IMPROVED DETECTION AND
SURVEILLANCE OF BLADDER
CANCER USING A POINT-OFCARE NMP22 ASSAY
Giora Katz MD, Raoul Salup MD,
And the
NMP22 Clinical Investigation Group
Author Disclosure1
Matritech, Inc. : Honorarium
1
NMP22 Clinical Investigation Group
Collaborating Investigators
Yitzhak Berger MD, Associates in Urology, West Orange, NJ
David Bock MD, Kansas City Urology Care, Kansas City, MO
Jeffrey Brady MD, Winter Park Urology Associates, Orlando, FL
M. Patrick Collini MD, Urology Associates of North Texas, Fort Worth, TX
Martin Dineen MD, Atlantic Urological Associates, Daytona Beach, FL
H. Barton Grossman MD, M.D. Anderson Cancer Center, Houston, TX
Vahan Kassabian MD, Georgia Urology, Atlanta, GA
Giora Katz MD, Lake City VAMC, Lake City, FL
Shiva Maralani MD, Michigan Urology, St. Clair Shores, MI
Edward Messing MD, University of Rochester Medical Center, Rochester, NY
Raoul Salup MD, James A. Haley VAMC, Tampa, FL
Mark Soloway MD, University of Miami School of Medicine, Miami, FL
Barry Stein MD, Rhode Island Hospital, Providence, RI
Alan Treiman MD, Urology Treatment Center, Sarasota, FL
Kevin Tomera MD, Alaska Clinical Research Center, Anchorage, AK
2
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.
3
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.
4
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.
5
Positive
Negative
Control
Test
6
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.
7
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
8
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.
94
%
92
Cysto
alone
90
88
Cysto
and
NMP22
86
84
82
New investigation
9
Surveillance
Patients with History of TCCB for Recurrence of
Bladder cancer
• Among the 668 patients
undergoing surveillance,
100
%
103 (15%) had
98
pathologically confirmed
recurrences.
96
Cysto
• Initial cystoscopy alone
94
alone
detected 91% (94/103) of
92
the malignancies.
Cysto
90
and
• Combination of cystoscopy
NMP22
with the NMP22 test (either
88
or both are positive)
86
identified 99% (102/103) of
TCCB
surveillance
the cancers , significantly
more than cystoscopy alone,
p = 0.005.
10
Patients At Risk
Improved Diagnosis of Aggressive Cancer with
Combination of Cystoscopy and NMP22
BladderChek Test
Muscle Invasive
High Grade
Cystoscopy
alone
55%
(6/11)
81%
(22/27)
Cystoscopy
& NMP22 Test
91%
(10/11)
93%
(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
11
Surveillance
Improved Diagnosis of Aggressive Cancer with
Combination of Cystoscopy and
NMP22 BladderChek Test
Muscle Invasive
High Grade
Cystoscopy
alone
64%
(7/11)
75%
(24/32)
Cystoscopy
& NMP22 Test
100%
(11/11)
97%
(31/32)
p=0.046
Cancers not seen by cystoscopy but detected by
NMP22 Test: TaG1, 2 CisG3, T1G3, 2 T2G3, 2 T4G3
12
Negative Predictive Value
when 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)
13
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.
14
Sensitivity for Detecting TCC: Diagnosis
100
90
80
70
60
50
40
30
20
10
0
Ta
T1
Tis
NMP22 Test = 57%
T2 +
Low
Grade
Md Grade
High
Grade
Cytology = 16%
15
Sensitivity for Detecting Cancer:
Monitoring
100
90
80
70
60
50
40
30
20
10
0
Ta
T1
Tis
NMP22 Test = 50%
T2 +
Low
Grade
Md Grade
Cytology = 12%
High
Grade
16
Specificity in Initial Diagnosis
No GU Disease No Cancer
NMP22
Test
90%
86%
(512/567)
(1072/1249)
100
90
%
Negative
NMP
80
70
60
50
40
30
20
10
0
NED
BPH
Cystitis
Calculi
17
Predictive Value: Surveillance
NMP22 Test
Cytology
Cystoscopy
PPV
NPV
41%
91%
(51/123)
(493/545)
41%
86%
(12/29)
(535/621)
91%
98%
(94/103)
(556/565)
Positive and negative predictive value are dependent
upon the prevalence of disease in the tested population
18
Sensitivity for Detecting Cancer:
Monitoring
100
90
80
70
60
50
40
30
20
10
0
Ta
T1
Tis
NMP22 Test = 50%
T2 +
Low
Grade
Md Grade
Cytology = 12%
High
Grade
19