Educational Presentation Educational Presentation to the ECCCto the ECCC

OralCDxOralCDx Brush Biopsy Brush Biopsy --Technique and IndicationsTechnique and Indications

Mark RutenbergCEO & Founder, CDx Laboratories

March 6, 2008

Whatever happened to cervical cancer?Whatever happened to cervical cancer?

In 1950, cervical cancer was the leading cause of cancer death in American women.

Between 1955 and 1992, cervical cancer incidence fell from 1st to 14th place.

Dysplasia Cancer

Basement Membrane

As in the cervix, if oral dysplasia is found and removed before the basement membrane is penetrated, then oral cancer can never get started.

Years LaterYears Later

Cervical cancer was conquered because we found a way to tell which women had cervical dysplasia –years before cervical cancer could even start.

The DentistThe Dentist’’s Dilemmas Dilemma

The ProblemThe Problem

About 10% of adult patients have small oral spotsAbout 10% of adult patients have small oral spots> 96% if these spots do not contain abnormal cells> 96% if these spots do not contain abnormal cellsOnly laboratory testing can determine that a spot is Only laboratory testing can determine that a spot is not dysplastic. not dysplastic. CanCan’’t subject 10% of all patients to a scalpel biopsy t subject 10% of all patients to a scalpel biopsy to find the small number of them that have a to find the small number of them that have a dysplastic spot. dysplastic spot.

The DentistThe Dentist’’s Dilemmas Dilemma

The ResultThe Result

Harmless appearing precancerous oral spots are Harmless appearing precancerous oral spots are often allowed to progress until they look often allowed to progress until they look ““suspicioussuspicious””By that time they are typically oral cancers. By that time they are typically oral cancers.

OralCDx BrushTestOralCDx BrushTest™™TThe Solution to the Dentisthe Solution to the Dentist’’s Dilemma s Dilemma

A routine test of the small, harmlessA routine test of the small, harmless--appearing, white appearing, white and red tissue spots that appear in about 10% of your and red tissue spots that appear in about 10% of your patients patients

Used to determine which 4% of these common spots Used to determine which 4% of these common spots contain unhealthy cells (dysplasia).contain unhealthy cells (dysplasia).

OralCDx detects dysplasia long before it can penetrate OralCDx detects dysplasia long before it can penetrate the basement membrane and cause any harm the basement membrane and cause any harm –– years years before it can develop into an oral cancer before it can develop into an oral cancer

OralCDx BrushTestOralCDx BrushTest™™TThe Solution to the Dentisthe Solution to the Dentist’’s Dilemmas Dilemma

OralCDx is not intended to test OralCDx is not intended to test ““suspicioussuspicious”” oral oral lesions. These should continue to be sent to the lesions. These should continue to be sent to the oral surgeon for a scalpel biopsy.oral surgeon for a scalpel biopsy.

OralCDx is intended to test OralCDx is intended to test ““everydayeveryday”” oral spots oral spots to detect the 4% of them which may contain still to detect the 4% of them which may contain still harmless dysplasia harmless dysplasia -- years before a suspicious years before a suspicious lesion can form. lesion can form.

Brush Biopsy IndicationsBrush Biopsy Indications

White or red spots, chronic ulcerations, mucosal White or red spots, chronic ulcerations, mucosal lesions with an abnormal epithelial surfacelesions with an abnormal epithelial surface

Common, small, benignCommon, small, benign-- looking abnormalities looking abnormalities that have been routinely that have been routinely ““watchedwatched”” and not and not suspicious enough to warrant referral for biopsysuspicious enough to warrant referral for biopsy

Brush Biopsy ContraindicationsBrush Biopsy Contraindications

Lesions with intact normal epitheliumLesions with intact normal epitheliumfibromas, mucoceles, hemangiomas, submucosal fibromas, mucoceles, hemangiomas, submucosal masses, pigmented lesionsmasses, pigmented lesionshighly suspicious lesions (immediate scalpel biopsy)highly suspicious lesions (immediate scalpel biopsy)lesions with obvious etiology: herpes, aphthous lesions with obvious etiology: herpes, aphthous ulcerations, traumaulcerations, trauma

What to Expect in What to Expect in Your PracticeYour Practice

Known benign entities

Highly suspicious lesions

Harmless appearing, white or red spots of

unknown origin

fibromas, mucoceles, linea alba, Fordyce granules, aphthous ulcers, traumatic

ulcers, herpes labialis, amalgam

tattoos

Several times each

day

Once or twice each yearSeveral times a week

Presentation

Frequency in average practice

Action Observe or treat

BrushTest Scalpel biopsy

““Small oral spots are very common. We see Small oral spots are very common. We see them in about 10% of our patientsthem in about 10% of our patients””..

