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Educational Presentation Educational Presentation to the ECCC to the ECCC OralCDx OralCDx Brush Biopsy Brush Biopsy -

• Technique and Indications

Technique and Indications

Mark Rutenberg CEO & 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 Later Years 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 Dentist The Dentist’ ’s Dilemma s Dilemma

• The Problem

The Problem

• About 10% of adult patients have small oral spots

About 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 cells

• Only laboratory testing can determine that a spot is

Only laboratory testing can determine that a spot is not dysplastic. not dysplastic.

• Can

Can’ ’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 Dentist The Dentist’ ’s Dilemma s Dilemma

• The Result

The Result

• Harmless appearing precancerous oral spots are

Harmless appearing precancerous oral spots are

• ften allowed to progress until they look
• ften allowed to progress until they look

“ “suspicious suspicious” ”

• By that time they are typically oral cancers.

By that time they are typically oral cancers.

OralCDx BrushTest OralCDx BrushTest™ ™ T The Solution to the Dentist he Solution to the Dentist’ ’s Dilemma s Dilemma

• A routine test of the small, harmless

A 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 BrushTest OralCDx BrushTest™ ™ T The Solution to the Dentist he Solution to the Dentist’ ’s Dilemma s Dilemma

• OralCDx is not intended to test

OralCDx is not intended to test “ “suspicious suspicious” ” oral

• ral
• lesions. These should continue to be sent to the
• lesions. These should continue to be sent to the
• ral surgeon for a scalpel biopsy.
• ral surgeon for a scalpel biopsy.
• OralCDx is intended to test

OralCDx is intended to test “ “everyday everyday” ” oral spots

• ral 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 Indications Brush Biopsy Indications

• White or red spots, chronic ulcerations, mucosal

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

• Common, small, benign

Common, small, benign-

• looking abnormalities

looking abnormalities that have been routinely that have been routinely “ “watched watched” ” and not and not suspicious enough to warrant referral for biopsy suspicious enough to warrant referral for biopsy

Brush Biopsy Contraindications Brush Biopsy Contraindications

• Lesions with intact normal epithelium

Lesions with intact normal epithelium

• fibromas, mucoceles, hemangiomas, submucosal

fibromas, mucoceles, hemangiomas, submucosal masses, pigmented lesions masses, pigmented lesions

• highly suspicious lesions (immediate scalpel biopsy)

highly suspicious lesions (immediate scalpel biopsy)

• lesions with obvious etiology: herpes, aphthous

lesions with obvious etiology: herpes, aphthous ulcerations, trauma ulcerations, trauma

What to Expect in What to Expect in Your Practice Your 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 year Several 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 patients them 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 untreated untreated” ”. . “ “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 about about 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 start

years before it can even start” ”. .

Proper Patient Communication is Key Proper Patient Communication is Key

OralCDx Testing OralCDx Testing

Two Components Two Components

• Office

Office Procedure Procedure-

• OralCDx

OralCDx BrushTest BrushTest

• Laboratory Analysis

Laboratory Analysis -

• Computer

Computer-

• assisted inspection specifically

assisted inspection specifically designed for oral dysplasia. designed for oral dysplasia.

The OralCDx Test Kit The OralCDx Test Kit

Components of kits: Components of kits:

• ral BrushTest instrument
• ral BrushTest instrument
• precoded glass slide and

precoded glass slide and matching coded test matching coded test requisition form requisition form

• alcohol/carbowax fixative

alcohol/carbowax fixative pouch pouch

• container for submitting the

container for submitting the contents contents

OralCDx BrushTest OralCDx BrushTest

• Brush is sterile

Brush is sterile

• Two cutting surfaces

Two cutting surfaces

• Cytology 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 basal intermediate and basal

Exfoliative Oral Cytology Exfoliative Oral Cytology

• Banoczy;

Banoczy; Int Dent J Int Dent J: 1976 : 1976

• False negative rate for leukoplakia: 69%

False negative rate for leukoplakia: 69%

• Folsom et al. 1972

Folsom et al. 1972 Oral Surgery Oral Surgery

• False negative rate for oral cancer: 31%

False negative rate for oral cancer: 31% Cytology is not an acceptable or reliable Cytology is not an acceptable or reliable method of evaluating oral lesions for method of evaluating oral lesions for precancer and cancer precancer and cancer

Guidelines for Anesthesia Guidelines 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 required required

• For highly inflamed or ulcerated lesions, local or

For highly inflamed or ulcerated lesions, local or topical anesthesia may be used topical anesthesia may be used

• Topical anesthesia

Topical anesthesia

• gels, sprays and creams OK

gels, sprays and creams OK

• intments should not be used
• intments should not be used

Brush Biopsy Technique Brush Biopsy Technique

Review Review

• 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 brush should see a slight bend in the brush

