Bladder Cancer Academy 2017: Bladder Cancer Biomarkers: New and Old

Schaumburg, IL ( Dr. Cookson gave a great talk on bladder cancer biomarkers. He began his talk with a summary of current clinical practice. This included cystoscopy with biopsy (the gold standard), imaging with CT urogram, and urine based testing, which today include cytology, FISH, NMP-22, BTA. STAT and TRAK, ImmunoCyt and lastly, the new CxBladder. Cystoscopy and urine cytology have been recommended in all guidelines for quite some time, but some urinary biomarkers are now being recommended to be incorporated as well.

More than 30 urinary biomarkers have been reported, but only a few have been FDA approved. Currently their use in diagnosis is controversial and their role in surveillance is evolving. Potentially, urinary biomarkers with high sensitivity and specificity would be able to replace the gold standard of cystoscopy. Cystoscopy has a sensitivity and specificity of approximately 90% with the advantages of enabling the urologist to accurately visualize the lesions. The disadvantages of cystoscopy include its invasiveness and relatively high cost. Furthermore, it may be inconclusive with grossly abnormal appearing bladder in different settings (Foley catheter, inflammation). It also has potential complications, including infection, bleeding, perforation and retention.

Urinary cytology, the most prevalent biomarker used to date is highly specific, very sensitive for high grade disease, non-invasive and relatively cheap. However, it has poor sensitivity for low grade disease and is highly dependent on the cytopathologist’s expertise.

Some of the current used urinary biomarkers are protein based. These include BTA stat and BTA TRAK. They have similar sensitivity and specificity, ranging between 62-68%, and 73%, respectively. Sensitivity of both depends on tumor grade, stage and size. Other protein based biomarkers include NMP22 and NMP22 bladderchek. These tests detect nuclear mitotic apparats protein, with a sensitivity of 67% and specificity of 75%. They are FDA approved for screening and diagnosis. Unfortunately, they have a high false positive rate caused by stones, infection, hematuria, and instrumentation.

UroVysion (FISH) is a cell based urinary biomarker, detecting alteration in chromosomes 3,7,17 and loss of 9p21 locus. It is a multi-target, multicolor fluorescence based biomarker. It is has been FDA approved form 2005 for the detection of recurrent non muscle invasive bladder cancer (NMIBC), having a sensitivity of 73% and specificity of 90%, requiring trained personnel and special equipment. It functions well in detecting high grade disease and can also detect occult CIS. Patients with positive FISH results during BCG therapy are 3-5 times more likely to experience bladder cancer recurrence and 5-13 times more likely to have disease progression (p<0.01). Therefore, FISH can be useful if post BCG cytology is equivocal. 

ImmunoCyt is a cocktail of 3 monoclonal antibodies: LDQ10, M344 (mucin glycoprotein), and 19A211 (CEA). Its sensitivity is 81% and specificity is 75% and it identifies tumor associated antigens in urothelial carcinoma cells. Similar to other markers, it requires trained personnel, lacks specificity compared to cytology, and requires 500 negative cells for it to be negative.

Lastly, Cxbladder is a relatively new urinary biomarker, measuring the gene expression of 5 multiplex mRNA (uRNA) biomarkers, with a sensitivity of 83%, and specificity of 85%. It incorporates previous urothelial carcinoma history to represent a bladder cancer signature. Its clinical utility is in primary detection and surveillance detecting disease recurrence.

In order to avoid and replace cystoscopies, the diagnostic test must have a high negative predictive value (NPV). Urovysion has an NPV higher than 80%, but based on survey data, this is not acceptable by most patients, willing to forgo cystoscopy, only if the NPV is higher than 95%. Studies have shown the Cxbladder monitor is an effective rule out test with high sensitivity 91% and high NPV of 96%.

Approximately a 1/3 of urine cytology specimens are reported as atypical. This represents usually suspicious or abnormal cells of uncertain significance. Inflammation, instrumentation, and post BCG therapy can yield atypical cytology results. Combined data from 2 prospective studies evaluating the usefulness of FISH in the setting of atypical cytology to detect urothelial carcinoma, have demonstrated to result in a reduction of biopsy rate of between 68%-83%.

In the setting of non-muscle invasive bladder cancer (NMIBC), the NCCN guidelines states that consideration should be given to FDA approved urinary biomarkers, FISH or NMP22 in monitoring for recurrence only (category 2a). However, the AUA guidelines state that in surveillance of NMIBC, urinary biomarkers should not be used in place of cystoscopy (Grade B), but they may be used to assess response to intravesical BCG therapy.

New genetic biomarkers for bladder cancer have been introduced, including the AssureMDX (Discovery study). This involves DNA methylation of 3 genes: TWIST1, ONECUT2, and OTX1. It basically analyzes the mutation status of 3 bladder cancer known genes – FGFR3, TERT, and HRAS. This has been found to have a sensitivity of 97%, specificity of 83%, PPV of 23% and NPV of 99.9%.

Dr. Cookson concluded his informative presentation reiterating that cystoscopy and cytology remain the gold standard for diagnosis and surveillance. Urinary markers are used to assist in the management of NMIBC, in surveillance, reflex testing in cases of atypical cytology, and monitoring response to BCG therapy. Prospective studies using combinations of markers can potentially reduce need for cystoscopy during surveillance, improve patient satisfaction and quality of life, and reduce cost.

Presented By: Michael Cookson, MD, MMHC, The University of Oklahoma Health Sciences Center

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 Bladder Cancer Academy - June 9 - 10 - Schaumburg, Illinois, USA