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BCaMonitor NMIBC Biomarkers Slide Resource
BCaMonitor NMIBC Biomarkers Slide Resource
BCaMonitor NMIBC Biomarkers Slide Resource
management of
non-muscle
invasive bladder
cancer (NMIBC)
Peer reviewed by
Jørgen Bjerggaard Jensen
Aarhus University Hospital, Aarhus, Denmark
Joost Boormans
Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Hugh Mostafid
Royal Surrey County Hospital, Guildford, UK
Overview
Haematuria
NMIBC
Up to 70% of patients experience + risk stratification
recurrence within 2 years of primary
treatment
Disease
management
Up to 10-15% eventually
progress to MIBC
* ** **
1. Babjuk M et al. EAU 2020 Guidelines on non-muscle-invasive Bladder Cancer (TaT1 and CIS).
2. Moch H et al. WHO Classification of Tumours of the Urinary System and Male Genital Organs (4 th edition) 2016, Lyon, France.
NMIBC risk stratification1
NMIBC
1. Babjuk M et al. EAU 2020 Guidelines on non-muscle-invasive Bladder Cancer (TaT1 and CIS).
NMIBC recurrence and progression1
1. Babjuk M et al. EAU 2020 Guidelines on non-muscle-invasive Bladder Cancer (TaT1 and CIS).
Cystoscopy and cytology:
Current guidelines for diagnosis
Use voided urine cytology as an adjunct to cystoscopy to detect high-grade tumour. Strong
1. Babjuk M et al. EAU 2020 Guidelines on non-muscle-invasive Bladder Cancer (TaT1 and CIS).
Cystoscopy and cytology:
Current guidelines for diagnosis (I)
Cystoscopy (usually white light)
• High sensitivity for papillary tumours: 86%1 • Lower sensitivity for carcinoma in situ (CIS):
• Moderate to high specificity: 43-98%2 55%1
High number of false positives 45% of patients with CIS are missed
• Operator-dependent assessment risk of
bias
100
90 86% 86%
80 76%
70
55%
Sensitivity
60
50
40
30
20
10
0
Overall Low grade High grade CIS
1. Daneshmand S et al. Urol Oncol 2018; 36:361.e1-361. 2. Jocham D et al. Eur Urol 2008; 53:1138-1150.
Cystoscopy and cytology:
Current guidelines for diagnosis (II)
Cytology
• High specificity: 93%1 • Moderate sensitivity in high-grade tumours: 54%1
Low number of false positives 46% of high-grade tumours are not detected
• Low sensitivity in low-grade (G1/G2) tumours: 11%1
89% of low-grade tumours are not detected
100
90 • Operator-dependent assessment with variable
80 results across institutions2
70
58%
54% • High rate of atypical (inconclusive) results3
Sensitivity
60
50 41%
40
30
20 11%
10
0
Overall Low grade High grade CIS
1. Freifeld Y et al. BJU Int 2019; 124:251-257. 2. Raitanen M-K et al. Eur Urol 2002; 41:284-289. 3. VandenBussche CJ et al. Cancer Cytopathol 2018; 126:381-389.
Cystoscopy: Current guidelines for surveillance
EAU 2020 guidelines1
Recommendations for follow-up Strength rating
Base follow-up of TaT1 tumours and carcinoma in situ (CIS) on regular cystoscopy. Strong
Patients with low-risk Ta tumours should undergo cystoscopy at three months. If negative, Weak
subsequent cystoscopy is advised nine months later, and then yearly for five years.
Patients with high-risk tumours should undergo cystoscopy and urinary cytology at three Weak
months. If negative, subsequent cystoscopy and cytology should be repeated every three
months for a period of two years, and every six months thereafter until five years, and then
yearly.
Patients with intermediate-risk Ta tumours should have an in-between (individualised) Weak
follow-up scheme using cystoscopy.
1. Babjuk M et al. EAU 2020 Guidelines on non-muscle-invasive Bladder Cancer (TaT1 and CIS).
The cystoscopy surveillance schedule:
EAU guidelines in practice
Diagnosis: cystoscopy
The number of cytoscopies a patient has to undergo in case no recurrence happens. In case of recurrence, the follow-up start from the beginning again.