• Rotate clockwise 10 times or more

Rotate clockwise 10 times or more

• Pink 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 membrane membrane

• If lesion bleeds, stop brushing and transfer material

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

Tips for Performing a Brush Biopsy Tips for Performing a Brush Biopsy

• For

For thick,white spots thick,white spots and and

• For spots on the

For spots on the hard palate hard palate and gingiva and 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 rotations require 15 or 20 rotations

• For Ulcerations

For Ulcerations

• sample only the periphery and

sample only the periphery and not the center of the ulcer not the center of the ulcer

The Brush Biopsy Technique The Brush Biopsy Technique

Transfer Cells Transfer Cells

• Evenly spread the

Evenly spread the specimen over the specimen over the entire slide entire slide – – bar bar code facing up code facing up

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

The Brush Biopsy Technique The Brush Biopsy Technique

Apply Fixative Apply Fixative

… … by flooding slide with by flooding slide with liquid liquid

Complete paperwork Complete paperwork place slide and slide holder place slide and slide holder into mailer into mailer

Full instructions included in each OralCDx test kit

Analysis of OralCDx Specimens Analysis of OralCDx Specimens

Analysis is aided with a Analysis is aided with a highly specialized neural highly specialized neural network network-

• 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 cells cells

The OralCDx Computer The OralCDx Computer

• Originally developed for missile defense

Originally developed for missile defense

• Every brush biopsy specimen is analyzed for:

Every brush biopsy specimen is analyzed for:

• Abnormal cellular morphology

Abnormal cellular morphology

• Signature spectral abnormality of the

Signature spectral abnormality of the keratin protein keratin protein

• Cytometric evaluation of nuclear DNA

Cytometric evaluation of nuclear DNA content content

OralCDx Interpretation OralCDx Interpretation

• OralCDx computer does

OralCDx computer does not make the diagnosis not make the diagnosis

• OralCDx computer assists

OralCDx computer assists in the search for in the search for precancerous and precancerous and cancerous cells cancerous cells

• Pathologist utilizes both

Pathologist utilizes both computer and standard computer and standard microscopic evaluation microscopic evaluation

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

CDx Laboratories

OralCDx Result OralCDx Result “ “Negative Negative” ”

“ “Negative Negative” ” -

• no cellular

no cellular abnormalities abnormalities

• All OralCDx

All OralCDx “ “negative negative” ” lesions require lesions require the same the same careful clinical careful clinical follow follow-

• up as

up as “ “negative negative” ” histologically histologically sampled lesions sampled lesions

OralCDx Result OralCDx Result “ “Positive Positive” ”

“ “Positive Positive” ” – – definitive cellular definitive cellular evidence of evidence of epithelial epithelial dysplasia or dysplasia or carcinoma carcinoma

• Almost every

Almost every “ “positive positive” ” lesion lesion will prove to be will prove to be dysplasia or dysplasia or carcinoma carcinoma

Scalpel biopsy to provide additional information regarding the nature and degree

• f the abnormality detected with OralCDx

OralCDx Result OralCDx Result “ “Atypical Atypical” ”

“ “Atypical Atypical” ” -

• abnormal

abnormal cellular changes cellular changes

• The probability

The probability that a patient that a patient with an with an “ “atypical atypical” ” report report has a precancer has a precancer is is ~ ~ 4 40% 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 mailed mailed

“ “positive positive” ” and and “ “atypical atypical” ” reports reports include include images of images of abnormal abnormal cells found cells found

OralCDx BrushTest OralCDx 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 “ “partial partial” ” and needs to be repeated. and needs to be repeated.

• You will receive a

You will receive a “ “negative negative” ” report only if the report only if the sample was complete. sample was complete.

OralCDx MULTICENTER OralCDx MULTICENTER U.S. TRIAL U.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 Centers Centers

• 945 patients enrolled

945 patients enrolled

• Results were presented as the cover article

Results were presented as the cover article

• f the
• f the Journal of the American Dental

Journal of the American Dental Association (JADA) Association (JADA) October October, 1999

, 1999

U.S. Multicenter Clinical Trial U.S. Multicenter Clinical Trial -

• Sensitivity Data

Sensitivity 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 lesion correctly 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<.05

Statistical Sensitivity > 96% p<.05

U.S. Multicenter Clinical Trial U.S. Multicenter Clinical Trial -

• Specificity

Specificity Data Data

• 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 not not have an abnormal have an abnormal OralCDx result? OralCDx result?

