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18th Meeting of the EAU Section of Oncological Urology (ESOU21)

ESOU 2021: Biomarkers in the Diagnosis and Follow-up of Bladder Cancer in 2021: Where Do We Stand?

(UroToday.com) The European Association of Urology (EAU) Section of Oncological Urology (ESOU) 2021 Virtual meeting included a presentation by Dr. Evanguelos Xylinas discussing the status of biomarkers in the diagnosis and follow-up of bladder cancer in 2021. Dr. Xylinas notes that there are currently two unmet needs, both an economic burden and patient burden. A study from 2016 found that bladder cancer cost the EU €4.9 billion in 2012, with health care accounting for €2.9 billion (59%) and representing 5% of total health care cancer costs. Specifically, bladder cancer accounted for 3% of all cancer costs in the EU (€143 billion) in 2012 and represented an annual health care cost of €57 per 10 EU citizens.1 Furthermore, the cost of surveillance for low-risk NMIBC has been estimated at >$52,000, >$146,000 for intermediate-risk, and >$366,000 for high-risk disease.


Dr. Xylinas notes there is an overuse of unneeded cystoscopies. A study from the Veterans Affairs Health System defined surveillance overuse as >1 cystoscopy if followed <1 year, >2 cystoscopies if followed 1 to <2 years, or >3 cystoscopies if followed for 2 years.2 These authors found that overuse occurred in 75% of patients (852/1135), with an excess of 1,846 more cystoscopies performed than recommended. After adjusting for 14 factors, overuse of cystoscopy was associated with patient race (OR 0.49, 95% CI 0.28-0.85 unlisted race vs White), having 2 comorbidities (OR 1.60, 95% CI 1.00, 2.55 vs no comorbidities), and earlier year of diagnosis (OR 2.50, 95% CI 1.29, 4.83 for 2005 vs 2011, and OR 2.03, 95% CI: 1.11, 3.69 for 2006 vs 2011). 

Dr. Xylinas notes that although cystoscopy is easy to perform, it is invasive and can cause substantial discomfort and anxiety for patients. Survey data suggest that patients would accept a urine-based biomarker rather than a cystoscopy if the sensitivity of the test were >90-95%. Urine cytology is the oldest biomarker that we have, with a specificity that is higher than other established biomarkers (96-99%), but with limited sensitivity (34-45%), especially in low-grade tumors. Other “old” alternative commercially available biomarkers (which are rarely to seldom used) include NMP22, BTA, UroVysion, and ImmunoCyt.           

ADX Bladder is a new biomarker that is an ELISA test that utilizes detection of minichromosome maintenance protein (MCM) 5. These proteins are a member of a larger family of MCM proteins that play a pivotal role in the initiation of DNA replication and are highly expressed in cells that are proliferating and in cells that proliferation potential; expression is low or absent in healthy differentiated cells. Dr. Roupret’s group published a study last year assessing the diagnostic performance of ADX Bladder in patients undergoing cystoscopic surveillance in nonmuscle invasive bladder cancer follow-up.3 Among 1,431 eligible patients 127 were diagnosed with a bladder cancer recurrence. The overall sensitivity for the ADX bladder test in detecting bladder cancer recurrence was 44.9% (95% CI 36.1-54) with a 75.6% sensitivity for non-pTa low-grade tumors (95% CI 59.7-87.6). The specificity was 71.1% (95% CI 68.5-73.5) and the overall negative predictive value was 93% (95% CI 91.2-94.5). Ultimately, ADX bladder was able to rule out the presence of a non-pTa low-grade recurrent tumor with a NPV of 99.0%.

Several other new biomarkers have also emerged. Bladder EpiCheck is a real-time PCR urinary test that detects changes in DNA methylation associated with bladder cancer in a panel of 15 genes, providing a numeric value between 0 and 100 (EpiScore) based on the methylation patterns present (positive score is Episcore >60). As follows is a table of outcomes of studies assessing Bladder EpiCheck:

ESOU_Bladder_EpiCheck.png



Xpert Bladder Cancer Monitor is a test that has 5 mRNA targets, including ABL1, CRH, IGF2, UPK1B, and ANXA10. This assay is performed in a self-contained cartridge using GeneXpert Systems (Cepheid) with a turnaround time of 90 minutes.

Dr. Xylinas concluded his presentation with the following take-home messages:
  • Biomarkers area improving, but they are not ready for prime time for primary diagnosis
  • In the surveillance setting, there is a high medical need – they are ready for prime time, but not yet able to fully replace cystoscopy
  • NMP-22 and FISH are expensive and have insufficient efficacy
  • ADX bladder, epigenetics, and mRNA biomarkers are showing early promise
  • Alternating cystoscopy and markers could be the eventual winner in the surveillance disease space
Presented by: Evanguelos Xylinas, MD, Bichat Hospital, Paris Descartes University, Paris, France

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 18th Meeting of the EAU Section of Oncological Urology (ESOU21), January 29-31, 2021

References:
  1. Leal J, Luengo-Fernandez R, Sullivan R, et al. Economic burden of bladder cancer across the European Union. Eur Urol 2016 Mar;69(3):438-447.
  2. Han DS, Lynch KE, Chang JW, et al. Overuse of Cystoscopic Surveillance Among Patients with Low-risk Non-muscle-invasive bladder cancer: A National Study of patient, provider, and facility factors. Urology 2019 Sep;131:112-119.
  3. Roupret M, Gontero P, McCracken SRC, et al. Diagnostic accuracy of MCM5 for the Detection of Recurrence in Nonmuscle Invasive Bladder Cancer Followup: A Blinded, Prospective Cohort, Multicenter European Study. J Urol. 2020 Oct;204(4):685-690.