Hurdles in NMIBC management
• Moderate specificity and moderate sensitivity in CIS
Limitations of • Operator dependent, decreased sensitivity under bacillus Calmette-
cystoscopy Guerin (BCG) treatment
• Invasive procedure and reduced compliance over time
• Logistic burden: commute to and time in hospital
• Morbidity
“Proven clinical
“100%
“92% sensitivity and
sensitivity,
sensitivity, specificity for
independently
excluding low and high
of tumour stage
Ta-LG” grade bladder
and grade”
cancer”
“Clinical
studies
demonstrate a
combined 95% “A
sensitivity” breakthrough
NPV of 97%”
Biomarkers: What do the numbers mean?
“Proven clinical
“100%
“92% sensitivity and
sensitivity,
sensitivity, specificity for
independetly of
excluding Ta- low and high
Sensitivity, specificity, negative predictive value (NPV) and positive
LG” grade bladder
tumour stage
and grade”
cancer”
predictive value (PPV) can guide the selection of the most appopriate
“Clinical biomarker test
studies
demonstrate a
combined 95% “A
sensitivity” breakthrough
NPV of 97%”
Quality parameters for diagnostic tests (I)
TP
Sensitivity = =
TP + FN +
= the proportion of diseased persons who
True negative (TN)
receive a positive test result
False positive (FP)
The lower the sensitivity, the more diseased patients
receive an incorrect negative test result (high false
False negative (FN) negative rate)
Test result
Negative 2 (FN) 50 (TN) Negative 10 (FN) 37 (TN)
TP 4 TP 20
Sensitivity = = = 67% Sensitivity = = = 67%
TP + FN 4+2 TP + FN 20 + 10
TN 50 TN 37
Specificity = = = 53% Specificity = = = 53%
TN + FP 50 + 44 TN + FP 37 + 33
TN 50 TN 37
NPV = = = 96% NPV = = = 79%
TN + FN 50 + 2 TN + FN 37 + 10
TP 4 TP 20
PPV = = = 8% PPV = = = 38%
TP + FP 4 + 44 TP + FP 20 + 33
Example: changing prevalence
Scenario 1: Scenario 2:
Disease prevalence = 6% Disease prevalence = 30%
The same diagnostic test is used in both scenarios
Truth Truth
Diseased Healthy Diseased Healthy
The prevalence
Positive
of the disease
4 (TP) 44 (FP)
in the cohort impacts
Positive
the NPV
20 (TP)
significantly
33 (FP)
↓
Test result
Test result
Negative 2 (FN) 50 (TN) Negative 10 (FN) 37 (TN)
Therefore,
Sensitivity =
TP NPV’s
=
4of different cohorts cannot be
= 67% Sensitivity =
TP compared
=
20
= 67%
TP + FN 4+2 TP + FN 20 + 10
TN 50 TN 37
Specificity = = = 53% Specificity = = = 53%
TN + FP 50 + 44 TN + FP 37 + 33
TN 50 TN 37
NPV = = = 96% NPV = = = 79%
TN + FN 50 + 2 TN + FN 37 + 10
TP 4 TP 20
PPV = = = 8% PPV = = = 38%
TP + FP 4 + 44 TP + FP 20 + 33
Example: changing sensitivity
Scenario 1: Scenario 2:
Disease prevalence = 5% Disease prevalence = 5%
Sensitivity = 80% Sensitivity = 0%
Specificity = 80% Specificity = 80%
Truth Truth
Diseased Healthy Diseased Healthy
Positive 4 (TP) 19 (FP) Positive 0 (TP) 19 (FP)
Test result
Test result
Negative 1 (FN) 76 (TN) Negative 5 (FN) 76 (TN)
TP 4 TP 0
Sensitivity = = = 80% Sensitivity = = = 0%
TP + FN 4+1 TP + FN 0+5
TN 76 TN 76
Specificity = = = 80% Specificity = = = 80%
TN + FP 76 + 19 TN + FP 76 + 19