““We BrushTest common oral spots because We BrushTest common oral spots because they sometimes contain unhealthy cells that they sometimes contain unhealthy cells that may eventually become oral cancer if left may eventually become oral cancer if left untreateduntreated””. .

““Even if a spot is found by the BrushTest to Even if a spot is found by the BrushTest to contain unhealthy cells contain unhealthy cells that is nothing to worry that is nothing to worry aboutabout as it is typically still harmless. It can then as it is typically still harmless. It can then be easily removed and we will have prevented be easily removed and we will have prevented a problem a problem -- years before it can even startyears before it can even start””..

Proper Patient Communication is KeyProper Patient Communication is Key

OralCDx TestingOralCDx Testing

Two ComponentsTwo ComponentsOffice Office ProcedureProcedure-- OralCDx OralCDx BrushTestBrushTestLaboratory AnalysisLaboratory Analysis -- ComputerComputer--assisted inspection specifically assisted inspection specifically designed for oral dysplasia.designed for oral dysplasia.

The OralCDx Test KitThe OralCDx Test Kit

Components of kits: Components of kits: oral BrushTest instrument oral BrushTest instrument precoded glass slide and precoded glass slide and matching coded test matching coded test requisition formrequisition formalcohol/carbowax fixative alcohol/carbowax fixative pouchpouchcontainer for submitting the container for submitting the contentscontents

OralCDx BrushTestOralCDx BrushTestBrush is sterileBrush is sterileTwo cutting surfacesTwo cutting surfacesCytology instruments collect only Cytology instruments collect only superficial cells. Brush biopsy superficial cells. Brush biopsy collects cells from all three collects cells from all three epithelial layers: superficial, epithelial layers: superficial, intermediate and basalintermediate and basal

Exfoliative Oral CytologyExfoliative Oral Cytology

Banoczy; Banoczy; Int Dent JInt Dent J: 1976: 1976False negative rate for leukoplakia: 69%False negative rate for leukoplakia: 69%

Folsom et al. 1972 Folsom et al. 1972 Oral SurgeryOral SurgeryFalse negative rate for oral cancer: 31%False negative rate for oral cancer: 31%

Cytology is not an acceptable or reliableCytology is not an acceptable or reliablemethod of evaluating oral lesions formethod of evaluating oral lesions forprecancer and cancerprecancer and cancer

Guidelines for AnesthesiaGuidelines for Anesthesia

Causes minimal or no bleeding or pain Causes minimal or no bleeding or pain Topical or local anesthesia is generally not Topical or local anesthesia is generally not requiredrequiredFor highly inflamed or ulcerated lesions, local or For highly inflamed or ulcerated lesions, local or topical anesthesia may be usedtopical anesthesia may be used

Topical anesthesia Topical anesthesia gels, sprays and creams OKgels, sprays and creams OKointments should not be usedointments should not be used

Brush Biopsy TechniqueBrush Biopsy TechniqueReviewReview

The flat surface should be used in most cases. The flat surface should be used in most cases. Apply firm pressure against the lesion Apply firm pressure against the lesion -- you you should see a slight bend in the brushshould see a slight bend in the brushRotate clockwise 10 times or moreRotate clockwise 10 times or morePink tissue or microbleeding indicates that the Pink tissue or microbleeding indicates that the brush has penetrated to the basement brush has penetrated to the basement membranemembrane

If lesion bleeds, stop brushing and transfer material If lesion bleeds, stop brushing and transfer material to slideto slide

