Professor of Surgery/Urology/ Radiation Oncology University of Colorado

E.DavidCrawford,M.D.

PSA: Why 1.5 is the New 4?

Disclosures Consultant: MDxHealth, and Genomic Health, 3D Bx Speaker: Ferring, Bayer, Janssen, Pfizer, Astellas

Your Opinion

Are you satisfied with the current state of prostate cancer early detection ?

•  Yes •  No

2

The answers I have heard:

•  Both FP and Urologists are concerned •  Each have different reasons •  Common Areas: Screening

parameters, informed decision, risks and benefits

•  However, both specialties believe there is a value to early detection in some men

3

PSA Based Screening

Flying High

Worlds shortest vacation: USPSTF

Drecommenda4on•  DoNotOrder•  SharedDecisionMaking

Crecommenda4on(May2018)

Why is 1.5 the New 4

Family practice physicians are

confused by our message

•  Cutoffs of 2.5 and 4 •  PSA velocity •  PSA density •  Age Specific PSA •  % free PSA •  Complex PSA •  phi •  PCA3 •  SelectMDx •  4K •  HELP!

6

Why is 1.5 the New 4

We need a simple message for those that

order PSA

7

64.923.7

[VALUE] 1.3

InternalMedicine

FamilyMedicine

Urology

Hem/Onc

90%ofPSAs-orderedbyFP/IntMed

Original Article Mortality Results from a Randomized Prostate-Cancer Screening Trial

Gerald L. Andriole, M.D., E. David Crawford, M.D., Robert L. Grubb, III, M.D., Saundra S. Buys, M.D., David Chia, Ph.D., Timothy R. Church, Ph.D., Mona N. Fouad, M.D., Edward P. Gelmann, M.D., Paul A. Kvale, M.D., Douglas J. Reding, M.D., Joel L. Weissfeld, M.D., Lance A. Yokochi, M.D., Barbara O'Brien, M.P.H., Jonathan D. Clapp, B.S., Joshua M. Rathmell, M.S., Thomas L. Riley, B.S., Richard B. Hayes, Ph.D., Barnett S. Kramer, M.D., Grant Izmirlian, Ph.D., Anthony B. Miller, M.B., Paul F. Pinsky, Ph.D., Philip C. Prorok, Ph.D., John K. Gohagan, Ph.D., Christine D. Berg, M.D., for the PLCO Project Team

AndrioleGL,etal.NEnglJMed.2009;360(13):1310–1319.

Ini4alPSA<1ng/mlScreenevery5-10years

9

Defining an Appropriate PSA Level

•  Patients and Methods: •  350,000 HMO-Henry Ford System •  Men in system 1997-2008 •  Initial PSA between 1-5ng/ml •  Minimum 5 years follow-up •  No 5 ARIs

•  Results: •  Mean age 55 years •  Mean PSA 1.0 •  African American: 29% •  Detected Cancer: 2%

MenEligible:21,502

Is there a PSA level that is “safe?” YES

10

19-foldIncreaseinriskforAfricanAmericans

12%

8%

6%

4%

2%

0%Percen

tdevelop

ingprostatecan

cer

0.51%

7.85%

15-foldIncreaseinrisk

Percen

tdevelop

ingprostatecan

cer10.39%

ROCCurveforAllPa4entsPSA<1.5ng/mLPSA1.5-4ng/mL

1.0

0.8

0.6

0.4

0.2

0

0 0.2 0.4 0.6 0.8 1.01-Specificity

Es4matedAreaC=0.87251

Maximumsensi4vityandspecificityatPSA1.5ng/mL

OverallStudyPopula4on(21,500)

10%

CrawfordED,etal.BJUInt.2011;108(11):1743-1749.

5-yearDiagnosisRate

>1.5to4isa“dangerzone”

Surrogate for: 1.  BPH-most common

2.  Prostate Cancer Prostate Health 3.  Long term PCa risk

4.  Evaluate-Don’t Biopsy everyone with > 1.5 ng/ml !!!!

5.  Use PCMs to help determine whom to biopsy

AWayForward:PSA>1.5ng/mL

Will this level subject a lot of men to unneeded evaluation ?

73%PSA<1.5ng/ml

Bio-referenceLabs.

