1. Prostate Cancer 101Cell 616 Joshi Alumkal, MD Assistant Professor of Medicine May 6, 2009

2. Outline • Background on prostate and prostate cancer • Androgens and AR • Epidemiology • Progression model • Molecular events • Prevention • Prostate cancer screening and diagnosis • Treatment • Localized prostate cancer • Prognostication • Metastatic prostate cancer • Disease states model • Pre/post hormonal therapy • Is AR still a target after castration? • Moving beyond hormones to target AR and prostate cancer

3. Background

4. Urinary bladder Prostate Rectum Rectal surface

5. Schematic depiction of the cell types within a human prostatic duct Androgen Receptor - Androgen Receptor + Abate-Shen C., Shen M. M. Genes Dev. 2000;14:2410-2434

6. Prostate: An androgen-responsive organ • Prostate develops after puberty due to production of testosterone and more active metabolite dihydrotestosterone, which activate AR, the androgen receptor • AR is a transcription factor which binds to consensus sequences and turns on target genes such as PSA • Prostate contributes to fertility by producing enzymes which aid in fertilization of egg • Testosterone depletion can prevent prostate formation and cancer • Eunuchs do not develop prostates and hence do not get prostate cancer • Testosterone administration has not been found to cause prostate cancer in epidemiological studies or animals models • May raise one’s PSA level though and prompt a diagnostic work-up

7. AR Active HSP90 HDAC6 Ac HDAC6 Ac Alpha-tubulin AR ERG, PSA, and other AR target genes

8. Prostate Cancer Public Health Impact/Demographics • Prostate cancer is the most common cancer in men • 187,000 new cases estimated for 2008 • 50,000 recurrences despite early detection and treatment • Prostate cancer is also the second most lethal cancer • 27,050 deaths estimated for 2008 • Previously rare in men <50 • 1/5 men will be diagnosed in their lifetime

9. Race and prostate cancer • African-Americans are at increased risk of prostate cancer development and have more aggressive disease • Even when one accounts for screening and treatment • Unknown why • Extremely rare in Asian populations… • Until they move to the U.S.

10. Diet and Prostate Cancer • High consumption of broccoli is associated with lower prostate cancer risk • Kristal, Kolonel, Giavanucci • Why? • High consumption of red meat particularly charred red meat is associated with increased risk • PhIP adducts • Asians who move to US are at increased risk • Diet?

11. Viruses and prostate cancer • Men with mutations in an anti-viral gene called RNase L more likely to • have this virus’ cDNA present in their cancer tissue • No causal link demonstrated yet

12. Nelson, et al NEJM 2003

13. Different roads to gene silencing Genetic + + - Epigenetic - + + = heritable control of gene expression in the absence of DNA sequence changes • DNA methylation • Histone methylation Herman and Baylin NEJM 2003

14. Increase in ERG Increase in EZH2 Increase in LSD1 Increase in Sonic hedgehog signaling Nelson, et al NEJM 2003

15. ERG and Prostate Cancer • Recent information suggests that ERG is commonly up-regulated in prostate cancer • This gene is expressed because it is linked to TMPRSS2, which AR turns on • ERG over-expression leads to enhanced invasion and increases one risk of cancer recurrence • The VCaP prostate cancer cell line harbors this translocation Science 2005

16. Transgenic ERG mice develop PIN (prostate cancer precursor lesions) Benign PIN Klezovitch , et al PNAS 2008

17. NEJM 2008

18. Prevention

19. Inhibits 5-alpha-reductase enzyme which converts • testosterone to more active dihydrotestosterone agonist of AR protein • -Leads to loss of AR function • Similar results presented last week at AUA meeting for related drug • dutasteride

20. Cumulative Incidence of Prostate Cancer Diagnosed in a Biopsy Performed for Cause or after an Interim Procedure Need to treat 16 men to prevent 1 cancer

21. Screening/Diagnosis

23. Prostate cancer screening • PSA is very sensitive and easy to do • Widely adopted in 1989 • Led to surge in new diagnoses • However, • Many men will be diagnosed with non-life-threatening cancers with which (rather than of which) they might have died • Evidence for improvement in survival with treatment is modest NNT=20 • Bill-Axelson, et al NEJM 2005 • May be leading to lead-time bias • No high quality RCT has shown a survival benefit

24. Critical appraisal of screening tests • Does it do more harm than good? • Specific ?s to ask: • Is there an RCT that early diagnosis leads to improved survival and/or QOL? • Are the early diagnosed patients willing partners in the treatment? • How do benefits/harms compare in screened/unscreened? • Do the frequency and severity of the target disorder warrant the degree of effort and expenditure?

