Molecular Marker Screening Cuts Need for Cystoscopy

Becky McCall

March 12, 2012

March 12, 2012 (Paris, France) — A bladder cancer screening protocol using a combination of 4 molecular markers reduces the need for cystoscopy by 75%, compared with dipstick testing alone, according to the results of the Bladder Cancer Urine Marker Project. The findings were presented here at the European Association of Urology 27th Annual Congress.

The researchers found that the use of a sequential protocol for bladder cancer screening (dipstick urine testing followed by molecular marker screening, followed by cystoscopy if the results are ambiguous) considerably reduced the number of cystoscopy recommendations with very few missed cancers.

"Molecular markers might make screening for bladder cancer more cost efficient, but likely only in high-risk groups," principal investigator Chris Bangma, MD, professor and chair of the Department of Urology at Erasmus Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.

Dr. Bangma explained that despite the development of therapies over recent years, invasive bladder cancer mortality has not decreased.

We wanted to see if the old method of cystoscopic diagnosis could be improved on with modern methods of molecular markers. He added that with previous screening programs, which rely on home microhematuria tests, only 8% of tests trigger evaluation for urothelial cancer.

"Our screening program was partly a feasibility study to discover the real incidence of bladder cancer, but we also wanted to construct a protocol that would be cost effective in population-based screening, and less invasive," Dr. Bangma added.

In the study, 88% of the 1984 men (all older than 50 years) performed the home dipstick test every day for 14 days, and 23.5% had a positive hematuria reading. These men were invited for further work-up and supplied samples for molecular marker testing.

"We introduced the extra molecular marker step, which reduced the requirement for cystoscopy and made it easier for patients to comply with screening," noted Dr. Bangma.

Four molecular marker tests were used: NMP22, an established test with a low specificity and sensitivity; the FGFR3 mutation snapshot assay, which identifies bladder cancers with a good prognosis; a microsatellite analysis, which is a compilation of 20 genetic tests; and a custom methylation-specific multiplex ligation-dependent probe amplification test, which picks up epigenetic changes.

Of the men who underwent molecular marker testing, 1.2% had positive tests and therefore underwent cystoscopy. "Use of the molecular markers reduced the need for cystoscopy by 75%," Dr. Bangma reported.

Of the 71 men who underwent cystoscopy, 4 early bladder cancers and 1 kidney cancer were identified. A registry check conducted a year later showed that 1 bladder cancer and 1 kidney cancer had been missed.

"This is a very low rate of cystoscopy, compared with historic studies. Our protocol reduces cystoscopy and identifies tumors at an early curative stage," Dr. Bangma said. "Without these molecular markers, if we wanted to screen the whole population, we would have to perform an enormous number of cystoscopies, which is not acceptable or cost effective."

"We calculated that our stepwise protocol costs €80 per man, which would be feasible on a wider scale," said Dr. Bangma. "Finding 4 cancers in 6500 men is not cost effective. Of course, we do not know about their long-term mortality; the numbers are too low for making conclusions."

Dr. Bangma explained that at least 80% of tumors were found with the combination of molecular marker tests, despite the small numbers in the study. He added that since the start of their study in 2008, technological developments have facilitated the convenience of the protocol. "For example, we now need reduced amounts of DNA for testing, and therefore less urine."

Even so, rolling out this protocol to the whole population would be impractical, Dr. Bangma noted. High-risk groups, such as smokers, need to be targeted; they had more positive urine tests in the study (odds ratio, 1.47, 95% confidence interval, 1.0 to 2.2; P = .04), he said.

Another well-defined group at high risk for bladder cancer are individuals who work in heavy-metal industries. A population in Germany is currently being screened for this, Dr. Bangma noted.

"The other avenue for these tests and protocols might be in countries such as China, where there is a very high incidence of bladder cancer, or in some African countries where many people are infected with schistosomiasis, for example."

In his concluding comments, Dr. Bangma remarked with regret that despite efforts to detect early bladder cancers and treat them, few have actually helped reduce mortality because of the low numbers detected. "There might need to be more emphasis on treatments, but unfortunately, we've been looking for 20 years and haven't found anything new yet."

Colin Dinney, MD, chair of the Department of Urology at the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News that he agrees that screening for bladder cancer is a critical issue that needs to be addressed, but he expressed reservation about the application of the research.

"Unfortunately, despite the reasonable specificity of these tests, the utility of this approach is limited by the prevalence of the disease and, thus, the positive predictive values are too low to make routine screening feasible in an unselected population. However, [tailoring this approach to] a high-risk population based on epidemiologic and genetic factors could be a step toward developing an effective strategy for screening," Dr. Dinney concluded.

Nicholas James, MD, professor of clinical oncology at the University Hospitals Birmingham, United Kingdom, also commented on the study for Medscape Medical News.

He explained that this research rests on the presumption that because the bladder tumor is bathed in urine, tumor-related molecules should be detected in the urine sample.

"It aims to use some of these tests to screen for bladder cancer in an asymptomatic population but sadly fails to show sufficient utility," Dr. James said. "You would need to do thousands of tests to ultimately reveal very few cancers."

Although adding a second round of testing for molecular markers "offered some improvement, it was still insufficiently precise, with more than 6000 men screened, leading to more than 70 cystoscopies and only 4 bladder cancers.... It's a logical study, but it is nowhere near feasible as a screening test," said Dr. James.

"The authors acknowledge that this hit rate is simply not good enough to justify costs, damage, and anxiety with all those cystoscopies to pick up a tumor possibly only a month or so earlier," he concluded.

The study was financed by 2 patient foundations. The NMP-22 test kit was manufactured and supplied without cost by Matritech (Newtown, Massachusetts). Dr. Bangma, Dr. Dinney, and Dr. James have disclosed no relevant financial relationships.

European Association of Urology (EAU) 27th Annual Congress: Abstract 447. Presented February 26, 2012.

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