20%1.51-4ng/ml

400,000PSAtests

PSA ≥1.5ng/mL BPH

Predicting Enlargement & Risk of Progression

Adapted from Roehrborn CG et al. Urology. 1999;53:581–589. *Crawford ED et al. J Urol. 2006;175:1422–1427.

13

Prostatevolum

e(m

L)

65

60

55

50

45

40

35

301 2 3 4 5 6 7

SerumPSA(ng/mL)

Age(years)

65

Riskof

progression*

PSAof1.5surrogateforenlargedprostate

PSA and Primary Care

15

Are we sure we are not missing significant cancers

with the 1.5 cutoff?

•  PLCO data and cut offs: Mortality Results from a Randomized Prostate-Cancer Screening Trial. New England Journal of Medicine, 360, 1310-1319, 2009.

•  University of Toronto data

•  Genomic marker data

16

Evaluation of an Aggressive Prostate Biopsy Strategy in Men Younger than

50 years of Age Hanan Goldberg, Zachary Klaassen, Thenappan Chandrasekar,

Christopher J.D. Wallis, Ants Toi, Rashid Sayyid, Bimal Bhindi, Michael Nesbitt, Andrew Evans, Theo van der Kwast, Joan Sweet, Nathan Perlis, Robert J. Hamilton, Girish S. Kulkarni, Antonio Finelli, Alexandre Zlotta,

and Neil Fleshner Princess Margaret Cancer Centre, Department of Surgery, Division

of Urology, University Health Network, University of Toronto, Toronto, Canada

PSA<1.5:DohighgradecancersrouUnelyexist?

92.9%

78.9%73.7%

79.2% 81.4%

7.1%

21.1% 17.5% 14.6% 14.6%

0.0%0.0% 5.3% 4.2% 2.5%0.0%0.0%

3.50% 2.1% 1.5%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

PSA<=1 PSA(1-1.5) PSA(1.5-2) PSA(2-2.5) Total

BiopsyResults

Nocancer Gleason6 Gleason7 Gleason8-10

Manufacturer Cut-offs: phi ≥ 27, 4KScore ≥ 7.5%, and SelectMDx > 0% Revised Cut-offs: phi ≥ 52.7, 4KScore ≥ 20%, and SelectMDx > 0%

Howdomolecularmarkersperformwiththe1.5ng/mlcutoff

phi,4KScore,SelectMDx

Prostate Cancer Clinical Needs

1.  Screening: Primary Care Physicians (PCPs) need a simple message

2.  Early Detection: Identify patients with clinically significant PCa earlier

3.  Reduce Unnecessary repeat prostate biopsies

4.  Enhance risk stratification: Surveillance vs. Interventional Therapy

5.  Germline Mutations-Role of Urologist

20

Prostate Cancer: Clinical Needs

1.  Screening: Primary Care Physicians (PCPs) need a simple message: 1.5ng/ml

2.  Informed decision: It should happen like with other tests “routinely performed” by FP

21

22

Early Detection a Way Forward

Vital signs and many tests routinely performed by PCPs before informed decision

•  Informed decision when tests are abnormal

•  Why not PSA?

•  73% of men require no discussion

PSAtreatedlikeotherlabtests:•  lipids•  electrolytes•  weight•  BP-rou4ne

Men’shealthbroaderissue>1.5ng/mlsurrogateforBPH,ProstaUUs,ProstateCancer

RoehrbornCG,etal.Urology.1999;53(3):581–589.

Shared Decision making

•  Provision of information

–  Balanced and evidence based

–  Harms and benefits of each option

•  Elicitation of patient’s perspective

–  Asking about prior experiences

–  Understanding and discussing concerns

–  Delineating preferences regarding screening options

•  Guiding final decision making (without directing)

FengB,etal.AnnFamMed.2013Jul-Aug;11(4):315-23.