• 100% (196/196) for

100% (196/196) for “ “positive positive” ” CDx results CDx results

• 92.9% (182/196) for

92.9% (182/196) for “ “atypical atypical” ” CDx results CDx results

• Statistical Specificity for a CDx

Statistical Specificity for a CDx “ “positive positive” ” > 97%, > 97%, p < .05 p < .05

• Statistical Specificity for a CDx

Statistical Specificity for a CDx “ “atypical atypical” ” > 90%, > 90%, p < .05 p < .05

OralCDx Positive Predictive OralCDx Positive Predictive Value Value

• Probability that a patient with an abnormal

Probability that a patient with an abnormal OralCDx result will be OralCDx result will be “ “positive positive” ” by scalpel by scalpel biopsy biopsy

• The PPV of an abnormal OralCDx result is 2

The PPV of an abnormal OralCDx result is 2-

• 16X higher that of an abnormal mammogram

16X higher that of an abnormal mammogram

• r atypical Pap smear.
• r atypical Pap smear.

Scalpel Biopsy Scalpel Biopsy

Scalpel biopsy Scalpel biopsy – – invasive invasive and associated with and associated with morbidity morbidity

• Reserved for highly suspicious

Reserved for highly suspicious lesions that may be cancer lesions that may be cancer

• Infrequent: several times yearly

Infrequent: several times yearly

• Not for common, small, benign

Not for common, small, benign-

• looking lesions that may be

looking lesions that may be dysplastic dysplastic

• Frequent: several times weekly

Frequent: several times weekly

OralCDx OralCDx -

• One of the Most Accurate and Highly

One of the Most Accurate and Highly Predictive Tests in Medicine Predictive Tests in Medicine

SCALPEL BIOPSY

5 Pos 10 Neg

100

Harmless appearing white or red spots which previously would not have been tested

85

14 atypical 1 positive

The PPV of an atypical

OralCDx

~ 40%

Positive Predictive Value (PPV)

The PPV of an atypical Pap Smear is 5-20% The PPV of an atypical Mammogram is 2.6-16%

Data from > 300,000 patients

14

atypical

The BrushTest in Practice The BrushTest in Practice

JADA JADA Study: March, 2002 Study: March, 2002

• 930

930 dentists and dental hygienists dentists and dental hygienists were were examined examined

• 10% had a benign appearing oral lesion

10% had a benign appearing oral lesion

• All lesions brush biopsied

All lesions brush biopsied

• 3 lesions proven precancerous

3 lesions proven precancerous OralCDx identified 3 precancers in OralCDx identified 3 precancers in dentists, preventing oral cancer from dentists, preventing oral cancer from getting started getting started

• Not

Not “ “FDA approved FDA approved” ” but but “ “510K cleared 510K cleared” ” as as “ “substantially equivalent to standard examination lights substantially equivalent to standard examination lights sold to dentists and physicians prior to 1976 sold to dentists and physicians prior to 1976” ”

• Cannot be legally marketed as a

Cannot be legally marketed as a “ “test test” ” 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 non

The 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 Blue Toluidine Blue

For Carcinoma For Carcinoma – – High sensitivity High sensitivity For 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.

OralCDx OralCDx can be used can be used to routinely test to routinely test all all unexplained spots unexplained spots to protect to protect all all of your patients against

• f your patients against
• ral cancer
• ral cancer

Reimbursement Reimbursement

• The majority of both the dentist

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

• Dentist

Dentist’ ’s fee for performing the test s fee for performing the test

• Specific CDT Code is widely covered by dental $75

Specific CDT Code is widely covered by dental $75-

• $125

$125

• Average fee for service range $120

Average fee for service range $120-

• 175

175

• Medicare > $120

Medicare > $120 – – Important for nursing home practices Important for nursing home practices

• Dentist

Dentist’ ’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 patient

OralCDx lab bills the patient’ ’s medical insurance $95 s medical insurance $95

• >97% of medical plans cover a portion of this fee.

>97% of medical plans cover a portion of this fee.

Certification Certification

• 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 options

Three course options

• Lunch and Learn in your office

Lunch and Learn in your office

• 15 minute conference call with dentists and staff

15 minute conference call with dentists and staff

• Free ADA CE

Free ADA CE www.adaceonline.org www.adaceonline.org

OralCDx BrushTest Summary OralCDx BrushTest Summary

• The 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 cancers thousands of oral cancers

• Free ADA Online Course:

Free ADA Online Course: www.adaceonline.org www.adaceonline.org

Detection of Dysplasia to Detection of Dysplasia to Prevent Cancer Prevent Cancer

Test For Dysplasia Test For Dysplasia

• Pap smear (1960

Pap smear (1960’ ’s) s)

• Colonoscopy (1980

Colonoscopy (1980’ ’s) s)

• Oral BrushTest

Oral BrushTest (2000 (2000’ ’s) s)

Cancer Prevented Cancer Prevented

Cervical cancer Cervical cancer Colon cancer Colon cancer Oral Cancer Oral Cancer