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.
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