TN 76 TN 76
NPV = = = 99% NPV = = = 91%
TN + FN 76 + 1 TN + FN 79 + 5
TP 4 TP 0
PPV = = = 17% PPV = = = 0%
TP + FP 4 + 19 TP + FP 0 + 19
Example: changing sensitivity
Scenario 1: Scenario 2:
Disease prevalence = 5% Disease prevalence = 5%
Sensitivity = 80% Sensitivity = 0%
Specificity = 80% Specificity = 80%
Truth Truth
Diseased Healthy Diseased Healthy
Positive 4 (TP) 19 (FP) Positive 0 (TP) 19 (FP)
Besides disease prevalence,
Test result
Test result
Negative 1 (FN) 76 (TN) Negative 5 (FN) 76 (TN)
test sensitivity also has a significant impact on NPV
TP 4 TP 0
Sensitivity = = = 80% Sensitivity = = = 0%
TP + FN 4+1 TP + FN 0+5
TN 76 TN 76
Specificity = = = 80% Specificity = = = 80%
TN + FP 76 + 19 TN + FP 76 + 19
TN 76 TN 76
NPV = = = 99% NPV = = = 91%
TN + FN 76 + 1 TN + FN 79 + 5
TP 4 TP 0
PPV = = = 17% PPV = = = 0%
TP + FP 4 + 19 TP + FP 0 + 19
Diagnostic quality parameters: how to use them
Rule IN
1. A high PPV + 2. High specificity
Ensures that a patient with a Ensures that a patient with a
positive test result, is affected positive test result is affected
Depends on prevalence: if
everybody is affected, the PPV
would be 100%
Depends on prevalence: if
everybody is unaffected,
the NPV would be 100%
Negative
Surveillance
cystoscopy ± cytology
Tumour Surveillance
detection cystoscopy ±
& resection ± Re-TURBT cytology ± Instillations
Positive Treat:
TURBT ± instillations
Ease of interpretation
FDA approved / CE-IVD marked
FDA approval/CE mark
CE (Conformité Européenne); FDA: Food and Drug Administration; IVD: in vitro diagnostic
Diagnosis & surveillance
Validated
UroVysion: Scientific evidence Ease of interpretation:
• Review paper1
PERFORMANCE
• 21 studies comprising 2,852
individuals
• Performance characteristics 53% 79% 80%
provided for mix of diagnosis and
surveillance
SENSITIVITY SENSITIVITY SPECIFICITY
LOW GRADE HIGH GRADE
“The broad range of sensitivity and specificity for UroVysion FISH reported in different papers is notable and may
“
not only reflect patient selection, study design, and tumour prevalence, but also technical aspects such as cutoff
definitions and experience of laboratory staff.
Development phase
Ease of interpretation
Technology/device
requirements Spectrophotometer or plate reader
Clinical application Diagnosis of bladder cancer in patients with haematuria / bladder cancer follow-up
Diagnosis
ADXBLADDER: Validated
Scientific evidence for diagnosis Ease of interpretation:
Percentage
60 55 53
Sensitivity
“ ADXBLADDR has the potential to replace
“
cytology as an adjunctive test in bladder cancer
40 NPV
diagnosis 20
0
Low High CIS pTa ≥ pT1
1. Dudderidge T et al. Eur Urol Oncol 2020; 3: 42-46. grade grade
Surveillance
ADXBLADDER: Validated
Scientific evidence for surveillance Ease of interpretation:
Ease of interpretation
0
Sensitivity High Grade Specificity NPV
“Xpert Bladder Cancer Detect represents a promising
new tool for adjunctive use in combination with other
Sensitivity
1. van Valenberg FJP et al. Eur Urol Suppl 2017; 16: e190.