•  An Efficient Use of Time or Another Exercise is Futility

•  Matt T. Rosenberg, MD

•  A concerned doctor

23

The Implementation of Shared Decision Making Has Failed in Other Diseases as Well

Variable BreastCA Colorectal(W) Colorectal(M) ProstateCA

Discussedreasonstohavetest(pros)

Notatall/liile 47 41 33 48

Some/alot 53 59 67 51

Discussedreasonsnottohavetest(cons)

Notatall/liile 92 87 87 93

Some/alot 8 13 14 7

HoffmanRM,etal.AmerJPrevMed2014;47(3):251-259

Prostate Cancer: Clinical Needs

1.  Screening: Primary Care Physicians (PCPs) need a simple message: 1.5ng/ml

2.  Informed decision: It should happen like with other tests “routinely performed” by FP

3.  Identifying significant cancers/reducing unnecessary biopsies

25

ProstateCancer:ClinicalNeeds

•  EarlyDetec4on:Iden4fypa4entswithclinicallysignificantPCa

BeyondPSA…

•  PSA alone to guide prostate biopsy decisions: END •  Need better risk assessment to detect clinically

significant cancers –  Reduce unnecessary biopsies –  Reduce over-detection of indolent disease

•  We have these tools and they are genomic markers

Which of these men is harboring aggressive, potentially lethal, prostate cancer?

Very Low Risk

Very Low Risk

Very Low Risk

Risk Stratification for Clinically Significant PCa

29

PCP/Urologist PSA>1.5

Urologist Repeat PSA,

Genomic Test

Very Low Risk

for GS ≥ 7 PCa

Consider Biopsy

Increased Risk

for GS ≥ 7 PCa

Avoid Biopsy

For patients being considered for prostate biopsy

Genomic Tests: SelectMDx, phi and 4K score

Sample Patient Report

Identification of Men for Prostate Bx:

High Risk •  Increased risk for

aggressive cancer

•  Men who may benefit from biopsy

Very Low Risk •  98% NPV for aggressive

cancer

•  May avoid biopsy

•  Return to routine screening

Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Leyten et al. Clin Cancer Res, 2015

VeryLowRiskRiskforCSPCa

Studypopula4onconsistedofsequen4allytestedpa4ents(N=418)who:§  receivedaSelectMDxtestbetweenMay2016andApril2017,and §  wereundergoingevalua4onforini4alprostatebiopsy

Contactednon-academicurologyprac4ceswithlargestSelectMDxtes4ngvolume§  Fivecommunityurologyprac4cesagreedtopar4cipate

Studyendpoint:§  Numberofini4albiopsiesperformedonmenwithSelectMDxposi4vevs.SelectMDxnega4veresults§  Cancerdetec4onratesinSelectMDxposi4vevs.nega4vemen§  Focusongroupofmenbiopsied<3monthsanerSelectresults

§  MedicalrecordreviewconductedApril2018tocollectpa4entclinicalinforma4on

ImpactsProstateBiopsyDecision-makinginRou4neClinicalPrac4ce

SelectMDxClinicalU4lity-StudyOverview

32

•  Subjectdemographicsat4meofSelectMDxTes4ng

SelectMDxClinicalU4lity-StudyPopula4on

AllSubjects SelectMDxnegaUve

SelectMDxposiUve P-value*

#PaUents(%oftotal) 418(100%) 255(61%) 163(39%) N/AAge(years)

Median(IQR)Mean

67(62-72)

67

66(60-70)

66

69(64-74)

69P<0.001

SerumPSA(ng/mL)Median(IQR)

Mean

5.1(3.8-7.1)

5.8

4.4(3.3-5.5)

4.5

7.1(5.2-9.0)

7.8P=0.001

DREresultNormal

Abnormal/SuspiciousN/A

336(80%)75(18%)7(2%)

236(93%)14(5%)5(2%)

100(61%)61(37%)2(1%)

P<0.001

RaceCaucasian

African-AmericanOtherN/A

375(90%)37(8.9%)3(0.7%)3(0.7%)

228(89%)22(9%)3(1%)2(1%)

147(90%)15(9%)

02(1%)

N.S.

FamilyHistoryofprostatecancerYes(%)No(%)N/A(%)

66(16%)316(76%)36(9%)

47(18%)187(73%)21(8%)

19(12%)129(79%)15(9%)

0.075

*ForSelectMDxposi4vevs.SelectMDxnega4vepa4ents

33

•  ImpactsProstateBiopsyDecision-makinginRou4neClinicalPrac4ce

SelectMDxClinicalU4lity-Results

Cancerdetec4on:pa4entsbiopsiedwithin3monthsofSelecttes4ng

SelectMDxnegaUve SelectMDxposiUve

Biopsies(%oftotalN) 9(3.6%) 71(43%)

PCaposiUve 4 27

GleasonSum(GG*)

