Disrup've Technologies Construc've or Destruc've ? Focus on Prostate Biopsies and what drives them and results

3DbiopsyClaricoreShearletMDxHealth

COI

A disrup've 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 disrup've technology.

•  Internet• Ar:ficialIntelligence•  SpaceColoniza:on•  3DPrin:ng• MedicalInnova:onsgeneedi:ngDNAtes:ngCRISPRESWLRobotsCTMRINGIEMRs

• HighSpeedTravel• Robo:cs• BlockchainTechnology• AutonomousVehicles• AdvancedVirtualReality• RenewableEnergy

Disrup6ve

Construc6ve Destruc6ve

Moststartoutasconstruc:vebutsomeendupdestruc:ve

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

My focus will be primarily on Prostate as relates to or influences biopsies • PSA• ProstateBiopsy• ProstateImaging• ProstateGenomics• ProstateTreatmentModali:es• ProstateHealth

PSA Disrup've Technology Construc've to Disrup've and back to Construc've

• CONSTRUCTIVE:

• Breakthroughmarker• Heraldedasthemostimportanttumormarkerinoncology• UnprecedentedinMonitoringofDisease•  Inexpensive,availableinminutes•  Earlydetec:on–PrevalenceversusIncidence

PSA Destruc've

• Pa:entS:mulatedAnxiety• PhysicianStressAmplifier• Overdiagnosisleadingtoovertreatment•  Isoforms• AQempttomakeitsignaloutwhomtobiopsy

History and Direc'on: PSA Based Screening

Flying High

Worlds shortest vaca'on: USPSTF

Drecommenda:on•  DoNotOrder•  SharedDecisionMaking

Crecommenda:on(May2018)

Can we make PSA Construc've in 2018

• YES

Familyprac:cephysiciansareconfusedbyourmessageTheyorder

90%ofPSA

•  Cutoffsof2.5and4•  PSAvelocity•  PSAdensity•  AgeSpecificPSA• %freePSA•  ComplexPSA•  phi•  PCA3•  SelectMDx•  4K•  HELP!

Is there a simple cut-off andPSA level that is “safe?” YES

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19-foldIncreaseinriskforAfricanAmericans

12%

8%

6%

4%

2%

0%Percen

tdevelop

ingprostatecan

cer

0.51%

7.85%

15-foldIncreaseinrisk

Percen

tdevelop

ingprostatecan

cer10.39%

ROCCurveforAllPa:entsPSA<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

Es:matedAreaC=0.87251

Maximumsensi:vityandspecificityatPSA1.5ng/mL

OverallStudyPopula:on(21,500)

10%

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

5-yearDiagnosisRate

>1.5to4isa“dangerzone”

Pa:entsandMethods:•  350,000HMO-HenryFord

System•  Meninsystem1997-2008•  Ini:alPSAbetween1-5ng/ml•  Minimum5yearsfollow-up•  No5ARIs

Results:•  Meanage55years•  MeanPSA1.0•  AfricanAmerican:29%•  DetectedCancer:2%

Surrogatefor:1.   BPH-mostcommon

2.   ProstateCancer ProstateHealth3.   LongtermPCarisk

4.   Evaluate-Don’tBiopsyeveryonewith>1.5ng/ml!!!!5.   UsePCMstohelpdeterminewhomtobiopsy

AWayForward:PSA>1.5-4ng/mL

73%<1.5NG/ML

PSA alone to guide prostate biopsy decisions: END Risk Stratification for Clinically Significant Pca ANOTHER DISRUPTIVE TECHNOLOGY

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

FamilyPrac::oner Urologist

Rou6neLab/PSA

PSA<1.5RepeatPSA5years

PSA>1.5

phi4K

SELECTMDx

LowRisk

HighRisk

TRUSBx

ConsiderreferraltoUrologist

Copyright:E.D.Crawford,2017

Sharedcare

Pa'ent/Physician Website

www.pcmarkers.com

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Guidingyouthroughtheneweststateoftheartprostatecancerdiagnos:candprognos:ctests

Make Genomics/PSA Great Again

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Focus will be primarily on Prostate

• PSA• ProstateBiopsy• ProstateImaging• ProstateGenomics• ProstateTreatmentModalites• Prostate

