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.