GS3+3(GG1) 2 8

GS3+4(GG2) 2 9

GS4+3(GG3) 0 3

GS8(GG4) 0 4

GS9-10(GG5) 0 3

*GG=ISUPGradeGroup

34

•  ImpactsProstateBiopsyDecision-makinginRou4neClinicalPrac4ce

SelectMDxClinicalU4lity-Conclusions

§  SelectMDxhadasignificantimpactonini4alprostatebiopsydecision-makinginaU.S.communityurologyserng

§  Overall5-foldhigherbiopsyrateinmenwithSelectMDxposi4vevs.nega4veresults§  SelectMDxnega4vemenwhowerebiopsiedhadhigherserumPSAlevelsvs.SelectMDx

nega4veswhodidnotreceiveabiopsy

§  Inmenbiopsiedwithin3monthsofSelectMDxtes4ng§  Biopsyrate10-foldhigherinSelectMDxposi4vevs.nega4vemen§  High-gradecancersdiagnosedinSelectMDxposi4vemen

§  Theseresultsreflecttheclinicalu4lityofSelectMDxinrealworldclinicalprac4ce

SelectMDxversusProstateHealthIndexintheidenUficaUonofhigh-gradeprostatecancer

GretchenP.Hoyer,E.DavidCrawford,MD,PaulArangua,WhitneyN.Stanton,FranciscoG.LaRosa,MD,WendyPoage,M.ScoiLucia,MD,AdrianvanBokhoven,PhD,andPriyaN.Werahera,PhD

UniversityofColoradoDenverAnschutzMedicalCampus,Aurora,CO

§  Screeningmenpoten4allyatriskforprostatecancer(PCa)isessen4altoreducemorbidityandmortalitythroughearlydiagnosis.

§  Currently,themostcommonscreenhasbeenabloodtestforprostate-specifican4gen(PSA)andadigitalrectalexamina4on(DRE),butrecentresearchhassuggestedthatthesetwoscreeningmethodsmaynotreduceoverallmortality1.Therefore,beierdiagnos4cmethodsareneeded.

§  SelectMDXandProstateHealthIndex(phi)aretwobiomarkertestsdesignedforearlyprostatecancerdetec4on.

§  Thecurrentdiagnos4cgoldstandardisthe3DStagingSatura4onBiopsy(3DSSB),whichcaniden4fy98%ofprostatecancersthroughtransperinealneedlebiopsiesoftheen4reprostatein5mmincrements2.

§  Thegoalofthisprojectwastodeterminethediagnos4caccuracyofphiandSelectMDxanddetermineifonetestissignificantlymoreeffec4vethantheotheratdiagnosingprostatecancer.

§  70totalpa4entswereselectedfromanIRBapproveddatabaseof257menwhounderwenta3DSSBbetween2010and2018attheUniversityofColoradoHospital.

§  603DSSBpa4entswhohadbeentestedwithphiandSelectMDxwereselected.Inaddi4on,10pa4entswhoweremissingphiweretestedretrospec4velywithpa4entspecimensstoredintheUniversityofColoradoCancerCenterBiorepository.Theretrospec4vetes4ngwasdoneatTheUrologyCenterofColorado.

Table1:Themean,median,andstandarddevia4onoftheageandtest

resultsforthe70men.Medianageofthemenwas65(34-78)yrswithamedianPSAof2.82(0.32-56.74ng/dl).

*phiscore>27indicatedPCa,phiscore>52indicatedHGPCa4

Table2:Sensi4vity,Specificity,Nega4vePredic4veValue(NPV)andPosi4vePredic4veValue(PPV)forphiandSelectMDx.phihasahighsensi4vity(79%)andPPV(84%)foranyPCa,butthelowNPV(45%)indicatesthatphimightmissimportantPCa.ForHGPCa,SelectMDxhasabeieroverallperformancewithahighsensi4vity(81%)andspecificity(75%)witha60%PPVand90%NPV.

Tables3and4:DeLongTestROCcomparisonsfor7variablesinbothHG

PCaandanyPCa.ROCanalysisshowedthatneitherphinorSelectMDxissignificantlybeierthantheotheratdiagnosinganyPCa(p=0.17)orHGPCa(p=0.22).

