The role of protein- and cell-based urinary biomarkers for bladder cancer detection and surveillance is controversial, and in 2017 these assays have yet to come into widespread use among urologists. Their uptake is expected to increase, however, considering that the AUA/Society of Urologic Oncology “Guideline on Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer” that was released in 2016 identifies situations for using urinary biomarkers, according to Badrinath R. Konety, MD.
The role of protein- and cell-based urinary biomarkers for bladder cancer detection and surveillance is controversial, and in 2017 these assays have yet to come into widespread use among urologists. Their uptake is expected to increase, however, considering that the American Urological Association/Society of Urologic Oncology “Guideline on Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer” (NMIBC) that was released in 2016 identifies situations for using urinary biomarkers, according to Badrinath R. Konety, MD.
According to the guideline, clinicians may use select urinary biomarkers to assess response to intravesical chemotherapy with bacillus Calmette-Guérin (UroVysion Bladder Cancer Kit) and to adjudicate equivocal cytology (UroVysion and ImmunoCyt). It also states, however, that urinary biomarkers should not be used in place of cystoscopic evaluation for surveillance of NMIBC. In addition, the guideline states that neither urinary biomarkers nor cytology should be routinely used during surveillance of a patient with a history of low-risk cancer and a normal cystoscopy.
Several urinary biomarkers have been approved by the FDA for use in bladder cancer detection and/or surveillance (table). These include fluorescence in situ hybridization (FISH [UroVysion]), nuclear matrix protein 22 (NMP22 [NMP22 and NMP22BladderChek]), bladder tumor antigen (BTA [BTA stat and BTA TRAK]), and fluorescent immunohistochemistry (ImmunoCyt/uCyt+).
Other urine-based tests marketed by clinical laboratories that meet Clinical Improvement Act standards include CertNDx and Cxbladder Triage, Cxbladder Detect, and Cxbladder Monitor. CertNDx assesses mutations in fibroblast growth factor receptor 3, which may be associated with lower grade bladder tumors that have a good prognosis, and is used in combination with cytology. The Cxbladder tests measure five genes (CDC2, HOXA13, MDK, AGFBP5, CXCR2). Cxbladder Triage also analyzes phenotypic and clinical risk factors and is intended for primary evaluation of patients with hematuria to reduce the need for an invasive workup in patients who have a low probability of having bladder cancer. Cxbladder Detect is intended for evaluation of patients presenting with hematuria as an adjunct to cystoscopy. Cxbladder Monitor combines the genomic biomarkers with patient-specific clinical factors and is used to monitor for bladder cancer recurrence.
Next: Cytology vs. biomarkers
Voided urine cytology has been the mainstay for urine-based bladder cancer detection, and it has the advantage of having very high specificity.
Dr. Konety“If the cytology comes back positive, then there is a greater than 90% chance that cancer is present. However, a negative result is not that helpful because the majority of low-grade tumors have negative cytology, and that limitation of cytology is the gap that the newer biomarkers are trying to fill,” said Dr. Konety, professor and chair of urology at the University of Minnesota, Minneapolis.
As another drawback, there is a turnaround delay of several days for cytology, whereas some of the other biomarkers (BTA stat, NMP22BladderChek) are point-of-care tests that generate immediate results. In addition, the results of cytology can be variable because there are at least five official values for the results, and the interpretation is reader dependent. In contrast, some of the second- and third-generation biomarker tests provide a result that is cut and dry-the test is either positive or negative.
Consistent with the AUA/SUO guideline, Dr. Konety observed that the biomarkers seem to be finding the greatest application in the follow-up of patients diagnosed with bladder cancer and particularly as a second-level test in the setting of atypical urine cytology. It appears they are being used less often for initial diagnosis in patients with hematuria.
In order to investigate the uptake of the newer urinary biomarker tests for bladder cancer surveillance, Dr. Konety and colleagues conducted an analysis using Medicare data. Their methods did not include analyses of any individual assays, but the results showed that overall use of biomarkers by urologists increased from 11% in 2000 to 26% in 2011.
Commenting on the findings, Dr. Konety described the uptake as “stagnated” and said he does not believe that the new urinary markers have led to a change in approach to management of bladder cancer.
“The lament of people who have been doing research with the new urinary biomarkers is that these diagnostic tools have not been adopted to the extent that might be expected considering their specificity is in the 50% to 80% range. This reluctance is difficult to reconcile when juxtaposed against the high reliance on PSA for prostate cancer screening and monitoring, taking into account that as a stand-alone marker, PSA has a specificity of only about 25%,” Dr. Konety said.
He suggested multiple factors to explain the limited utilization of the bladder cancer biomarkers.
“Cost may be an issue, although the protein-based markers are covered by insurance and not that expensive, which may explain why the qualitative NMP22 assay may have the greatest use overall. And while the FISH assay was initially very expensive, costing thousands of dollars, it has now come down in price,” he said.
Logistics is another consideration, but uncertainty of how to apply the results clinically likely plays a major role.
“Because guidelines have not definitively advocated for or against biomarkers for diagnosis or surveillance, urologists have not been compelled to use them. In fact, the current AUA guideline on diagnosis, evaluation, and follow-up of asymptomatic microhematuria in adults, which is from 2012, doesn’t even advocate for cytology in the workup. That creates a high bar for justifying the use of these newer, more expensive markers,” Dr. Konety said.