Tips for Performing a Brush BiopsyTips for Performing a Brush BiopsyFor For thick,white spotsthick,white spots andandFor spots on the For spots on the hard palate hard palate and gingivaand gingiva

rotate very firmly and rotate very firmly and repeatedly over the center and repeatedly over the center and periphery of the lesion. May periphery of the lesion. May require 15 or 20 rotationsrequire 15 or 20 rotations

For UlcerationsFor Ulcerationssample only the periphery and sample only the periphery and not the center of the ulcernot the center of the ulcer

The Brush Biopsy TechniqueThe Brush Biopsy Technique

Transfer CellsTransfer Cells

Evenly spread the Evenly spread the specimen over the specimen over the

entire slide entire slide –– bar bar code facing upcode facing up

Hold the slide up to a light – ensure the cellular material is visible on the slide

The Brush Biopsy TechniqueThe Brush Biopsy Technique

Apply FixativeApply Fixative

…… by flooding slide with by flooding slide with liquidliquid

Complete paperworkComplete paperworkplace slide and slide holder place slide and slide holder

into mailer into mailer

Full instructions included in each OralCDx test kit

Analysis of OralCDx SpecimensAnalysis of OralCDx Specimens

Analysis is aided with a Analysis is aided with a highly specialized neural highly specialized neural networknetwork--based image based image processing system specifically processing system specifically designed to detect even the designed to detect even the fewest oral precancerous and fewest oral precancerous and cancerous cells scattered cancerous cells scattered among thousands of normal among thousands of normal cellscells

The OralCDx ComputerThe OralCDx Computer

Originally developed for missile defenseOriginally developed for missile defenseEvery brush biopsy specimen is analyzed for:Every brush biopsy specimen is analyzed for:

Abnormal cellular morphologyAbnormal cellular morphologySignature spectral abnormality of the Signature spectral abnormality of the keratin proteinkeratin proteinCytometric evaluation of nuclear DNA Cytometric evaluation of nuclear DNA contentcontent

OralCDx InterpretationOralCDx Interpretation

OralCDx computer does OralCDx computer does not make the diagnosisnot make the diagnosisOralCDx computer assists OralCDx computer assists in the search for in the search for precancerous and precancerous and cancerous cellscancerous cellsPathologist utilizes both Pathologist utilizes both computer and standard computer and standard microscopic evaluationmicroscopic evaluation

1 / 1000th of a slide1 / 1000th of a slide

CDx Laboratories

OralCDx ResultOralCDx Result““NegativeNegative””

““NegativeNegative”” --no cellularno cellularabnormalities abnormalities

All OralCDx All OralCDx ““negativenegative””lesions require lesions require the same the same careful clinical careful clinical followfollow--up as up as ““negativenegative””histologically histologically sampled lesionssampled lesions

OralCDx ResultOralCDx Result““PositivePositive””

““PositivePositive”” ––definitive cellulardefinitive cellularevidence ofevidence ofepithelialepithelialdysplasia ordysplasia orcarcinomacarcinoma

Almost every Almost every ““positivepositive”” lesion lesion will prove to be will prove to be dysplasia or dysplasia or carcinomacarcinoma

Scalpel biopsy to provide additional information regarding the nature and degree of the abnormality detected with OralCDx

OralCDx ResultOralCDx Result““AtypicalAtypical””

““AtypicalAtypical”” --

abnormalabnormal

cellular changescellular changes

The probability The probability that a patient that a patient with an with an ““atypicalatypical”” report report has a precancer has a precancer is is ~~ 440% 0%

The OralCDx laboratory can provide you with specific guidance on how to follow-up each “atypical” report.

Reports Reports are faxed are faxed and and mailedmailed

““positivepositive””and and ““atypicalatypical””reports reports include include images of images of abnormal abnormal cells foundcells found

OralCDx BrushTestOralCDx BrushTest

If you did not obtain a complete transepithelial If you did not obtain a complete transepithelial sample sample –– it is safe for you and the patient it is safe for you and the patient –– the the lab will notify you that the sample was lab will notify you that the sample was ““partialpartial””and needs to be repeated. and needs to be repeated. You will receive a You will receive a ““negativenegative”” report only if the report only if the sample was complete. sample was complete.