AnyPCa(Gleason3+3orhigher) HGPCa(Gleason3+4orhigher)*

Sensi4vity

Specificity PPV NPV Sensi4vity Specificity PPV NPV

phi 79.25% 52.94% 84.00% 45.00% 50.00% 85.42% 61.11% 78.85% SelectMDx 45.28% 76.47% 85.71% 30.95% 81.82% 75.00% 60.00% 90.00%

Figures1and2:ThegraphedROCcurvecomparisonsforthesixvariables

forbothanyPCa(len)andHGPCa(right).PairwisecomparisonoftheROCforphiandSelectMDxshowednosta4s4callysignificantdifferenceinthediagnos4caccuracyofthetests.

Table5:Theresultsfromthemul4variatelogis4cregressionanalysisusing

sixvariables.Mul4variatelogis4cregressionanalysisshowedthatphiissignificantlybeierthanSelectMDxdiagnosinganyPCa(coefficient=0.054,p=0.005)whereasSelectMDxissignificantlybeierthanphidiagnosinghigh-gradePCa(coefficient=8.45,p=0.0002).

§  Theareaunderthereceiveroperatorcurve(ROC)foreachindependentvariable(SelectMDx,phi,p2PSA,PSA,FreePSA,and%FreePSA)andaDeLong3testwasusedtocomparethearea.

§  Amul4variatelogis4cregressionwasalsodonetocomparethesixvariablesandtodeterminethebestmodelfit.

§  Bothanalysesweredoneforbothanyprostatecancer(53/70pa4ents)andhigh-gradeprostatecancer(22/70pa4ents).

IwouldliketothanktheCancerLeagueofColorado,BinghamResearchFounda4on,andtheUCCCforfinancialsupport.Addi4onalthankstoDr.AdriaanvanBokhoven,Dr.PriyaWerahera,PaulArangua,andZacharyGrasmickfortheirsupportandexper4se.

Age PSA FreePSA %FreePSA P2PSA PHIscore

Median 65 2.83 0.44 0.17 11.9 41.82

Mean 63.21 3.58 0.55 0.18 15.85 47.10

StandardDev. 8.12 3.33 0.51 0.10 16.86 46.38

AnyPCa(3+3orhigher)Comparison PvaluePHIvs.PSA 0.0190P2PSAvs.FreePSA

0.0045

PHIvs.FreePSA 0.0152SelectMDxvs.PHI 0.1712

HGPCa(3+4orhigher)Comparison PvalueFreePSAvs.PSA 0.0276PHIvs.FreePSA 0.0461SelectMDxvs.%FreePSA 0.0494PHIvs.P2PSA 0.0497SelectMDxvs.P2PSA 0.0109SelectMDxvs.PHI 0.2248

0

20

40

60

80

100

0 20 40 60 80 100100-Specificity

Sensitivity

PSAFree_PSAPercent_Free_PSAP2PSAPHISelect_MDx_1

0

20

40

60

80

100

0 20 40 60 80 100100-Specificity

Sensitivity

PSAFree_PSAPercent_Free_PSAP2PSAPHISelect_MDx_2

AnyPCa(3+3andhigher) HGPCa(3+4andhigher)

Bestmodelfit phi SelectMDxCoefficient 0.054 8.45Pvalue 0.005 0.0002

ConclusionsPhiissignificantlybeierthanSelectMDxdiagnosinganyPCawhereasSelectMDxissignificantlybeierthanphidiagnosinghigh-gradePCa.Overall,SelectMDxisamuchbeierbiomarkertestcomparedtophifordiagnosingclinicallysignificantHGPCa.

1.   Andriole,G.L.,etal..(2012).JNCIJournaloftheNaBonalCancerInsBtute,104(2),125–132.

2.   LaRosa,etal.(2014).JournalofOncoPathology,2(1).3.   DeLong&Clarke-Pearson.(1988).Biometrics,44(3),837-845.4.   Crawford,E.D.,etal.(2015).JournalofUrology.193(4).E740-741.

