Although patient outcomes are yet to improve, the combination of advancing knowledge, technological breakthroughs and new treatments is setting the stage for a genomic revolution in the treatment of bladder cancer, according to James Catto, MB, ChB, PhD, FRCS, who presented the annual European Association of Urology (EAU) Lecture Monday morning at AUA2017.
“It’s clinical outcomes that drive change in practices, and in bladder cancer we certainly aren’t doing that well. The survival rates are not improving. Indeed, they sometimes look like they are going backward,” said Dr. Catto, professor of Urology at the University of Sheffield and an Honorary Senior Clinical Research fellow at the University of Oxford, United Kingdom.
“After cystectomy, it’s no better,” he continued. “The current data show no improvement in survival after cystectomy over the last 30 years. And failure is common, whether it’s due to staging or inappropriate or inadequate systemic treatments. Bladder sparing approaches to treatment are very interesting and very appealing, but they are making limited impact.”
That limited impact is partly due to the selective nature of case referrals by urologists and partly attributable to disease biology, as many tumors do not respond to trimodal therapy.
“And on the back of all that is the huge cost, as bladder cancer is one of the most expensive human cancers to manage,” Dr. Catto said. “It accounts for 3 percent of all cancer costs and $5 billion per year is spent in the European Union on this disease, which is not good, particularly because outcomes are not improving.”
The lack of new treatments is the main reason that outcomes remain poor, Dr. Catto said. But the rapid rate of technological advances over the past several years, particularly in the area of genetic sequencing, is giving researchers and clinicians hope that outcomes will soon begin to improve.
“Technology has advanced so fast and we now have faster and more powerful machines that can sequence genomes fast and inexpensively, and they are fusing diagnosis to treatment,” Dr. Catto explained. “At the moment, they are still held in these large super computers, but the future will be laptop USB sticks that will allow for sequencing in a wide variety of settings. You will end up with a pathology chip that you can put in your laptop and it will do the analysis for you.”
This evolving technology has already led to significant research advances, allowing investigators to identify a number of candidate gene approaches to study the underlying mechanisms of bladder cancer and its potential treatments.
“In my lab, for example, we were trying to look at drug resistance — cisplatin resistance, specifically,” Dr. Catto said. “We took a bunch of cell lines and we plotted their sensitivity to cisplatin. We grew them up over the next few months and made them resistant to cisplatin and we then were able to work out the mechanism that was driving them.”
Dr. Catto and his colleagues determined that the cells were pumping in cysteine, a free radical scavenger, which led to the production of glutathione.
“So, by a simple mechanism this cell would turn on and become very resistant to cisplatin,” Dr. Catto said. “We could reverse this by reinserting the microRNA, and in tumor cohorts we could show that survival was affected.”
In the U.S. and Europe, several precision medicine and sequencing programs have produced similar advances and Dr. Catto said more are on the way.
“The future is going to be about precision medicine,” he said. “We now have a better knowledge of bladder cancer genomics than ever before, and we’re learning more every day.”