Department of Urology

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Markers for Bladder Cancer and Renal Cell
Carcinoma

• Professor Peter Mulders
• University Hospital Nijmegen
• The Netherlands
• EAU Milan, March 2008

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Bladder cancer

• It is a disease with many events (frequent)
• Patients are monitored 4 million cystoscopies
  are estimated to be performed in the EU/US every
  year
• A significant problem for health care (budgets)
• However It is (usually) not a lethal disease ?
  limited interest of cancer foundations

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Cancer incidence and prevalence
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Health economics bladder cancer(Botteman et al.,
Pharmacoeconomics 2003)

• Bladder cancer fifth most expensive cancer
• Per patient cost from diagnosis until death
  highest of all cancer, k 96-187 (2001 values)
• Current diagnostics not cost effective (markers?)
• Current therapies not cost effective
• Current frequent follow up not cost effective
• No new developments
• No awareness

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Bladder cancer lifetime costs(Avritscher et al,
Urology 2006, 68, 549-53)

• Costs of treatment and complications
• 60 of costs related to treatment
• 30 of costs related to complications
• Two scenarios
• worst means shorter survival (cheaper) but more
  complications (expensive)
• Best scenario the other way around
• Life time costs between k99 (worst scenario) and
  k120 (best scenario)

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Diagnostic tools in urinary TCC
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Golden standard 1 voided urinary cytology

• high specificity but low sensitivity
• useless in case of infection or during
  intravesical therapy
• operator dependent
• low inter- and intra-observer reproducibility

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(No Transcript)
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Diagnostic urinary markers??
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Marker reviews (Lotan, Urology 2003, van Rhijn,
Eur Urol 2005)

• All test sensitivities gt cytology (low grade!)
• All test specificities lt cytology
• CIS sensitivities surprisingly low
• Markers can be used in follow up
• and can potentially replace routine cytology
• but cannot replace cystoscopy

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Some new ones

• NMP22 dipstick (BladderChek)
• FISH (Urovysion)
• Immunocyt

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NMP-22 BladderChek

• FDA approved for monitoring and diagnosis
• Rapid test 4 drops, read after 30 minutes
• NMP22 cut-off of 10 Units/mL

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NMP22 BladderChek(Grossman et al., JAMA, 2005)

• 79x bladder cancer in 1331 participants
• NMP22 sens 44/79 (55.7), spec 85.7
• Sens cytology 12/79 (15.8), spec 99.2
• NMP22 detected 4 cancers first missed on UCS (3
  invasive and 1 CIS)
• Good adjunct to UCS, cost effective

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NMP22 BladderChek follow-up(Grossman et al.,
JAMA, 2006)

• 103 pts with bladder cancer of 668 in FU
• Sensitivity cystoscopy 91.3
• UCS and NMP22 sensitivity improved to 99
• NMP22 detected 8/9 cancers missed on UCS
  (cytology 3/9)
• Spec NMP22 49.5

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Conclusion new urinary markers

• Value of current markers needs validation in
  specific cohorts
• In a few words
• NMP22 POC simple
• Urovysion good (?) but complicated
• Immunocyt good but complicated

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Can we expect new techniques

• High throughput DNA micro arrays with SNP (small
  nucleotide polymorphism) chips
• 2003 Hoque
• 300 SNP chip
• 24 SNP DNA changes in 31/31 cases screened,
  versus 1/14 controls

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• Affymetrix 250,000 SNP chip
• 1 Proband from each high risk family

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• Exciting micro deletion 177kb at 8p22 (160 kb
  upstream of TSG DLC1)

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Urinary biomarker proteomics (Munro et al, Int J
Cancer 2006)

• 130 profiles tested (118 TCC, 109 controls)
• 23 protein peaks differentially expressed between
  TCC and healthy/controls
• TCC detection results
• In test set (n54) sens 71.7, spec 62.5
• In validation set (n43) sens 78.3, spec 65.0

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Markers for Renal Cell Carcinoma

• EAU Milan, March 2008

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Renal cell carcinomaGeneral aspects

• RCC accounts for 3 of all adult tumors
• 100.000 patients die from rcc every year
  worldwide
• Most aggressive GU tumor

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RCC associated antigen G250/MN/CAIX

• Present in gt85 of all RCC, 99 of the clear-cell
  subtype
• No expression in normal kidney

Mulders etal, J Urol 2006 Mab G250 has clinical
efficacy in mRCC patients
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Immunohistochemical stainsA, representative of a
low CAIX staining lt 86B, representative of
high CAIX staining gt 85
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Survival of gt5 years was only seen in patients
with high CAIX expressing tumors.
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Take Home Message

• Bladder cancer markers can be used for follow-up
  but not for screening
• Renal cell cancer marker CA-IX is important for
  response of therapy