Introduc4on

References

Acknowledgements

Results

Methods

#30

Formoreinforma4on,contactGretchenHoyeratgretchen.hoyer@ucdenver.edu

Assessment of Prostate Cancer Risk in Men with PSA < 1.5

Whitney Stanton, E. David Crawford MD, Paul Arangua, Wendy Poage, Adrie van Bokhoven, PhD, M. Scott Lucia, MD, Wendy Poage¹, Gretchen Hoyer, Francisco G. La Rosa, MD, John Hoenemeyer, MD, and Priya N. Werahera, PhD

University of Colorado Anschutz Medical Campus, Aurora, CO, ¹Prostate Condition Education Council, Aurora, CO

• For decades, assessment of prostate cancer risk among men relied upon demographical and clinical factors including prostate-specific antigen (PSA) levels in blood and digital rectal exams (DRE)

• Conventional PSA cut-off level has been 4.0 ng/mL, however, Prostate Cancer Prevention Trial (PCPT) results show that ~15% of men with “normal” PSA levels had high grade prostate cancer (4)

• There is a lack of consensus as to the correct PSA cutoff level for screening and an unmet clinical need to identify patients at increased risk for high-grade prostate cancer

• Combining PSA with well-validated prostate cancer biomarkers (PCM) may hold the key to improving risk assessment and selection of patients at risk for clinically significant prostate cancer

• We describe our findings on the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on

patients with PSA levels below 1.5 ng/mL that may represent a “safe zone” where risk of high-grade prostate cancer is extremely rare

I. Introduction and Objectives

• phi measures the [-2]proPSA biomarker, an isoform of free PSA

• Crawford et al. found that the median phi (52.7 vs 39.7; p = 0.04) was significantly different between patients with Gleason score ≥ 7 and <7 cancer (2)

• 4KScore is a blood test that incorporates a panel of four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, and human kallikrein protein biomarkers

• Konety et al. found that 4KScore < 20% represents a high negative predictive value and specificity for diagnosing high grade cancer at biopsy (3)

• SelectMDx test uses post-DRE urine samples to provide the likelihood of detecting high-grade cancer upon subsequent biopsy

• From 2012 to 2016, a total of 601 men were screened for prostate cancer with PSA/DRE and several serum and urine-based PCMs (phi, 4KScore, and SelectMDx) during the annual Prostate Cancer Awareness Week (PCAW) at the University of Colorado Hospital

• We investigated the test results of above PCMs in a cohort of men with PSA < 1.5 ng/mL to determine whether they are at risk for high-grade prostate cancer

• High-grade prostate cancer is defined as Gleason score ≥ 7 that include Gleason patterns 4/5 and recognized for poor clinical prognosis

• In this study, we used phi ≥ 52.7, 4KScore ≥ 20%, and SelectMDx > 0% as the cutoffs to identify patients at risk for high-grade prostate cancer

II. Methods

III. Results

IV. Conclusions

• The results of our analysis with three PCMs suggest that men with PSA < 1.5 ng/mL are at very low risk for high grade prostate cancer, which is supported by our previously reported findings in a screening population (1)

• A PSA > 1.5 ng/mL represents a danger zone for prostate cancer (1), and several PCMs can be used to determine if a patient is at risk for an aggressive cancer

V. References 1. Crawford ED, Rosenberg MT, Partin AW, Cooperberg MR, Maccini M, Loeb S, Pettaway CA, Shore ND, Arangua P,

Hoenemeyer J, et al. An Approach Using PSA Levels of 1.5 ng/mL as the Cutoff for Prostate Cancer Screening in Primary Care. Urology 2016 Oct;96:116-20

2. Crawford, E. David, Paul Arangua, Clifford Jones, Wendy Poage, Nelson Stone, Francisco G. La Rosa, Stacy Loeb, and Priya N. Werahera. "Mp60-08 Prostate Health Index Is An Effective Marker For Risk Stratification Of Prostate Cancer Patients." The Journal of Urology 193.4 (2015): n. pag. Web.

3. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore® Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices. Rev Urol. 2015;17(4): 231-40.

4. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N.Engl.J Med. 2004 May 27;350(22):2239-46

• In a PSA range of 1.5 - 4.0 ng/mL, 15% (17/113) patients had a positive phi result, 7.8%

(4/51) patients had a positive 4KScore result, and 1.3%

(1/75) of patients had a positive SelectMDx result

• In a PSA range of < 1.5 ng/mL, one patient who was

screened with 4KScore was at risk for having high grade

prostate cancer

VI. Acknowledgements

I would like to thank my lab personnel, Dr. E. David Crawford, Dr. Priya Werahera, and Paul Arangua for their mentorship and support. Additionally, thank you to the Prostate Condition Education Council and the Schramm Foundation for financial support. For further inquires or questions, please email whitney.stanton@ucdenver.edu.