OralCDx MULTICENTER OralCDx MULTICENTER U.S. TRIALU.S. TRIAL

Participants: Oral Medicine, Oral Participants: Oral Medicine, Oral Pathology and Oral Surgery Departments Pathology and Oral Surgery Departments at 35 major U.S. Academic Dental at 35 major U.S. Academic Dental CentersCenters945 patients enrolled945 patients enrolledResults were presented as the cover article Results were presented as the cover article of the of the Journal of the American Dental Journal of the American Dental Association (JADA)Association (JADA) OctoberOctober, 1999, 1999

U.S. Multicenter Clinical Trial U.S. Multicenter Clinical Trial --Sensitivity DataSensitivity Data

If an oral lesion would be found to be precancerous or If an oral lesion would be found to be precancerous or cancerous using scalpel biopsy and histology, would it cancerous using scalpel biopsy and histology, would it also be detected using CDx?also be detected using CDx?CDx CDx correctly detected every lesioncorrectly detected every lesion diagnosed as diagnosed as precancer or cancer using scalpel biopsy and histology precancer or cancer using scalpel biopsy and histology (n=131)(n=131)Measured False Negative Rate = 0% Measured False Negative Rate = 0% Statistical Sensitivity > 96% p<.05Statistical Sensitivity > 96% p<.05

U.S. Multicenter Clinical Trial U.S. Multicenter Clinical Trial --SpecificitySpecificity DataData

What is the What is the probability that a lesion which is not probability that a lesion which is not dysplastic or cancerous will dysplastic or cancerous will notnot have an abnormal have an abnormal OralCDx result?OralCDx result?100% (196/196) for 100% (196/196) for ““positivepositive”” CDx resultsCDx results92.9% (182/196) for 92.9% (182/196) for ““atypicalatypical”” CDx resultsCDx resultsStatistical Specificity for a CDx Statistical Specificity for a CDx ““positivepositive”” > 97%, > 97%, p < .05p < .05Statistical Specificity for a CDx Statistical Specificity for a CDx ““atypicalatypical”” > 90%, > 90%, p < .05p < .05

OralCDx Positive Predictive OralCDx Positive Predictive ValueValue

Probability that a patient with an abnormal Probability that a patient with an abnormal OralCDx result will be OralCDx result will be ““positivepositive”” by scalpel by scalpel biopsybiopsy

The PPV of an abnormal OralCDx result is 2The PPV of an abnormal OralCDx result is 2--16X higher that of an abnormal mammogram 16X higher that of an abnormal mammogram or atypical Pap smear.or atypical Pap smear.

Scalpel BiopsyScalpel BiopsyScalpel biopsy Scalpel biopsy –– invasiveinvasive

and associated withand associated with

morbiditymorbidityReserved for highly suspicious Reserved for highly suspicious lesions that may be cancerlesions that may be cancerInfrequent: several times yearlyInfrequent: several times yearly

Not for common, small, benignNot for common, small, benign--looking lesions that may be looking lesions that may be dysplasticdysplasticFrequent: several times weeklyFrequent: several times weekly

OralCDx OralCDx -- One of the Most Accurate and Highly One of the Most Accurate and Highly Predictive Tests in MedicinePredictive Tests in Medicine

SCA

LPEL

BIO

PSY

5Pos

10Neg

100Harmless appearing

white or red spots which previously would not have been

tested

85

14atypical

1 positive

The PPV of an atypicalOralCDx

~ 40%

Positive Predictive Value (PPV)

The PPV of an atypical Pap Smearis 5-20%

The PPV of an atypical

Mammogram is 2.6-16%

Data from > 300,000 patients

14atypical

The BrushTest in Practice The BrushTest in Practice

JADA JADA Study: March, 2002 Study: March, 2002 930 930 dentists and dental hygienistsdentists and dental hygienists were were examined examined 10% had a benign appearing oral lesion10% had a benign appearing oral lesionAll lesions brush biopsiedAll lesions brush biopsied3 lesions proven precancerous3 lesions proven precancerousOralCDx identified 3 precancers in OralCDx identified 3 precancers in dentists, preventing oral cancer from dentists, preventing oral cancer from getting startedgetting started

Not Not ““FDA approvedFDA approved”” but but ““510K cleared510K cleared”” as as ““substantially equivalent to standard examination lights substantially equivalent to standard examination lights sold to dentists and physicians prior to 1976sold to dentists and physicians prior to 1976””Cannot be legally marketed as a Cannot be legally marketed as a ““testtest”” because the because the patient can have dysplasia and the light will not find it. patient can have dysplasia and the light will not find it. Potential high false negative rate for early dysplasia.Potential high false negative rate for early dysplasia.The BrushTest is the only nonThe BrushTest is the only non--invasive way to know invasive way to know that a common oral spot is not precancerous. that a common oral spot is not precancerous.

