New Bladder Cancer Grouping Predicts Treatment Response

Cedars-Sinai Cancer Center researchers, in partnership with colleagues in Colorado and the Netherlands, have found a specific form of bladder cancer that is more likely to reject first-line treatment. Their findings, published in Science Translational Medicine, could point medics in the direction of more aggressive or tailored treatments for some patients with specific subtypes of the disease, potentially saving lives.

“These findings provide a potential tool for determining how well patients initially treated for high-risk bladder cancer that isn’t yet muscle-invasive will respond to the most common follow-up therapy,” said Dan Theodorescu, MD, Ph.D., co-senior author of the study and director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “With this information, clinicians can make more informed and timely decisions about aggressive surgical treatment or take advantage of new options being created through precision medicine.”

Each year, over 80,000 Americans are diagnosed with bladder cancer, with the majority of tumors being non-muscle invasive, meaning they are detected in the tissue that borders the inner surface of the bladder and do not impact the bladder muscle. These tumors are categorized as low-, intermediate-, or high-risk depending on their size, rate of growth, and propensity to spread.

Following surgical removal of a tumor, most patients with higher-risk cancers receive a course of immunotherapy known as Bacillus Calmette-Guérin (BCG). BCG therapy is intended to assist the body’s immune system in fighting cancer recurrence, but it only improves 50% of people with high-risk non-muscle invasive bladder cancer.

For the remaining 50%, the cancer returns within five years, with a 20% chance of developing to severe illness and substantial fatality rates.

“Patients who don’t respond have been exposed to unnecessary toxicity from BCG treatment, and because of the delay in receiving more aggressive treatment, their chances of survival may have been compromised,” Theodorescu said. Our goal with this study was to find a new way to identify these patients before they receive BCG therapy and direct them immediately to surgical removal of the bladder or other more aggressive therapies, which may reduce quality of life but have excellent long-term outcomes.

The researchers used genetic profiling of non-muscle invasive bladder tumors from 132 patients who had never undergone BCG treatment and 44 patients whose disease recurred after BCG treatment to accomplish this. They found three separate subtypes of these tumors and compared them to patients’ clinical outcomes to see if the subgroups were associated with cancer recurrence.
One of the subtypes, known as BCG Response Subtype 3 (BRS3), was found to be more closely connected with decreased progression-free survival (time until the cancer recurred) than the other two. The study also discovered that BRS3 was the most common subtype among patients whose cancer returned following BCG therapy.

The researchers were also able to demonstrate that a commercially accessible test may correctly detect BRS3 tumors. A larger follow-up study is being conducted to corroborate this finding.

Theodorescu received a presidential citation from the American Urological Association for “elucidating the underpinnings of urothelial cancer,” which is the most common type of bladder cancer, at the 2023 AUA Annual Meeting in April.

“I’m very humbled and honored to be recognized by clinical peers at the American Urological Association,” Theodorescu said. “This citation recognizing my scientific achievements means a lot to me.”

As a graduate student in the 1990s, Theodorescu became interested in bladder cancer and has subsequently worked in the topic, developing an international network of partners.

“What is particularly satisfying about this study is that it was imagined and designed when one of the co-senior authors, Dr. Tahlita Zuiverloon, now a faculty urologic surgeon at Erasmus University Medical Center in the Netherlands, was a postdoctoral fellow in my lab, and the other, Dr. James Costello, professor of pharmacology at the University of Colorado, is someone I helped recruit when I was cancer center director there. The three of us have a number of bladder cancer projects that we hope will change clinical practice in the pipeline, so we’re very excited about the future.”

Theodorescu is widely recognized for his research on the molecular mechanisms behind bladder cancer and its response to various therapy. He is credited with discovering genes that regulate tumor growth and dissemination, as well as novel biomarkers that enable tailored therapy techniques. He has created innovative medications for bladder and other cancers, as well as effective combo therapies to target tumors that are resistant to traditional immunotherapy.

Theodorescu and colleagues have launched a follow-up trial to track high-risk non-muscle invasive bladder cancer patients over time as the next stage in their BRS3 research.

“The aim of this new trial is to further determine whether BRS3 can help us predict patients’ response to treatment,” Theodorescu said. We believe that this marker can also help us investigate alternatives to BCG treatment and ultimately improve outcomes and survival rates for non-muscle invasive bladder cancer patients.

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