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1 Enterprise Interest None

2 Molecular Pathology of Prostate Cancer: An Update George J. Netto, M.D. Professor and Chair of Pathology The Robert and Ruth Anderson Endowed Chair of Pathology University of Alabama at Birmingham Birmingham, AL USA

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4 Overview Introduction: Do No Harm! Morphology: ISUP Circa 2050? Molecular Aspects of Prostate Cancer Oncogenesis Molecular Biomarkers for Prognosis Genomic Signatures / Commercial Genomic Assays

5 CA Cancer J Clin. 2012

6 Overtreatment????

7 PSA Screening Strategies To Do No Harm?? PLCO Cancer Screening Trial 3.7 vs 3.4 deaths per person-years? Contamination in ctrl arm European Randomized Study of Screening for PCa 29% Relative risk reduction of DOD = 1.07 death /1000 men 1055 screened & 37 cancers Rx to save 1 life 2013 AUA Guidelines strongest evidence benefit vs harm: yrs age group provider-patient shared decision-making AUA now recommend against routine screening in other groups Schroder FH et al. N Engl J Med 2012 Bokhorst LP et al. Eur Urol 2013 Carter HB. BJU Int 2013

8 Molecular Markers & Genomic Signatures BIOLOGICALLY INSIGNIFICANT PCA LETHAL PCA

9 MORPHOLOGY

10 Histopathological Refinements ISUP Consensus Recommendations

11 November 2014: 65 pathology experts & 17 clinicians (urologists, radiation oncologists, and oncologists) from 19 countries

12 BJU International 2013

13 RP Data From 5 Institutions Since 2005 ISUP Modified Gleason Grade System University of Pittsburgh: J. Nelson, A. Parwani MSKCC: V.Reuter, S.Fine, A.Vickers, J. Eastham, D. Sjoberg CCF: C. Magi-Galluzzi, E. Klein, J. Ciezki, C. Reddy Karolinska: L. Egevad, P. Wiklund, T. Nyberg Johns Hopkins: J. Epstein, M. Han

14 GrGp 1 GrGp 2 GrGp 3 GrGp 4 GrGp 5

15 New Grading System? Grade Group 1 (<6) Only individual discrete well-formed glands Grade Group 2 (3+4) Predominantly well-formed glands with a lesser component of poorly- formed/fused/cribriform glands Grade Group 3 (4+3) Predominantly poorly formed/fused/cribriform glands with a lesser component of well-formed glands Grade Group 4 (4+4/3+5/5+3) Only poorly-formed/fused/cribriform glands or Predominantly mix of well-formed and lack of glands Grade Group 5 (4+5/5+4/5+5) Lack gland formation (or with necrosis) with or w/o poorly formed/fused/cribriform glands

16 10/22 (45%) cases with G7 (5% Pattern 4) on Bx have pathologically insignificant tumor in the RP GS, ptstage, total tumor volume, and rate of insignificant tumor in RP were not significantly different between GS 3+3=6 and GS7 (5% Pattern 4)

17 Grade Group 1 IMPLICATIONS ON ACTIVE SURVEILLANCE Grade Group 2 : 10% Gleason Pattern 4

18 GENOMICS

19 Prostate Carcinoma Inherited Germline Genetic Alterations Environmental Life style Factors PCA Somatic Genetic & Epigenetic Alterations

20 Mixed model of common and rare genetic variants with different effect size determining genetic risk of prostate cancer Eeles et al Nat Urol Rev 2014

21 Estrogens Exposure Genetic Succeptibility SNPs Risk Variants RNASEL/MSR1/HPC Mutations Overcooked/ Char-broiled Red Meat Heterocyclic Amines Polycyclic Aromatic Hydrocarbons Chronic Inflammation Prostate Epithelial Cell Damage Epigenetic Silencing (eg. GSTP1) Early Somatic Genetic Alterations Prostate Cancer Precursor PIA PIN Prostate Cancer Infectious Agents STD? Etiological factors implicated in PCA development

22 Normal prostate epithelium TMPRSS2-ERG rearrangement GSTP1 promoter hypermethylation Proliferative Inflammatory Atrophy PIN Critical Telomeres shortening C-myc alteration p27 loss NKX3.1 loss Localized PCa PTEN loss Metastatic PCa Telomerase activation: Immortalization AR mutation AR amplification Netto, G: Adv Anat Pathol 2013 Castration Resistant PCa