Surveillance
Xpert Bladder Cancer Monitor: Validated
Scientific evidence for surveillance Ease of interpretation:
Ease of interpretation
Excluding LG Ta recurrences
1. Witjes JA et al. Eur Urol Oncol 2018; 1: 307-13. 2. Lozano F et al. EAU2019, poster 709.
Surveillance
Bladder EpiCheck: Validated
Scientific evidence for surveillance Ease of interpretation:
Ta CIS T1+
1. Kavalieris L et al. J Urol 2017; 197: 1419-26.
Uromonitor
Uromonitor
Type of test Sensitive multiplex competitive allele-specific discrimination real-time PCR
Markers • TERT promoter mutations [c.1-124C>T (TERTp-124) and c.1-146C>T (TERTp-146)]
• FGFR3 mutations [p.R248C (FGFR3-248) and p.S249C (FGFR3-249)]
Development phase
Technology/device
requirements None – sample shipment to central lab
“
specificity, an important upgrade in comparison to 60
the cystoscopy and cytology combination.
40
Uromonitor Cystoscopy Cytology Cystoscopy + Uromonitor +
1. Batista R et al. Front Genet 2019; 18: 1237. cytology cystoscopy
Urodiag
Urodiag
Type of test Highly specific multiplex quantitative real-time PCR
Markers • Mutations in FGFR3 gene (S249C – R248C – G372C – Y375C)
• Level of DNA methylation of HS3ST2 – SEPTIN9 – SLIT2
Development phase
Technology/device
requirements Not indicated
Clinical application Diagnosis of bladder cancer in patients with haematuria / bladder cancer follow-up
Diagnosis & surveillance
Discovery
Urodiag: discovery study Validation
required Ease of interpretation:
0
pTa pT1 CIS Low grade High grade
(N=55) (N=11) (N=2) (N=47) (N=25)
1. Roperch J-P et al. BMC Cancer 2016; 16:704.
How to choose the appropriate biomarker
test?
Biomarkers for “rule IN”
Negative
Surveillance
cystoscopy ± cytology
Tumour Surveillance
detection cystoscopy ±
& resection ± Re-TURBT cytology ± Instillations
Positive Treat:
Rule in patients who have bladder cancer & TURBT ± instillations
patients with recurrence and/or progression
High specificity:
Low false positive rate minimise the number of
unnecessary procedures Workup / treat:
High PPV: Equivocal Biopsy/CT/TURBT/
A patient with a positive test result, is affected instillations
Biomarkers for rule IN for diagnosis
PPV NR NR NR NR
1. Schmitz-Dräger BJ et al. Urol Int 2015; 94:1-24. 2. Dudderidge T et al. Eur Urol Oncol 2020; 3: 42-46. 3. van Valenberg FJP et al. Eur Urol Suppl 2017; 16: e190.
4. O’Sullivan P et al. J Urol 2012; 188: 741-7.
Biomarkers for rule IN for surveillance
1. Roupret M et al. J Urol 2019; doi: 10.1097/JU.0000000000001084 2. van Valenberg FJP et al. Eur Urol 2019; 75: 853-860.
3. Kavalieris L et al. J Urol 2017; 197: 1419-26. 4. Witjes JA et al. Eur Urol Oncol 2018; 1: 307-13. 5. Lozano F et al. EAU2019, poster 709
Biomarkers for “rule OUT”
Negative
Surveillance
cystoscopy ± cytology
Tumour Surveillance
detection cystoscopy ±
& resection ± Re-TURBT cytology ± Instillations
Overall
High grade
1. Schmitz-Dräger BJ et al. Urol Int 2015; 94:1-24. 2.Roupret M et al. J Urol 2019; doi: 10.1097/JU.0000000000001084. 3. Van Valenberg FJP et al. Eur Urol Suppl 2017; 16: e190.
4. Kavalieris L et al. J Urol 2017; 197: 1419-26. 5. Witjes JA et al. Eur Urol Oncol 2018; 1: 307-13. 6. Lozano F et al. EAU2019, poster 709.
Conclusion
Conclusion
• Biomarker tests used as “rule in” test need to have a high specificity
and high PPV
• Positive cytology is considered gold standard to rule-in high grade tumours,
given its high specificity (93%)
• However, 10-15% of the cytology results are “atypical”
• At the moment, none of the biomarker tests have a specificity higher than
cytology
• Biomarker tests used as “rule out” test require a high sensitivity, high
specificity and high NPV
• Bladder EpiCheck is the only biomarker test, validated for surveillance, that
provides a high sensitivity, high specificity and high NPV for ruling out HG
tumours