Next: Performance and advantages
Dr. Konety said there is good evidence to show that use of urinary biomarkers to adjudicate equivocal cytology helps to avoid unnecessary additional workup. There is also research that demonstrates including urinary biomarker testing in a surveillance paradigm increases the detection rate for recurrences, said Dr. Konety, citing a study by van der Aa et al (J Urol 2010; 183:76-80) looking at how knowledge of results of a microsatellite marker urine test (not FDA approved) influenced the accuracy of cystoscopy performed as follow-up in patients with low-grade NMIBC.
The randomized study compared the number of histologically proven bladder cancer recurrences in patients who underwent cystoscopy on the basis of the urologist knowing that the urine test was positive and a control arm in which cystoscopy was performed routinely at 3, 12, and 24 months. During a median follow-up of 34 months, the number of detected recurrences was significantly greater in the group where the urologist performed cystoscopy based on the assay results, and in that arm, a recurrence was detected in almost one-third of the 131 cystoscopies done.
A total of 120 cystoscopies were performed in the control arm, of which only six detected a recurrence. The recurrence rate for patients who did not undergo cystoscopy because they had a negative test result was 7% and almost identical to that of the control arm.
“Perhaps the awareness of a positive urine test result improves detection of recurrence using cystoscopy because it leads to heightened awareness of subtle changes in the cystoscopic appearance of the bladder, or maybe it lowers the threshold for triggering the biopsy,” Dr. Konety said.
There are also data from studies supporting a role for biomarkers in evaluating response to intravesical BCG. Most of that evidence exists for the FISH assay, and it comes from large studies that are both manufacturer sponsored and conducted by independent investigators.
“All of the available studies reported that if a patient had a positive FISH before starting BCG and the assay turned negative after 6 weeks of BCG induction, the patient was likely to have a positive response to BCG, decreased likelihood of recurrence, and decreased disease progression. The proportion of patients who did not demonstrate disease progression after the FISH turned negative varied from study to study, but the basic outcome was consistent across all of the studies,” Dr. Konety said.
It is also possible that the urinary markers can detect changes at the cellular level prior to the development of endoscopically visible lesions. This phenomenon, which is referred to as an anticipatory positive result, has been described with FISH as well as with cytology.
“The false-positive rate with all of these markers can be as high as 30% to 50%, although it is generally in the 20% to 25% range. Not everybody, however, believes that all false-positive findings are truly false,” Dr. Konety explained.
“Data with FISH show that about 30% to 40% of patients who have a false-positive result will develop a tumor over the next few years. Whether the tumor developed subsequent to the test or the assay predicted its development is hard to say. However, those who argue in favor of the anticipatory positive result contend there must be an association with the earlier positive test if it remained positive until the tumor ultimately appeared.”
Further study is needed to establish that the FISH assay offers such increased sensitivity for early detection.
Next: The false-positive conundrum
The relatively high rate of false-positive results with the newer biomarkers compared to cytology is likely also a factor limiting their use.
“For example, I often receive calls from urologists who are unsure what to do when the FISH is positive and the patient undergoes a thorough workup with a complete upper tract evaluation and biopsy with negative findings,” Dr. Konety said.
“This false-positive conundrum also occurs with routine cytology, although considering the high specificity of cytology, some urologists would treat empirically with intravesical BCG until the cytology became negative. It may be more difficult to argue in favor of using that same approach based on a positive FISH considering that FISH tests for genetic changes. Unless there is evidence of a phenotypic change, urologists may not be comfortable being aggressive with treatment.”
Ongoing research with biomarkers includes a focus on developing tests that identify genomic alterations in cells found in the urinary sediment of patients with microhematuria in order to provide a tool that could accurately detect existing cancer or predict its subsequent development. In the area of recurrence monitoring, the ability to reliably detect or rule out cancer using a urine assay remains the holy grail for diagnostic evaluation as it would potentially eliminate the burdens of a more extensive workup, Dr. Konety said.
“Cystoscopy in the office is generally well tolerated, but avoiding repeated biopsies, upper tract studies, and CT scans would be an important advantage. It is interesting, however, that when patients with bladder cancer were asked about the level of performance a urine test should provide before they would be willing to stop undergoing cystoscopic monitoring, they wanted 95% sensitivity and specificity. With this information in mind, it is unlikely that patients or urologists would be willing to accept replacing cystoscopy with follow-up biomarker assays either in the initial diagnosis or surveillance paradigms for bladder cancer.”
The tests in development are characterizing methylation profiles of the genes, genetic mutations, or both. Companies working in this area include MDxHealth, Genomic Health, GenomeDx, Foundation Medicine, and Cepheid.
“These types of tests have the potential to not only determine whether or not a patient has or is likely to develop cancer, but they might also give clues about the tumor biology and its response to various treatments that could be used to guide treatment decisions,” Dr. Konety said.
“By identifying specific genomic and epigenomic markers, these tests might also be useful for personalized prediction of recurrence risk.
Disclosure: Dr. Konety is an investigator in a clinical trial for Genomic Health.
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