Adjunctive examination lights marketed as “aids to the oral cancer exam”

Toluidine BlueToluidine Blue

For Carcinoma For Carcinoma –– High sensitivityHigh sensitivityFor Dysplasia For Dysplasia –– Very Low sensitivity Very Low sensitivity (high false negative rate )(high false negative rate )

Summary: How Does OralCDx Summary: How Does OralCDx Help Prevent Oral Cancer?Help Prevent Oral Cancer?

Every oral cancer started, years earlier, as a Every oral cancer started, years earlier, as a harmless appearing small white or red spot that is harmless appearing small white or red spot that is clinically identical to the ones you see almost daily.clinically identical to the ones you see almost daily.

By testing every unexplained oral spot with the By testing every unexplained oral spot with the BrushTest you will identify, with high accuracy, BrushTest you will identify, with high accuracy, which may contain unhealthy cells which may contain unhealthy cells –– years before years before they can penetrate the basement and cause any they can penetrate the basement and cause any harm. harm.

OralCDxOralCDx can be used can be used to routinely test to routinely test allall unexplained spots unexplained spots to protect to protect allall of your patients against of your patients against

oral canceroral cancer

ReimbursementReimbursement

The majority of both the dentistThe majority of both the dentist’’s and the laboratorys and the laboratory’’s s charges are covered by most dental and medical planscharges are covered by most dental and medical plans

DentistDentist’’s fee for performing the test s fee for performing the test Specific CDT Code is widely covered by dental $75Specific CDT Code is widely covered by dental $75--$125$125Average fee for service range $120Average fee for service range $120--175175Medicare > $120 Medicare > $120 –– Important for nursing home practicesImportant for nursing home practicesDentistDentist’’s only cost is $10 for the OralCDx test kit. s only cost is $10 for the OralCDx test kit.

OralCDx laboratory Fee for analysis of the specimen OralCDx laboratory Fee for analysis of the specimen OralCDx lab bills the patientOralCDx lab bills the patient’’s medical insurance $95s medical insurance $95>97% of medical plans cover a portion of this fee.>97% of medical plans cover a portion of this fee.

CertificationCertification

Patients who see the ADA advertising regarding Patients who see the ADA advertising regarding the BrushTest contact OralCDx to learn which the BrushTest contact OralCDx to learn which dentists use it routinely to protect their patients. dentists use it routinely to protect their patients. Three course optionsThree course options

Lunch and Learn in your officeLunch and Learn in your office15 minute conference call with dentists and staff15 minute conference call with dentists and staffFree ADA CE Free ADA CE www.adaceonline.orgwww.adaceonline.org

OralCDx BrushTest SummaryOralCDx BrushTest SummaryThe tool to prevent oral cancer in all of The tool to prevent oral cancer in all of your patients is painless, easy to use, and your patients is painless, easy to use, and widely reimbursed. widely reimbursed. OralCDx has already been used to prevent OralCDx has already been used to prevent thousands of oral cancersthousands of oral cancersFree ADA Online Course: Free ADA Online Course: www.adaceonline.orgwww.adaceonline.org

Detection of Dysplasia to Detection of Dysplasia to Prevent CancerPrevent Cancer

Test For DysplasiaTest For Dysplasia

Pap smear (1960Pap smear (1960’’s) s) Colonoscopy (1980Colonoscopy (1980’’s)s)Oral BrushTest Oral BrushTest (2000(2000’’s)s)

Cancer PreventedCancer Prevented

Cervical cancerCervical cancerColon cancerColon cancerOral CancerOral Cancer