BioWorld International Correspondent
LONDON - A large-scale trial involving 3,000 patients is about to begin to evaluate a simple urine test for bladder cancer. The test, which detects a protein involved in cell division, could replace the battery of expensive and invasive tests currently used to diagnose cancer of the bladder.
Kai Stoeber, lecturer in the Wolfson Institute for Biomedical Research at University College London, told BioWorld International, "At present, patients who have lower urinary tract symptoms, such as blood in the urine, have to have a series of tests involving several visits to the hospital. These include flexible cystoscopy, where a telescopic camera is inserted into the bladder to look for abnormal growths. These tests cost about £1,200 per patient, and there are about 10 such patients in every hospital in the UK every week. Furthermore, cystoscopy is quite an unpleasant procedure."
The trial, which is being funded by Cancer Research UK, the UK's largest cancer research charity, will aim to find out if primary bladder cancer can be diagnosed with equal accuracy by the new test. It will also investigate whether the new urine test can accurately detect recurrence of bladder cancer in patients who already have been treated for the disease. Currently, such patients have to undergo cystoscopy every six to 12 months for the duration of their lives.
"A urine test, of course, could be performed much more frequently, say, every four weeks, to detect early relapse," Stoeber said.
One of the most exciting findings by the team is that during early trials the urine test gave a positive result in men who had prostate cancer confined to the prostate gland. Although the number of patients was small, the finding was statistically significant.
The multicenter trial to detect bladder cancer will therefore link up with an existing study of prostate cancer in northern England, to determine if the test can accurately diagnose prostate cancer, too.
An account of the initial evaluation of the test has been published in the July 17, 2002, issue of the Journal of the National Cancer Institute, in a paper titled "Diagnosis of Genito-Urinary Tract Cancer by Detection of Minichromosome Maintenance 5 Protein in Urine Sediments."
In the UK, bladder cancer is the fourth commonest cancer in men and the eighth commonest in women. There are nearly 13,000 cases a year in the UK, most of them in people over 65. Prostate cancer is the second commonest cancer in men, with more than 21,000 cases each year, again mostly in people over 65.
The foundation for the test was laid in the late 1990s when Stoeber, working with Gareth Williams, a professor of histopathology at University College London, and colleagues were studying the processes by which chromosomes replicate in mammalian cells. They were focusing on a set of about 20 proteins that form a so-called "prereplicative complex" at bidirectional origins of replication - the points at which the parental strands of the DNA are unwound and replication forks are established, allowing chromosomal replication to begin with the synthesis of two daughter strands.
Part of the complex is comprised of a family of six proteins called the minichromosome maintenance (MCM) proteins. Once the two parental DNA strands are separated, the MCM proteins form a hexamer and act as a replicative helicase, swiveling along the DNA molecule and continuing to separate the two parental strands.
Stoeber, Williams and their co-workers realized that one of those six proteins, MCM5, was present only in dividing cells. Stoeber said it took Williams' insight as a histopathologist to make the leap in understanding that eventually led to the development of the test.
"If you look at the epithelium of an organ, such as the bladder, it has about six layers of cells. Those right on the basement membrane are stem cells that divide quite slowly, but the next layer, which are derived from the stem cells, divide more quickly," Stoeber said. "As the cells work their way up to the surface, they differentiate and eventually slough off. Williams realized that in normal epithelium the dividing cells are not exposed, but that if a tumor was present, they would be." Far from relying on a specific cancer marker, he said, the test exploits a deviation from the normal tissue architecture of transitional epithelium.
For the initial trial, reported earlier this month in the Journal of the National Cancer Institute, Stoeber and colleagues tested blinded urine samples from 350 patients attending a urology clinic for investigation of symptoms or routine follow-up after treatment for bladder cancer. They found that their test had a sensitivity of 92 percent, and a specificity of 80 percent. That compares with a sensitivity of only 48 percent from traditional cytology.
Some of the patients who had false-positive results had bladder calculi, which would have disrupted the epithelium of the bladder. Others had organ-confined prostate cancer.