26. Number of Diagnoses of All Prostate Cancers (Panel A) and Number of Prostate-Cancer Deaths (Panel B) • What might explain a negative result in this randomized study of screening? • 50% of the control arm underwent screening

27. Cumulative Risk of Death from Prostate Cancer Median F/U= 9 years Never seen a curve like this Schroder F et al. N Engl J Med 2009;10.1056/NEJMoa0810084

28. Take homes for screening • Does it do more harm than good? • Personal matter • Specific ?s to ask: • Is there an RCT that early diagnosis leads to improved survival and/or QOL? • Yes improved DSS in ERSPC; NNT=48 ; No improved DSS in PLCO • F/U short • Are the early diagnosed patients willing partners in the treatment? • Yes • How do benefits/harms compare in screened/unscreened? • Unscreened do not have up-front and persistent harms of screening/treatment liked screened do • Screened have a marginal reduced risk of death in ERSPC • ? effect on QOL r/e development of symptomatic metastases • Do the frequency and severity of the target disorder warrant the degree of effort and expenditure? • Very personal decision • Presently, we do not have a screening test for aggressive prostate cancers

29. Diagnosis

30. Prostate gland Rectum

31. Definitions Grade = How well differentiated a tumor is How closely tumor histologically resembles non-tumor/ normal cells of that organ Low-grade = Close resemblance High- grade = Little resemblance

32. Gleason grading prostate cancer Assign a number to the primary/ predominant pattern. Assign a 2nd number to the secondary pattern. The sum of the numbers is the Gleason grade/score. Donald G. Gleason (VAMC) 1977

33. Gleason grading of prostate cancer Higher grade,worse prognosis grade 7 (3+4) grade 10 (5+5) Donald G. Gleason (VAMC) 1977

34. Grade (= how closely prostate cancer cells resemble normal prostate glands microscopically) Pattern 3 Gleason grade 3+3=6 Pattern 4 Gleason grade 4+4=8 Pattern 5 Gleason grade 5+5=10

35. True, et al PNAS 2006

36. Stage = Where the tumor is at time of diagnosis Localized = Tumor is confined to the organ of origin Regional spread = Tumor has invaded adjacent organs Metastatic = Discontiguous spread of tumor to other tissues T . N . M T1A, T1B, T1C Incidental (TUR/PSA) T2A, T2B , T2C Localized T3A, T3B , T3C and T4 Locally-advanced N(0) vs N(+) M(0) vs M(+) Metastatic

37. Take home points • All men have prostate cancer • The histology (grade) of a prostate cancer is a basis for selecting the type of treatment • Molecular determinants of grade are specific biomarkers and targets for therapy

38. Prostate cancer treatment

39. Treatment for localized prostate cancer • Institutional bias determines which modality is given • Radical prostatectomy • External beam radiation • Equal cure rates for early disease • No randomized, head-head data comparing these approaches • Brachytherapy • Most well-studied in low risk tumors • Androgen-deprivation therapy • Patients who are not candidates for surgery or radiation • Observation • Patients with very limited life expectancy due to co-morbid conditions • Patients with very favorable-appearing tumors

40. Treatment Outcomes in Prostate Cancer • Overall survival (OS) • Relapse-free survival (RFS) • PSA blood test is used to monitor relapse • No elevation in PSA or overt disease recurrence

41. Radical prostatectomy • Involves removal of the prostate, adjacent seminal vesicles, and regional lymph nodes • Can be performed as an open procedure or laparoscopically +/- robotic assistance • No head to data comparing the approaches • Allows for determination of the pathological extent of disease • Prognostic • May be therapeutic • Lymph node removal

43. Radical Prostatectomy Side Effects • Incontinence • Impotence • Common post-op but improves with time • Contrasts with XRT which is less frequent immediately post-treatment but increases with time • More common in older patients and those with erectile dysfunction pre-op

44. External Beam Radiation • Patients are divided into risk groups based upon historical outcomes with XRT clinical stage PSA Gleason score Low risk T1c-T2a <10 6 Int risk T2b 10-20 7 High risk >T3 >20 8-10 -- D’Amico (1998) JAMA 280:969

45. External Beam Radiation • Low risk patients • XRT alone • Intermediate risk patients • Neoadjuvant Hormonal Therapy->XRT + Concomitant Hormonal therapy • LHRH-agonist + an anti-androgen • High risk patients • Neoadjuvant Hormonal Therapy-> XRT + Concomitant Hormonal Therapy->Adjuvant for a total of 3 years • LHRH-agonist + an anti-androgen • Bolla, et al ASCO 2007

46. External Beam Radiation Side Effects • Acute • Irritative symptoms (rectum and bladder) • during treatment and afterwards • Chronic • Impotence • Lower frequency post-treatment than surgery but increases over time • More responsive to PDE inhibitors than post-surgical impotence • Irritative symptoms (rectum and bladder) • Risk of secondary malignancies

47. Brachytherapy (radioactive seed implantation) • Reserved for patients with Gleason scores <7 with clinical stage < T2b (tumors on only 1 side of the prostate) and PSA <10 • Follow-up data less mature • Side effects • Acute • Irritative symptoms (urinary) • Urinary retention • Chronic • Impotence • Irritative symptoms (rectal and urinary) • Fistulas • Bleeding

48. Prognostic pathologic parameters(classic) • Serum [PSA] • Stage • Grade Prognosis = Likelihood of the disease recurring after x years

49. Kattan nomograms • Useful tool to examine outcome for similar patients to one’s own using wither pre-operative or post-operative data • Developed from a retrospective database that was externally validated • Kattan

50. Multivariable Analysis of the Risk of Biochemical Recurrence N=151 * Preoperative PSA and postoperative Gleason score were treated as continuous variables #CI: Confidence interval Alumkal, et al 2008