 2.1 (1 in 48) 5.8 ( 1 in 17) 10 (1 in 10) Age-specific mortality, , SEER Estimated Probability of prostate cancer, American Cancer Society 2016 Rise in prostate cancer incidence with age is one of the steepest among all cancers Average age at diagnosis 67 y. Only 10% is diagnosed in men younger than 56 y Elderly patients have biologically aggressive disease & high mortality Median age of death 80 y

7 African American Men have the highest risk AAM have a 64% higher incidence & 2.3 times higher risk of mortality compared to Caucasian male AAM have an earlier age of onset of prostate cancer & faster transformation to aggressive phenotype SEER data, 2016

8 Risk based on family history: Meta-analysis of 31 independent studies 5-10% prostate cancers are inherited Patients with Lynch syndrome & germ-line BRCA2/ BRCA1 mutations have higher risk (2-5 folds ) Kicinski, PLOS one, 2011

9 Genomic/ molecular map of PC TCGA, Cell, 2015 Sartor & Bono, NEJM 2018

10 Germ-line mutations in DNA-repair genes (12% of advanced PC) Pritchard C, NEJM, 2016 Sartor & Bono, NEJM 2018

11 Breast & Prostate cancer risks of male BRCA1& BRCA 2 carriers Breast % of total male cancers <1% 25% BRCA1/2 mutation 10% 2% Life time risk, BRCA 1 mutation Life time risk, BRCA 2 mutation 1-5% 20% 5-10% 40% Risk, OR, BRCA1/2 mutation Prostate Breast/ BRCA2 Prostate/ BRCA2 Lecarpantier, J Clin Oncol 2017

12 Castro, J Clin Oncol 2013

13 Inherited genetic mutations are present up to 12% of prostate cancer PCA multi-gene panel is now commercially available Heritable Genes include BRCA2/BRCA 1 (HBOC syndrome), ATM, DNA MMR gene (LS) & HOXB13 (HPC) Giri, J Clin Oncol 2018

14 Disease burden Screening Risk assessment Treatment

15 What disease should we screen? Goal of screening is to diagnose in early stage & prevent mortality Disease should have a recognized latent or asymptomatic period An acceptable & executable screening test is available with reasonable accuracy Disease should have an acceptable treatment option Wilson and Jungner (1968)

16 Natural history of prostate cancer Salinas, Nature Reviews Urology, 2014

17 Prostate specific antigen (PSA) In 1979, Gerald Murphy & his colleagues at RPCI, Buffalo, NY discovered PSA as a marker of prostate cancer PSA, secreted by prostatic epithelial cells, has enzymatic functions that help to liquefy seminal fluid PSA is specific to the prostate, but not for prostate cancer Increased PSA levels are found in both cancerous & noncancerous prostate diseases FDA approved PSA-based screening in 1994

18 Performance of PSA based screening There is not a single PSA value which is diagnostic Accuracy improves with higher PSA threshold (>3-4 ng/ml) Only 25% of men with PSA positivity have biopsy positivity 15% of men with PSA <4 ng/ml can have PC Abnormal DRE combined with elevated PSA has a better detection rate Lilja, Nature Rev Oncol, 2008

19 Over-diagnosis Estimated 17-50% of patients were false positive by PSA screening & received unnecessary biopsy A large majority of screen-detected patients had indolent disease course & remained asymptomatic for life even without treatment Over-treatment 90% of screen-detected patients received treatment & were subjected to treatment related complications Treatment of early prostate cancer may not be beneficial, but is associated with complications death, surgical morbidity, urinary incontinence & sexual dysfunction USPSTF, Annals of Medicine, 2012

20 Does PSA-based screening save life?

21 PLCO, NEJM, 2009 ERSPC, NEJM, 2012 US trial (PLCO, n=76,693, age y) did not show any statistically significant reduction in mortality European Trial (ERSPC, n=1,62,366 in 8 European countries, age y) found a relative 21% reduction of prostate cancer death and a reduction in 1 death per 1000 men screened in age group, y

22 Estimated risk reduction of prostate cancer death: 25-31% Estimated risk reduction of prostate cancer death: 27-32% Psodikov, Ann Int Med, 2017

23 PSA based screening: 2017 USPTF draft recommendations Age Y : Potential benefit & harm are balanced. Decision should be individual one. High-risk patients (AA & Family Hx) should have discussion. Net benefit is small (Category C) Age 70 & above: Benefit do not outweighs harm. Do not screen (Category D)

24 Society screening recommendations American Cancer Society American Urologic Association Age to screening: Average Risk 50 y 40 y High risk (AAM, Family Hx) Frequency y 40 y Annual (every other year, if PSA <2.5) Annual Discontinuation Life expectancy <10 y Life expectancy <10 y All recommend shared decision between clinician and patient regarding screening

25 Impacts of new screening guidelines?

26 Jemal A, JAMA, 2015 Data from 18 Population based SEER registries, patients >50 y Screening rates increased by 10% from & decreased by 18% between Incidence decreases across all age, race and ethnicity group

27 Detection of advanced disease Welch, Gorski & Albertson, NEJM, 2015

28 NCI database (2004 -> 2013) Increase in metastatic prostate cancer incidence: 72% Decrease in early prostate cancer diagnosis: 37% Weiner, Prostate Ca & Prostatic Dis 2016

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30 Disease Burden Screening Risk Assessment Treatment

31 PSA kinetics (rate of PSA rise) can predict high-risk prostate cancer Carter, JAMA, 1992

32 Gleason Scores Pathologic diagnosis by Gleason grading is the gold standard of diagnosis of prostate cancer

33 Birkhahn, BJUI, 2011

34 Gleason Score 7 predicts highrisk prostate cancer & increased mortality Albertson, JAMA, 2005

35 Biochemical outcome of clinically localized prostate cancer : stratified by stage, PSA & GS Low-risk disease High-risk disease D Amico, JAMA, 1998

36 Risk stratification of early prostate cancer Stage Gleason Score Low-risk (all) T1-T2a (PSA detected, Confined, <50% of one lobe involved) Intermediate Risk (any) T2b-T2c (Confined, >50% of one lobe or both lobes involved) High Risk (any) >T3a (Extracapsular, Seminal vesicle or invasion to adjacent organs) PSA <10 ng/ml ng/ml >20 ng/ml Modified, NCCN, V

37 Approved genome-based risk prediction tools from tissue

38 Prostate cancer is the most commonly diagnosed cancer & 3 rd leading cause of cancer related mortality in American men Death from prostate cancer is declining each year Most of the recent data indicate that PSAbased screening saves life Early-stage prostate cancer is over-diagnosed & over-treated Risk stratification is important to decide who are the optimal candidates for treatment