23 ETS FUSIONS

24 TMPRSS2 (Transmembrane Protease, Serine 2) Prostate specific serine protease family (PSA, hk2, prostate/prss18, TMPRSS2) TMPRSS2 expression is regulated by androgen TMPRSS2 is highly expressed in prostate epithelium ERG (ETS Related Gene) Member of ETS transcription factor family ERG (ets-related gene) 21q22.2 ETV1 7p21.2 ETV4 17q21 Petrovics et al. Oncogene Most consistently overexpressed oncogene prostate cancer ERG: 279 kb TMPRSS2: 40 kb ~ 3 Mb

25 TMRSS2-ERG Fusion = POOR PROGNOSIS Perner et al. Cancer Res 2006 ERG Rearrangement by deletion associated with high stage and presence of metastasis Attard et al Oncogene 2007 Fusion by deletion but not by translocation had worse OS and DSS Duplication of fusion by deletion had extremely poor PGx (25%@ 8 yr) independent of Gleason score

26 Modern Pathology 2011

27 ERG EXPRESSION Status IHC vs FISH A Chaux et al. Am J Surg Path 2011

28 ERG IHC SP Diagnostic Application ERG IHC positivity is specific for PCa and HGPIN (15-30%): Resolving needle bx with atypical foci ATYP PCa risk on F/U after initial Dx of isolated HGPIN ERG IHC positivity role in establishing prostate lineage in metastatic adenocarcinoma Prostatic Small Cell Ca. (post androgen deprivation Rx) may not express ERG despite detectable TMPRSS2-ERG by FISH

29 Dancey J, Nat Rev Clin Ocol 2010 mtor Pathway

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31 Modern Pathol cases / 541 controls IHC nested case control study PTEN loss predicted recurrence (OR:2.2; p0.002)

32 Antje Krohn et al. Am J Pathol 2012 FISH on TMA study (4700 cases) PTEN mutations and methylation in subsets PTEN deletions in 20.2% (8.1% heterozyg ; 12.1% homozyg)

33 Antje Krohn et al. Am J Pathol 2012

34 Clin Cancer Res 2011

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38 Ried AHM et al. BJC 2010 Trans Atlantic Group Ahearn, Mucci and Lotan Health Professionals Follow-up & Physicians' Health Studies

39 Lotan T et al. Mod Path 2014

40 Mod. Path. 2016

41 Molecular Subtypes of PCA ETS - /SPINK1 - /SPOP (wt) /PTEN (homozygous del) / MYC (amp) AGGRESSIVE, HIGH GRADE TUMOR ETS + /SPINK1 - /SPOP (wt) /PTEN (wt) / MYC (wt) INDOLENT, LOW GRADE ETS - /SPINK1 + /SPOP (mut) /PTEN (wt) / MYC (wt) INTERMEDIATE BIOLOGIC BEHAVIOR Antonarakis ES et al. Cancer. 2012

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43 IMPLICATIONS ON ACTIVE SURVEILLANCE Grade Group 1 (IHC: normal PTEN) Grade Group 2 :10% Gleason Pattern 4 (IHC: normal PTEN) Grade Groups 2: Cribriform Pattern 4 Grade Groups 1&2: DCISP (Intraductal Ca)

44 PCA POST NGS GENOMICS

45 Lapointe et al PNAS 2004 Lapointe et al Cancer Res 2007

46 Berger et al, Nature 2011

47 Berger et al, Nature 2011

48 Integrative Genomics in Lethal PCa Grasso CS et al. Nature 2012 Rapid autopsy: 50 lethal CRPC and 11 OC Hormone naiive Exome Seq /acgh AR amplification/mutation TP53 and PTEN Loss Chromatin/histone remodeling genes (MLL complex) mutations Strong expression of TMPRSS2-ERG gene fusion = active AR signaling AR CNA/mutations/expression; AR target genes expression; ETS gene fusion genomic and transcript status AS PREDICTIVE MARKERS OF RESPONSES TO NOVEL ANTI-ANDROGEN DRUGS

49 Lethal PCA Mutational Landscape CS Grasso et al. Nature 2012

50 The Cancer Genome Atlas Research Network, 2015, Cell 163,

51 The Cancer Genome Atlas Research Network, 2015, Cell 163,

52 The Cancer Genome Atlas Research Network, 2015, Cell 163,

53 Conclusions Stratifying management based on biomarkers soon be integrated in current clinical managements standard of care Genetic familial risk assessment will guide screening strategy PTEN/ERG IHC ready for prime time (Active Surveillance) ETS/SPINK1/SPOP/PTEN/ MYC Genomic classifiers are promising in the correct setting More work remains Thank You!..