Prostate Biopsies: Long History

• VimSilvermanJAMA,1954• Menghini’sAspira:onNeedle•  Tru-cut•  FineNeedleAspira:on-justwhenpeaking• Ultrasound• AandBmodes• BK–introduc:on• BillCoonerandFredLee•  Themostdangerousweapontoday:AUrologistandBiop6cGun

US Guided Prostate Biopsy-Disrup've Technology •  “Transrectalultrasoundinthediagnosis,staging,guidedneedlebiopsy,andscreeningforprostatecancer”.LeeF.ProgClinBiolRes.1987;237:73-109

•  “Transperinealprosta:cbiopsyguidedbytransrectalultrasonography”.VallancienG,LeoJP,BrissetJM.ProgClinBiolRes.1987;243B:25-7

30 year old technology

Prostate Biopsy- Destruc've

•  1.2M:mesperyear(3.4Mworldwide)•  180,000newcasesprostatecancer•  TRUS:95%

•  Officeprocedure

•  TPMB5%•  ORprocedure

Biopsy Procedures Outlook to 2020, Global Data, July 2014.

End-fire be[er than side-fire: Construc've Technology

Bjurlin et al. Urol Clin North Am 14: 299, 2014.

20-60%increaseddetec:onrate

3D Biopsy Mapping is this Disrup've Technology ?

Transperineal Mapping Prostate Biopsy

Avariableneedle15-60mmcores-IsthisDisrup6ve?

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

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

3DBiopsy: Disrup've Technology

1. Variable Length Actuator and Needle:

Ø to replace existing biopsy devices-20M procedures/yr.

Ø First target market-prostate cancer (3.4M proc./yr.)

2. Integrated 4 Component System:

Ø To become the new standard of care for prostate cancer diagnosis and management

Ø Applicable to other organs such as breast, lung, liver

3. Integrated Pathology System:

Ø Revolutionary specimen management system

Ø Can be used for all tissue biopsies (>50M proc./yr.)

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ClariCore™ Op'cal 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

•  Started December 2015 at University of Colorado Hospital, Aurora, CO (PI: Dr. Crawford)

•  Other Participating Centers: •  Johns Hopkins University, Baltimore, MD (PI: Dr. Partin) •  Memorial Sloan-Kettering Cancer Center, New York, NY (PI: Dr. Eastham) •  The Urology Center of Colorado (TUCC), Denver, CO (PI: Dr. Karsh) •  Grand Strand Urology, Myrtle Beach, SC (PI: Dr. Shore)

•  Phase I study completed in April 2017

•  Number of patients enrolled: 200

Mul'center Phase I Clinical Trial for ClariCore™ System

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Update TRUS Data

AlgorithmPerformanceMeasures %(95%ConfidenceInterval)

Sensi6vity 85.95%(80.09–90.61%)

Specificity 87.98%(85.76–89.95%)

Nega6vePredic6veValue 97.05%(95.84–97.92%)

Posi6vePredic6veValue 57.61%(53.15–61.93%)

AreaUnderCurve 0.87(0.85–0.89)

Table 1. Diagnostic performance of the developed classification algorithm.

LUMEA Disrup've Technology

•  Transformingpathologyfordigitalage•  Integratedmachinelearningtools•  Lowerlabcostandimprovequality

LUMEA Specimen Handling

• BxBoard• GrossExamAI• BxChip

LUMEA AI Diagnos'cs: 6 cores in seconds

• BxLink(LIS)

AI

Focus will be primarily on Prostate

• PSA• ProstateBiopsy• ProstateImaging• ProstateGenomics• ProstateTreatmentModalites• Prostate

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MRI Definitely Disrup've But

§  Some potentially important cancers (15%-30%) conceal to MRI

–  1 out 5 patients with Gleason Score ≥ 7 cancer missed

§  Cost-effectiveness yet to be resolved

§  Technology remain in evolution

§  Interobserver variability between radiologists

§  Do you really need fusion biopsies or are cognitive just as good

Kasivisvanathan V et al. N Engl J Med 2018;378:1767-1777

Summary of Key Results in 612 Patients – Predictors of Detection

Significantpredictorsofdetec:on(univariate)•  Largersize•  HigherGS•  Indexlesionstatus•  Solitarytumor

RobReiter,MDFDUS8.18

PROMIS Trial: Challenges

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1.   UK cohort is “symptomatic” - May harbor large lesions (≥ 0.5cc) easily visible on mpMRI whereas US cohort is largely “asymptomatic” and may harbor smaller clinically significant (CS) lesions (≤ 0.5cc)

