SUO 2022: Real Life Impact of Cxbladder Tests on Diagnosis and Surveillance of Bladder Cancer

(UroToday.com) The 23^rd Annual Meeting of the Society of Urologic Oncology held in San Diego, CA was host to a session on the real life impact of Cxbladder tests for the diagnosis and surveillance of bladder cancer. Dr. Sia Daneshmand began his presentation by highlighting the two commonly used urine-based tests in the field of urothelial cancer: cytology and FISH. Cytology, which identifies cells that have sloughed off tumor and are caught in voided urine, is plagued by poor sensitivity (59 - 62%), high rates of atypical or suspicious findings, and inter-reader variability, which limit its utility as a “rule out test”, particularly for low-grade disease. Fluorescence In Situ Hybridization (FISH) test, which similarly identifies whole cells that have sloughed off tumor and caught in voided urine, is typically used as a reflex test following atypical cytology results. FISH interpretation is quantitative and depends on the number of cells with aneuploidy, with moderate rates of non-diagnostic results. Furthermore, this test has poor sensitivity (39%) with high variability.

Current tumor markers in this disease space include:

• Biochemical detection of proteins or other urinary compounds
  • Example: NMP22
• Detection of cellular antigen by immunohistochemistry or cytochemistry
  • Example: ImmunoCyt^TM
• Detection of genetic alterations
  • FISH, FGFR3
• RNA
  • Cepheid
  • Pacific Edge
• Methylation
  • MDxHealth
  • Nucleix
  • Bladder cancer

However, it is important to note that these biomarkers have not truly been adopted in clinical practice and, to date, their use has not been endorsed by current guidelines.

The limitations of cytology are further highlighted by work from Dr. Daneshmand’s group evaluating the efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer patients. In this study, out of the 13 patients who had disease recurrence based only on blue light flexible cystoscope, none had a positive cytology result. Although a positive UroVysion FISH test has been shown to be associated with a 3.3-fold increased risk of bladder cancer recurrence, the performance of this test remains poor:

• Sensitivity: 36%
• Specificity: 76%
• Positive predictive value: 40% (PPV)
• Negative predictive value (NPCV6yhn: 73%

As such, Dr. Daneshmand concluded that UroVysion FISH may be useful in risk-stratifying patients entering clinical trials who fail to respond to induction therapy, but individual patient decision remains limited due to the low test PPV.

The following urinary biomarkers are FDA approved for the detection of bladder cancer:

However, the 2016 AUA guidelines currently state that “a clinician should not use urinary biomarkers in place of cystoscopic evaluation” (Strong Recommendation). Similarly, the 2022 NCCN guidelines currently state that clinicians may consider urinary urothelial tumor markers for patients with high-risk, non-muscle invasive bladder cancer (category 2B).

As such, should we use markers for every patient? It appears that they are not necessary for every case, nor are they currently recommended by the AUA or EAU, and Dr. Daneshmand highlighted that one should not send cytology when looking at a tumor and getting a pathologic specimen in the operating room. The biggest unmet clinical need, however, remains what to do with patients with atypical findings on these urinary tests.

Cxbladder is a genomic test that is optimized for the detection and management of urothelial cancer. It can be used in the following clinical scenarios:

1. Hematuria evaluation:
   1. Cxbladder Triage: Optimized to rule out low-risk patients
   2. Cxbladder Detect: A detection test to help in the “rule-in” or “rule-out” of urothelial cancer
2. Surveillance:
   1. Cxbladder Monitor: Optimized to rule out urothelial carcinoma
3. Other compelling uses:
   1. Adjudication of atypical cytology and equivocal cystoscopy
   2. Patient in-home sampling allows for risk stratification to prioritize high-risk patients for immediate follow-up

It is important to highlight in the above figure that the NPVs of these tests are consistently in the 96% to 98.5% range, which strengthens these tests’ ability to rule out the presence of disease. In a 2019 publication by Konety et al. in European Urology, Cxbladder was shown to rule out 35% of urothelial carcinomas at a negative predictive value of 97%. While Cxbladder missed 8.5% of urothelial carcinomas, cytology comparatively missed 63% of these same tumors. Significantly, though, Cxbladder correctly adjudicated all patients diagnosed with urothelial carcinoma among those with atypical cytology and equivocal cystoscopy.¹ This highlights the utility of Cxbladder tests in patients with atypical cytology and/or cystoscopy findings.

Presented by: Sia Daneshmand, MD, Professor of Urology, Department of Urology, University of Southern California, Los Angeles, CA

Written by: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 23rd Annual Meeting of the Society of Urologic Oncology (SUO), Nov 30 – Dec 2, 2022. San Diego, CA

Reference:

1. Konety B, et al. Evaluation of Cxbladder and Adjudication of Atypical Cytology and Equivocal Cystoscopy. Eur Urol;76(2):238-43.