54 PCA Commercial Genomic Assays Genomic Assay Manufacturer FFPE Sample Comment Prolaris, Myriad Genetics RP or Bx Cell-Cycle Progression (CCP) Score Expression of 31 cell cycle genes; quantitative RT-PCR Oncotype DX Genomic Health Needle Bx Genomic Predictor Score (GPS) Expression of 12 genes; (androgen pathway, cellular organization, cell proliferation and stromal response) Risk assessment prior to treatment intervention Decipher TM GenomeDx RP or Bx Genomic Classifier (GC) Expression of 22 genes Calculate risk for metastasis post RP

55 Commercial Expression Assays Myriad Diagnostics Prolaris q RT-PCR panel 31 cell cycle progression (CCP) gene RP or Bx CCP: best predictor of BCR (also PSA) & time to DOD (HR: 2.57) CCP (413 pts; RP): - HR of 2.1 for of BCR for each unit increase in CCP score - CCP sub-stratify pts with low clinical risk (CAPRA-S 2) - Combining CCP and CAPRA-S improved the concordance index Cooperberg MR et al JCO 2013 Cuzick, J. et al. Lancet Oncol 2011

56 Commercial Expression Assays Genomic Health Oncotype DX Prostate Cancer Assay RT-PCR assay (needle Bx) 12 genes: androgen pathway (AZGP1, KLK2, SRD5A2, FAM13C); cellular organization (FLNC, GSN, TPM2,GSTM2); proliferation (TPX2) and stromal response (BGN, COL1A1,SFRP4) Genomic Prostate Score (GPS): - adverse pathologic outcome -? Active surveillance Klein EA et al Eur Urol 2014 Knezevic D et al BMC Genomics 2013

57 Commercial Expression Assays GenomeDx Decipher TM Affymetrix exon microarray (RP) Genomic Classifier (GC): 22 mrna and non coding RNA Risk of metastatic Disease GC outperformed Gleason grade; PSA dt and time to BCR in predicting metastatic progression (85 pts JHU) GC & CAPRA-S: Independent predictors of DSS (high risk RP cohort ) Guide in RadioRx decision in adjuvant/salvage Karnes et al J Urol 2013 absrtct Ross et al. Prostate Ca Prost Disease 2014

58 Conclusions Stratifying management based on biomarkers soon be integrated in current clinical managements standard of care Genetic familial risk assessment will guide screening strategy PTEN/ERG IHC ready for prime time (Active Surveillance) ETS/SPINK1/SPOP/PTEN/ MYC Genomic classifiers are promising in the correct setting More work remains Thank You!..

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62 Inherited Genetic Risk Factors Genomic Approach GWAS WES/WGS by NGS HOXB13 17q high OR (3-10x) - early onset and familial PCa Similar studies could define novel high risk criteria for screening Gudmundsson J et al. Nat Genet Ewing CM et al. N Engl J Med. 2012

63 Problems with Gleason System Inconsistent & Inaccurate Grouping: Various combinations have been used in the literature including some of the highest impact studies: Prostate Cancer Outcomes Study (NEJM): 2-4; 5-7; 8-10 Scandinavian Prostate Cancer Group Study (NEJM): 2-6, 7; 8-10 Prostate Cancer Intervention vs. Observation (NEJM): 2-6; 7-10 Prostate Cancer Prevention Trial (NEJM): 2-6; 7-10

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67 Ried AHM et al. BJC 2010 Trans Atlantic Group

68 Lapointe et al Cancer Res 2007

69 R Sullivan et al Clin Can Res Ott et al Clin Can Res 2013

70 Somatic Alterations Genetic and Epigenetic

71 Prostate Carcinoma Somatic Alterations Genetic Rearrangements TMPRSS2-ETS: TMPRSS2-ERG TMPRSS2-ETV1 TMPRSS2-ETV2 TMPRSS2-ETV3 TMPRSS2-ETV4 Other ETS Fusion Partners WGS Data: CADM2 MAGI2 Modified from DeMarzo et al Nat Rev Cancer 2007

72 PTEN/PI3K/mTOR Pathway PTEN loss occurs in 20% of localized and over 60% of metastatic PCa and has been associated with high Gleason Sc and pt stage, BCR and castration resistance/chemo-resistance Saal et al PNAS 2007: Gene expression signature of aberrant PTEN activity is associated with poor prognosis in PCa

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74 Berger et al, Nature 2011

75 Baca SC et al. Cell 2013 WGS: 57 PCa Abundant DNA translocations and deletions in interdependent manner chromoplexy disrupts multiple cancer genes coordinately Induces significant genomic derangement over relatively few events Model of punctuated cancer evolution

76 Cell 2013 Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes.

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