*manufacturer cut-offs: phi ≥ 27% and 4KScore ≥ 7.5%

Table: Positive PCMs from a Cohort of Men with PSA < 1.5 ng/mL using the cut-offs of phi: ≥ 52.7 and 4KScore ≥ 20%. 0% of patients with a PSA <1.5 ng/mL had positive phi and/or SelectMDx results. 1/80 patients had a positive 4KScore test result. • Out of 601 men, a total of 208 men had a PSA < 1.5 and were screened with PCMs to evaluate their risk of having high grade prostate cancer

Test Results of PCMs for Patients with PSA < 1.5 ng/mL

Year PCM Performed

Number of

Patients

Median Age

(range)

mean PCM ± STD (range)

Abnormal Test

Results (%)

Abnormal Test Results

(%)*

2012 Phi 58 62 (40 - 86)

25.3 ± 6.28 (8.5-41.6)

0/58 (0%)

28/58

(48.3%)

2015 4KScore 76 63

(35-85)

4.9 ± 4.06% (1-27%)

1/76 (1.3%)

13/76

(17.1%)

2016 SelectMDx 74 66

(27-80)

0.00

0/74 (0%)

0/74 (0%)

phi 4KScore SelectMDx

37

Cost-Effec4venessofSelectMDxinProstateCancerRiskAssessment SelectMDxcomparedtotheStandardofCare

•  Journal of Urology, 2018 in press

§  TheexpectedmeanQALYperpa4entunderthecurrentstandardwas10.796atacostof$11,060overan18-yearhorizon.Incorpora4ng

§  SelectMDxresultedinexpectedmeanQALYperpa4entandcosttobe10.841and$9,366,respec4vely,represen4nganaverage0.045QALYgainedatacost-savingsof$1,694perpa4ent.

§  Extrapola4ngthesedatatoaconserva4vees4mateof311,879menperyearundergoingbiopsy,onewouldexpectSelectMDxtoresultinanincremental14,035QALYgainedatacost-savingsof$528,323,026foreachyearlycohort.

§  TheSelectMDxstrategydominatedthecurrentstandardacrossawiderangeofsensi4vityanalyses.

Gleason 6 Active Surveillance

The Goal in 2018

What PCM helps us identify patient harboring high risk

cancers?

FamilyPrac44oner Urologist

RouUneLab/PSA

PSA<1.5RepeatPSA5years

PSA>1.5

phi4K

SELECTMDx

LowRisk

HighRisk

TRUSBx

ConsiderreferraltoUrologist

Copyright:E.D.Crawford,2017

Sharedcare

Transperineal Mapping Prostate Biopsy

ProView/3D Staging Biopsy Slides

June 15, 2017 Patient: GE MRN: 571….

62yoPSA1.8to3.9over3years

Pa4entGEMRN5

TRUS 12 cores negative CONFIRM MDx 3 gene

methylated

mpMRI no PIRADS 3-5 lesions

Staging Biopsy Gleason Summary

•  Gleason 3+3=6 in 2 out of 87 cores on the left (depicted in orange)

•  Gleason 3+4=7 in 2 out of 87 cores on on the right (depicted in blue)

•  Gleason 4+3=7 in 2 out of 87 cores bilateral (depicted in dark red)

•  Gleason 4+4=8 in 1 out of 87 cores on on the right (depicted in green)

Capsule & Biopsy Probes/Volumes

Top View of Prostate

How do false-negative biopsies happen? •  Challenges With Current Methods

Current challenges §  SOC: 12 core TRUS guided biopsy

§  The needle may miss the cancer

§  Pathologists can only interpret what is on the slide

A biopsy procedure samples less than 1% of the entire gland

1.AmericanUrologicalAssocia4onwebsite.Op4malTechniquesofProstateBiopsyandSpecimenHandling.Availableat:hip://www.auanet.org.AccessedMarch13,2018.2.ShenF,etal.JUltrasoundMed.2008;27(6):895-905.

Biopsy

Cancer

Field Effect

Testing can detect an epigenetic field effect associated with the presence of cancer at the

DNA level

HenriqueR,etal.MolCancerRes.2006;4(1):1-8.

