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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,[email protected]
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 [email protected].
*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.
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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
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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
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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
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Guidingyouthroughtheneweststateoftheartprostatecancerdiagnos4candprognos4ctests
Make Genomics/PSA Great Again
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Thank you
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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
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§ 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
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§ 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
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§ 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