Urinary Biomarkers Not Useful for Bladder Cancer Diagnosis

Janis C. Kelly

October 26, 2015

The hope that urine-based biomarkers might be a noninvasive alternative to cystoscopy for diagnosis of bladder cancer was dealt a setback by a new systematic review and meta-analysis that found that the currently available tests were not accurate enough to replace standard methods.

The analysis, published online October 27 in the Annals of Internal Medicine, included 57 studies of five FDA-approved urinary biomarkers for diagnosis of bladder cancer in adults who had signs or symptoms of bladder cancer or were undergoing surveillance for recurrent disease.

The biomarkers studied were quantitative or qualitative nuclear matrix protein 22 (NMP22), qualitative or quantitative bladder tumor antigen (BTA), fluorescent in situ hybridization (FISH), fluorescent immunohistochemistry (ImmunoCyt [Scimedx Corp]), and Cxbladder (Pacific Edge Diagnostics USA Ltd). Each was evaluated for accuracy against cystoscopy and histopathology as the reference standard.

"The sensitivity and specificity of urinary biomarkers are suboptimal. Even combining urinary biomarkers with cytology misses about 10% of cancers. When you look at the likelihood ratios, they are not all that strong," lead author Roger Chou, MD.

Dr Chou, who is professor of medicine, Division of General Internal Medicine and Geriatrics, Oregon Health and Science University, Portland, explained that the likelihood of bladder cancer did not change enough with either positive or negative urine biomarker results.

"In persons with an estimated likelihood of 5% for bladder cancer prior to testing (based on symptoms, age, risk factors, etc), a positive result increases the likelihood to 14% to 21%, and a negative result decreases it to 1.5% to 2.5%. In persons with a pretest likelihood of 20%, a positive test increases it from 39% to 56%, and a negative test decreases it to 6.8% to 11%. This means that around 10% of patients who have a negative biomarker test would still have bladder cancer. I think many clinicians would say that that percentage is too high to forego performing cystoscopies," he said.

Because patients who test positive for the presence of urinary biomarkers are routinely referred for cystoscopy, Dr Chou said that screening with biomarkers will not reduce the need for cystoscopies in that population. Furthermore, the researchers found that about half of positive biomarker test results were falsely positive, even among patients in whom the prevalence of bladder cancer was higher.

In an accompanying editorial, Phillip H. Abbosh, MD, PhD, and Elizabeth R. Plimack, MD, both from Fox Chase Cancer Center, Philadelphia, Pennsylvania, said that cost-effectiveness estimates suggest that even for patients with a history of superficial bladder cancer, "cystoscopy only" is the most cost-effective strategy for tumor detection. They also noted that tumors missed on cystoscopy were also missed by urinary biomarkers.

Dr Plimack, who is director or genitourinary clinical research and is associate professor in the Department of Hematology/Oncology, told Medscape Medical News, "If a urine-based test were available that would identify new or recurrent superficial lesions and allow providers to avoid in-office cystoscopy in patients testing negatively, a cost savings might be realized. In addition, many patients might be spared from a procedure that can sometimes be associated with discomfort, urinary tract infections, urethral strictures, and, rarely, hospitalization. In their current state, the tests are not exempting clinicians from other procedures."

Diagnostic sensitivity for bladder cancer ranged from 0.57 to 0.82; specificity ranged from 0.74 to 0.88. Sensitivity increased with higher tumor stage or grade. With some biomarkers, sensitivity was higher for initial diagnosis of bladder cancer than for diagnosis of recurrence. Dr Chou said that before a biomarker could be considered a candidate for replacing standard methods, he would like to see sensitivity and specificity be greater 90% and, ideally, close to 100%, especially with regard to sensitivity.

Quantitative NMP22 and qualitative BTA were similarly accurate in head-to-head comparisons. There were few head-to-head studies of other biomarkers.

Dr Chou suggested that urinary biomarkers might be helpful as an adjunct to standard surveillance to help determine the patients in whom there is a high likelihood for recurrence, even with a negative cystoscopy result, and that they might be helpful in situations in which the cytology results are equivocal.

"There are questions about whether biomarkers can be used to predict response to different types of therapy, predict prognosis, or predict recurrence, and more research seems to be warranted in those areas," Dr Chou added.

Better biomarkers might be on the horizon. Dr Plimack said that tests now under development that incorporate FGFR3 hot-spot mutations (which are present in the majority of superficial bladder cancers), that detect both FGFR3 point mutations and CpG island hypermethylation, or that detect more than one type of cancer-specific alteration (eg, immunohistochemistry plus point mutation or mRNA alterations) might increase sensitivity without compromising specificity.

The study authors, Dr Abbosh, and Dr Plimack have disclosed no relevant financial relationships.

Ann Intern Med. Published online October 27, 2015.

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