2.   Success/Failure based on a single PIRADS Lesion per Patient – Disease is multifocal and there can be more than one clinically significant (CS) lesion based on histopathology data

3.   Absence of Lesion-Level Analysis – Unclear whether mpMRI diagnosed all of the CS significant lesions based on histopathology as opposed one CS lesion per patient

4.   Anterior versus Posterior Lesions – TRUS biopsies miss anterior lesions. Need a comparison (sensitivity) of mpMRI and TRUS biopsy for posterior lesions

5.   Lack “concordance” and “discordance” information of PIRADS lesions and Histopathology – Unclear how this was done unless PIRADS lesions and corresponding cancer lesions are large (“symptomatic”) and quite obvious

ShearletAlgorithm

LesionSegmenta:onROIRadiologist

We Can Improve MRI Using Shearlets

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§  Reduceinterobservervariabili:es§  Diagnoseallimportantcancers§  Cost-effec:ve(reduce:me)

GleasonScore7and8tumors>0.5cc

UCH Study: mpMRI miss CS tumors

47pa:entshadmappingbiopsyaqerMRI34hadclinicallysignificantcancer

MRImissed6/34(18%)pa:entswithCScancer(table)

MRImissed10/25(40%)tumorswithGleasonScore≥7and27/60(45%)CScancer(table)

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•  Some potentially important cancers are MRI-invisible

•  Cost-effectiveness is yet to be resolved

•  High “interobserver variability” between radiologists

Indication to Biopsy by PIRADSv2 ≥ 3 Patient Level Lesion Level N = 47 (CS=34) N =122 (CS=60)

Sensitivity 82% 55% Specificity 54% 74% PPV 82% 67% NPV 54% (87%*) 63%

Somepa:entsmayharbormorethanoneCSlesion(figure)

Promising Preliminary Results Disrup've Technology

Classification Results for Malignant vs Benign ROIs Patient # Parameter Sensitivity Specificity Classification

Rate

1 ADC 100% 100% 100% DCE 100% 100% 100% T2W 60% 100% 80%

2 ADC 100% 100% 100% DCE 100% 100% 100% T2W 80% 60% 70%

3 ADC 100% 100% 100% DCE 100% 100% 100% T2W 100% 60% 80%

4 ADC 80% 100% 90% DCE 100% 100% 100% T2W 100% 100% 100%

Overall ADC 89% 100% 97% DCE 100% 100% 100% T2W 92% 83% 94%

§  Overallhighsensi:vityandspecificity§  Iden:fymalignantregionswithhighdegreeofaccuracy

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MRI and US image fusion

• Defini:onoffusion“Imagefusionistheprocessofcombiningrelevantinforma:onfromtwoormoreimagestoprovideamoreinforma:veimagethanthe

originalinputimages”1

Haghighat, MA et al Comp and electrical engineering 2011

Theore'cal Advantages/disadvantages of MR/TRUS Fusion Advantages•  ImprovedYield•  FewerTotalbiopsies•  BeQeraccuracy•  Addconfidencetodiagnosis(espforac:vesurveillance)

Disadvantages•  Increasedcost•  Maydiagnosemoreirrelevantcancers•  Maytaketheimageguidanceofprostatecanceroutofthespecialist’shands

Available Plaborms approved by FDA

• UroNav•  Invivo

•  Gainsville,FL

• Urosta:on•  Koelis

•  LaTronche,France

• ArtemiswithProfusetm

•  Eigen•  GrassValley,CA

mpMRI is clearly disrup've-

•  1.Thejuryiss:llout•  2.Noques:onthatdetectshighgradelesions,Butatwhatcostbothfinanciallyandclinically

•  3.Genomicsmarkersareimportanthavenotbeenevaluated•  4.InhandsoflessexperiencedfusionbiopsiesbeQer,butnotinthehandsofaseasonedultrasonograher

• MpMRIwillbedisrup:veandbacktoconstruc:ve

Next Disruptive Technology: Micro-Ultrasound?

