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IMPROVED DETECTION AND SURVEILLANCE OF BLADDER CANCER USING A POINT-OF-

CARE NMP22 ASSAY

Giora Katz MD, Raoul Salup MD, And the

NMP22 Clinical Investigation Group

Author Disclosure1

Matritech, Inc. : Honorarium

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NMP22 Clinical Investigation Group

Collaborating InvestigatorsYitzhak Berger MD, Associates in Urology, West Orange, NJDavid Bock MD, Kansas City Urology Care, Kansas City, MOJeffrey Brady MD, Winter Park Urology Associates, Orlando, FLM. Patrick Collini MD, Urology Associates of North Texas, Fort Worth, TXMartin Dineen MD, Atlantic Urological Associates, Daytona Beach, FLH. Barton Grossman MD, M.D. Anderson Cancer Center, Houston, TXVahan Kassabian MD, Georgia Urology, Atlanta, GAGiora Katz MD, Lake City VAMC, Lake City, FLShiva Maralani MD, Michigan Urology, St. Clair Shores, MIEdward Messing MD, University of Rochester Medical Center, Rochester, NYRaoul Salup MD, James A. Haley VAMC, Tampa, FLMark Soloway MD, University of Miami School of Medicine, Miami, FLBarry Stein MD, Rhode Island Hospital, Providence, RIAlan Treiman MD, Urology Treatment Center, Sarasota, FLKevin Tomera MD, Alaska Clinical Research Center, Anchorage, AK

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Introduction

• Early diagnosis of bladder cancer saves lives

• Cystoscopy is the “Gold Standard” in evaluation of the urinary bladder for presence of cancer

• AUA guidelines recommend combination of cystoscopy and adjunct tests in evaluation of urinary bladder for the presence of cancer in high risk patients.

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Nuclear Matrix Proteins and Transitional Cells of the Urinary Tract

• Nuclear matrix proteins (NMP) make up the structural framework of the nucleus and coordinate its functions.

• NMP22 is specific for transitional cells in the urinary tract.• Upon cell death NMP22 is released into the urine.

• Malignant transitional cells contain up to 80 times higher concentration of NMP22 levels than normal cells.

• Urine level of NMP22 > 10 U / ml is associated with a high probability of TCC.

• Unlike cytological examination, detection of NMP22 protein is not dependent on recovery of intact cells.

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NMP22 BladderChek Point-of-Care Device

Created to identify urinary NMP22 levels > 10 U/ml.– Can be performed by

non-physician staff members (CLIA exempt).

– Requires 4 drops of freshly voided urine.

– Results available in 30 minutes.

– Built-in quality control.

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NegativePositive

Control

Test

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OBJECTIVE

We investigated whether a point-of-care assay (NMP22® BladderChek® Test, Matritech, Inc., Newton, MA) can enhance detection of bladder cancer in patients undergoing cystoscopy for either initial evaluation or surveillance of TCCB.

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Study Design

• Two prospective studies: 23 facilities in 10 states; academic, private practice and VA– 1,331 patients scheduled for cystoscopy due to

increased risk of bladder cancer (hematuria (92%), history of smoking, irritative voiding symptoms),

– 668 patients with a history of bladder cancer under surveillance for recurrence

• Voided urine sample obtained for analysis of NMP22 marker (30 min, CLIA waived) and cytology prior to diagnostic cystoscopy

• Urologists were blinded to NMP22 and cytology results while performing and reporting the result of cystoscopy

• Further workup was based on clinical findings and results of cystoscopy and cytology

• TCC was diagnosed based on pathology

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Results:Evaluation of High Risk Patients Suspected of Having

Bladder Cancer

• Among 1,331 high risk patients screened for bladder cancer, 79 (6%) had pathologically confirmed transitional cell cancer.

• Initial cystoscopy alone detected 86% (68/79) of the cancers.

• Combination of cystoscopy and NMP22 test (either or both are positive), detected significantly more cancers, 94% (74/79), p = 0.014.

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New investigation

Cystoalone

CystoandNMP22

%

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Surveillance Patients with History of TCCB for Recurrence of

Bladder cancer• Among the 668 patients

undergoing surveillance, 103 (15%) had pathologically confirmed recurrences.

• Initial cystoscopy alone detected 91% (94/103) of the malignancies.

• Combination of cystoscopy with the NMP22 test (either or both are positive) identified 99% (102/103) of the cancers , significantly more than cystoscopy alone, p = 0.005.

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TCCBsurveillance

Cystoalone

CystoandNMP22

%

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Patients At Risk Improved Diagnosis of Aggressive Cancer with

Combination of Cystoscopy and NMP22 BladderChek Test

Muscle Invasive High Grade

Cystoscopy 55% 81%alone (6/11) (22/27)

Cystoscopy 91% 93%& NMP22 Test (10/11) (25/27)

p=0.046

Cancers not seen by cystoscopy but detected by NMP22 Test:Bladder CIS, T2, T3; Ureter T2; Renal Pelvis T1, T3

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Surveillance Improved Diagnosis of Aggressive Cancer with

Combination of Cystoscopy and NMP22 BladderChek Test

Muscle Invasive High Grade

Cystoscopy 64% 75%alone (7/11) (24/32)

Cystoscopy 100% 97%& NMP22 Test (11/11) (31/32)

p=0.046Cancers not seen by cystoscopy but detected by

NMP22 Test: TaG1, 2 CisG3, T1G3, 2 T2G3, 2 T4G3

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Negative Predictive Valuewhen both cystoscopy and NMP22 Test

are negative (Reliability of a negative result, driven by false

negative)

Evaluation of patients

at risk

99.5% (1072/1077)

Surveillance for recurrence of TCC

99.8% (493/494)

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CONCLUSIONS

• Combined with cystoscopy, the NMP22 point-of-care test can significantly improve detection of bladder cancer both in patients at risk and under surveillance.

• It can be performed by office staff, and delivers a clinically meaningful result during the patient visit.

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Sensitivity for Detecting TCC: Diagnosis

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Ta T1 Tis T2 + LowGrade

Md Grade HighGrade

Cytology = 16%NMP22 Test = 57%

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Sensitivity for Detecting Cancer: Monitoring

0

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Ta T1 Tis T2 + LowGrade

Md Grade HighGrade

Cytology = 12%NMP22 Test = 50%

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Specificity in Initial Diagnosis

No GU DiseaseNo Cancer

NMP22 90% 86%Test (512/567) (1072/1249)

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NED BPH Cystitis Calculi

% Negative

NMP

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Predictive Value: Surveillance

PPV NPV

NMP22 Test 41% 91%(51/123) (493/545)

Cytology 41% 86%(12/29) (535/621)

Cystoscopy 91% 98%(94/103) (556/565)

Positive and negative predictive value are dependent upon the prevalence of disease in the tested population

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Sensitivity for Detecting Cancer: Monitoring

0

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20

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60

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Ta T1 Tis T2 + LowGrade

Md Grade HighGrade

Cytology = 12%NMP22 Test = 50%