Despite efforts to identify highly sensitive urine-based markers that are able to better identify patients with a true risk of bladder cancer, primary evaluation still relies upon hematuria screening and urine cytology. Even in cases of abnormal cytology, assays to risk-stratify patients have yet to gain widespread clinical adoption or acceptance in professional guidelines. Workup and monitoring of patients requires unpleasant, sometimes unnecessary, invasive techniques leaving many in urology seeking better tests. Standard Tests Have Low Sensitivity Hematuria is relatively common in the general population (9 percent to 18 percent) while the prevalence of urinary tract cancers is low in the general population (0.01 percent to 3 percent), experts say, making screening for the disease difficult. Clinicians would like alternative measures that better identify patients who truly require further evaluation and those who can be spared unnecessary workup, including radiation exposure and invasive cystoscopy. “Using blood in the urine as an indicator for possible cancer when it is that common of a finding is problematic, and that is the inherent problem with bladder cancer screening,” says Ronald Loo, M.D., regional chief of urology at Southern California Permanente Medical Group in Los Angeles. “The holy grail would be a quick test with a marker indicating when it is most likely bladder cancer—a test that can distinguish the population reliably so you can safely avoid working up people at low risk.” While Loo says a “litany of urine markers” have been discovered, his group has taken a different approach by examining common risk parameters. “Rather than looking for a magical test, what if you took common parameters without sophisticated testing and expense. It turns out the most important factor is whether the patient sees blood in the urine,” Loo explains. “Published studies have historically alluded to this.” Loo’s findings are based on a study of real-world outpatient referrals from primary care physicians for patients with asymptomatic microscopic hematuria. His group developed a Hematuria Risk Index to predict cancer risk. In the algorithm, history of gross hematuria and age of 50 years or older were given four points, whereas factors with lower odds ratios (history of smoking, male sex, and greater than 25 RBC/HPF on a recent urinalysis) were given one point. Among the 4,414 patients that were evaluated for hematuria, 32 percent of patients were identified as having a low risk of cancer, and only 0.2 percent had a cancer detected. Of the 14 percent of patients identified as high risk, 11.1 percent had a cancer detected. Overall, the three-year incidence of urinary tract cancer was only 0.43 percent. “Most malignant tumors can be identified by a history of gross hematuria, a far more reliable indicator of the need for urologic evaluation and imaging,” writes Loo in a study published in the February issue of Mayo Clinical Proceedings.“Patients with microscopic hematuria younger than 50 years and with no history of gross hematuria may not benefit from further evaluation and therefore could avoid unnecessary risk from radiation exposure and invasive endoscopy.” While Loo says that the index requires further validation before being adopted into evidence-based clinical decisionmaking tools, the findings do not diminish the need to identify sensitive urine-based markers. “Let’s say our model is validated; bladder cancer markers can still improve the diagnostic resolution or accuracy even further,” Loo tells DTTR. “I suspect the lowest-risk patients are not a good place to do an expensive screening test and the highest-risk patients will still need to be worked up. What is left is the patients in the middle who may need further segregation to identify those at higher risk.” The Value of Bladder Cancer Testing Researchers agree the ultimate goal would to develop a highly sensitive and specific urinary assay for bladder cancer. At this point, a number of candidate markers are both being investigated and are in commercial use. The ultimate measure of an assay for bladder cancer is not just its diagnostic accuracy, though, but its value: Would use of the test ultimately save the system resources through avoidance of unnecessary referrals and costly workups? Some studies are beginning to emerge in the literature demonstrating the potential for eliminating cystoscopies. In a study published in the May issue of European Urology, investigators determined that when used as a reflex test on patients with atypical urine cytology, a negative ImmunoCyt/uCyt test (Scimedx, Denville, N.J.) may predict a negative cystoscopy in select patients, thus reducing urgency and further workup in those with no prior history or low-grade disease. uCyt is a triple immunofluorescent monoclonal antibody assay that detects cytoplasmic mucins and carcinoembryonic antigen. Reflex uCyt was performed retrospectively on 506 atypical voided urine samples in patients who received a cystoscopy within 90 days. In those with a history of urothelial carcinoma (UC) the researchers found that reflex uCyt showed a sensitivity of 73 percent, a specificity of 49 percent, and an NPV of 80 percent. Without prior history of UC, reflex uCyt had a sensitivity of 85 percent, a specificity of 59 percent, and an NPV of 94 percent. “When used as a reflex test to arbitrate atypical urine cytology, a negative ImmunoCyt result can be used to predict a negative cystoscopy in select patients,” write the authors, led by Anoebel Odisho from the University of California, San Francisco. “The high NPV can be used to modify the urgency and nature of further urologic work-up, both in those without a history of UC and in those with a history of low-grade UC in which a routine follow-up schedule with fewer cystoscopies can be maintained despite a reading of atypical cytology.” The authors say prospective evaluation is necessary. “Because physicians are trained to find cancer, they like a high PPV,” says Anthony Shuber, co-founder and chief technology officer of Predictive Biosciences (Lexington, Mass.), which offers the CertNDx line of bladder cancer tests for hematuria assessment, staging, and monitoring. “Personally I believe that if the performance of a noninvasive diagnostic is so good, physicians will move straight to the therapeutic rigid cystoscopy” thereby eliminating the need for invasive testing to rule out cancer’s presence. Predictive Biosciences’ assay, which uses a combination of DNA and protein markers, can stratify patient populations into three groups: those without bladder cancer, those who might have bladder cancer, and those who should receive the standard care. While currently guidelines do not support the use of urine markers in this way, prospective studies may provide the evidence it is safe to forgo invasive diagnostics. “Bladder biomarkers can obviate the need for cystoscopy and are a better indicator of urothelial cancers,” says R. Jeffrey Karnes, M.D., associate professor of urology at the Mayo Clinic in Rochester and investigator for Predictive Biosciences. “If it is negative there is good certainty the patient doesn’t have cancer. It obviates the need for a more thorough evaluation providing some reassurance. They might have something else, but it helps risk-stratify. If it is positive there is approaching 100 percent certainty they have bladder cancer, and you can fairly confidently take them to the operating room rather than have an office cystoscopy.” The Future of Bladder Cancer Testing While experts in urology are hopeful that national recommendations will adopt urine biomarkers in the future as a means of stratifying patients, manufacturers of these kits face other challenges, including persuading physicians to adopt the tests in routine practice and reimbursement. Given the uncertainty of future reimbursement coupled with the challenge of reaching physicians, some companies like Scimedx are finding the international market favorable to penetrate. “We were interested in adding the test to the company’s portfolio in large part because doesn’t require significant capital expense of equipment typically needed with cytometry testing,” says Thomas Britten, president of Scimedx, which manufactures the uCyt assay. “The test enables laboratories to get into bladder cancer test with an easy-to-read test, without significant investment, and with a test that runs one-third the cost per test of other kits. But adoption requires significant amounts of evangelizing.” And the sales cycle can be long. “It takes a significant amount of capital to see revenue. It may take a year or two to get a reference lab to buy a couple kits. As a small manufacturer, you must weigh where to deploy resources.” But despite the frustrations, Britten tells DTTR he sees a future for bladder cancer testing assays. “In the future, we can’t have an assay out there for every antibody. Operationally it will run cleaner if they’re with a high-quality multiplex assay. I am biased, but I see cytometry getting kicked. If you have an expensive test, few will get tested. Rapid tests, an early warning screening, would be nice, especially for at-risk groups. With a cheaper, easier alternative closer to the point of care with the doctor you can find cancer before there is a big problem.”

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