•  Systematic biopsies do not find enough cancer; false negative rates are too high

•  Some looking to dramatic shifts in care such as MRI/US-Fusion which requires multiple specialists, expensive equipment and much longer procedure times

•  Need a better ultrasound-based system to: •  Better visualize cancer -- and target suspicious regions during the biopsy procedure •  Improve the accuracy of ultrasound’s systematic sampling • Maintain the benefits of ultrasound – affordable, real-time,

known modality, standard of care

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

Micro-Ultrasound vs. MRI/Ultrasound Fusion

Micro-Ultrasound •  Real-time visualization,

real-time targeting •  Its ultrasound - - just much higher-

resolution (300%) ultrasound •  Just a few more minutes to perform

evidence-based PRI-MUS™ to identify and target suspicious regions

•  One urology-based visit

MRI/US Fusion •  Significant learning curve

(for urologists and for radiologists) •  ~40 minutes for MR scan

+ Read and score MR image with PI-RADS + fuse image with u/s + perform targeted biopsy + re-configure if any patient movement

•  Complex workflow •  Multiple patient visits •  Costly without additional

reimbursement codes •  High variability of results (expertise @ site,

radiologist, MR instrument, sequences)

Over 100 years old Infections

Disruptive Technology. NGS

Focus will be primarily on Prostate

• PSA• ProstateBiopsy• ProstateImaging

• ProstateGenomics• ProstateTreatmentModali:es• Prostate

Fox Hunt

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PCM Buckets

Ini6alBiopsy:Iden6fy

SignificantPCa

SelectMDx

phi

4kscore

Nega6veBiopsy:WhomtoRebiopsy

ConfirmMDx

SelectMDx

phi

4kscore

WhomtoofferGene6cTes6ng:

AmbryGene:cs

MyriadGene:cs

GeneDx

Invitae

WhotoofferInterven6onal

TherapyvsAc6veSurveillance

OncotypeDx

Prolaris

Decipher

Promark

Whomtotreatornottreatpost-prostatectomy:

Prolaris

Decipher

Focus will be primarily on Prostate

• PSA• ProstateBiopsy• ProstateImaging• ProstateGenomics• ProstateTreatmentModali6es• Prostate

Willet Whitmore, MSKCC 1963-1986

•  Istreatmentsufficientforthoseinwhomitisnecessary,andnecessaryforthoseinwhomitissufficient?

• Morepeoplemakealivingfromprostatecancerthandieofprostatecancer

•  20thcentury‘seekanddestroy’•  21stcentury‘targetandcontrol’

•  A.VonEschenbach•  Director,NCI

Goals for targeted abla'on

•  Iden:fythelesion–specificityandsensi:vity?•  US,MRI,3Dmapping,targetedbiopsy

•  AccurateStaging–whatishappingoutsidetheprostate?

•  BonescanandCATscan.roleforisotopes•  Guidance

•  localiza:on-canwegetthere?•  Precision•  Reproducibility–canwegothereagain

• Monitoring–weneedtoablateonlythetargetandminimizecollateraldamage

TFT Abla'on techniques: Disrup've Technology

• Photodynamictherapy• HIFU•  Focallaser•  FocalCryotherapy•  Electropora:on• ACabla:on

My Opinion

•  Idon’tbelieveinfocaltherapywhichascurrentlyprac:cedisrandomanddangerous.

•  IdobelieveinTargetedFocalTherapyformenwithhigherriskcancerbasedon3Dmappingbiopsies,notsatura:onormpMRI

•  IdobelievethatmostcasesofFTareperformedinlowriskpa6entswhoshouldbeofferedASorbeQeryetnotdiagnosed

•  IdobelievethatweshouldeliminateASandfindingmostGS6cancers

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

EMRs construc(ve becomes destruc(ve

• Whodotheyserve?•  pa:ents•  Hospitals•  Payers•  Lookatyourparagraphnotesofadecadeagoandcompareto4pagesofcutandpaste,templatesandworthlessinforma:onforurologists!

•  ButTherearelotsofadvantages:medsreview,druginterac:onandtripstoradiologytofindfilms

•  Likemanythingsagoodthingbecomesencumberedandsteepedinbureaucracyandhiddenagendas.Weneedtotakecontrolandreturnbalance

Who is benefi'ng ? 76% hike in prices , 7 years

An'trust lawsuit!

And finally the most Disrup've Technology

•  Thishascreateda“gene:c”muta:oninhumans• Changinghowwecommunicate,learn,andbehave•  Thisandcomputershaveputusoncall24/7• PhysicianBurnout-EMR-Mobilephones

Mobile phones

The way we communicate !