49

Methylation Negative

Methylation Positive

Low Risk Active Follow Up

Negative Prostate Biopsy

High Risk Repeat Biopsy

Routine Screening

Risk Profile

Personalized Risk Assessment

Patient Profile: Men being considered for repeat prostate biopsy

VanNesteL,etal.Prostate.2016;76(12):1078-1087.

DNA-methyla4ontes4ng

50

ConfirmMDx Positive Results

§  Personalized risk assessment for likelihood of harboring aggressive cancer

§  Men who benefit from MRI/biopsy and early detection

©2016 All rights reserved

ConfirmMDx Positive

51

ConfirmMDx Negative

•  Routine screening by PSA & DRE •  Results valid 24-30 months from previous biopsy

96% NPV for “significant” PCa 90% NPV for all PCa

Partin AW et al. (2014). J Urol. Stewart GD et al. (2013). J Urol

Conclusions

•  PSA 1.5 ng/ml is a reasonable cut point-nothing is perfect

•  PSA 1.5 ng/ml is simple for FP to remember

•  In general, informed Decision should happen after test abnormal

•  PSA 1.5-4 ng/ml is a grey zone: BPH, Ca P, prostatitis

•  Clinical evaluation and Genomic markers help determine whom to biopsy.

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Patient/Physician Website

www.pcmarkers.com

53

Guidingyouthroughtheneweststateoftheartprostatecancerdiagnos4candprognos4ctests

Make Genomics/PSA Great Again

54

Thank you

55

A�disruptive technology�is one that displaces an established�technology�and shakes up the industry or a ground-breaking product that creates a completely new industry. Harvard Business School professor Clayton M. Christensen coined the term�disruptive

technology.

•  Internet •  Artificial Intelligence •  Space Colonization •  3D Printing •  Medical Innovations gene editing DNA testing CRISPR ESWL Robots CT MRI NGI EMRs

•  High Speed Travel •  Robotics •  Blockchain

Technology •  Autonomous

Vehicles •  Advanced Virtual

Reality •  Renewable Energy

My focus will be primarily on Prostate as relates to or influences biopsies

•  PSA •  Prostate Biopsy •  Prostate Imaging •  Prostate Genomics •  Prostate Treatment Modalities •  Prostate Health

Transperineal Mapping Prostate Biopsy

Avariableneedle15-60mmcores-IsthisDisrupUve?

-----------------

3DBiopsy™ - The Next Dimension

60

§  A large number of biopsy cores are taken during mapping biopsy

–  80-120 biopsy cores

§  Biopsy needle deflection errors

–  Inaccurate localization of lesions

–  Some cancer lesions may be outside of the treatment zone

§  Lack necessary software for needle tracking and targeted focal therapy

ClariCore™ Optical Biopsy System

61

§  Shortcomings of Prostate biopsies

§  Over 90% of the biopsy cores are normal or negative cores

§  Some high risk cancers are missed

§  Pressure on pathology reimbursement

§  Increasing trend toward placing more patients under watchful-waiting or active surveillance in case of low grade disease

LUMEA AI Diagnostics: 6 cores in seconds

•  BxLink (LIS) AI

ShearletAlgorithm

LesionSegmenta4onROIRadiologist

WeCanImproveMRIUsingShearlets

63

§  Reduceinterobservervariabili4es§  Diagnoseallimportantcancers§  Cost-effec4ve(reduce4me)

Micro-Ultrasound vs. Conventional Ultrasound •  Novel micro-ultrasound system

operating at 29 MHz

•  Much higher than conventional 6-9MHz

systems

•  300% improvement in resolution – both axial and lateral – down to 70 microns

•  Enables real-time targeting of biopsies

•  Commercial version with clinical approvals (CE, FDA, Health Canada) is available now

Exact Imaging’s ExactVu™ 29 MHz Micro-Ultrasound System

Micro-Ultrasound: When it makes a difference Hard to see Isoechoic lesions

Pathology results: Gleason 7

Pathology results: Gleason 7

Pathology results: Gleason 7

Tissues with slightly different echogenicities that have

distinct and irregular borders

Normal inflammation around capsule causing hypoechoic

area? No, scalloped edges are suspicious

Over 100 years old Infections

Disruptive Technology. NGS

In my opinion the most disruptive technology in Urology /Medicine is EPIC & other EMRs-LATER