Researchers have developed a new strategy to identify which patients with non–muscle-invasive bladder cancer may be most likely to resist first-line treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, according to a new study published by Jong et al in Science Translational Medicine. The findings could guide clinicians toward more aggressive treatment or more targeted therapies for some patients with specific subtypes of bladder cancer and could increase the rate of survival.
“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,” explained co–senior study author Dan Theodorescu, MD, PhD, Professor of Surgery as well as Pathology and Laboratory Medicine, the PHASE ONE Foundation Distinguished Chair, and Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai. “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,” he added.
Background
Over 80,000 U.S. individuals are diagnosed with bladder cancer each year, and the majority of their tumors are non–muscle invasive. These tumors are classified as low, intermediate, or high risk based on their size, speed of growth, and how likely they are to metastasize.
Once a tumor has been surgically resected, most patients with higher-risk tumors receive a course of BCG immunotherapy. Although the therapy is designed to help the body’s immune system fight off cancer recurrence, it benefits only 50% of patients with high-risk non–muscle-invasive bladder cancer.
For the 50% of patients who don’t respond to treatment, the cancer typically recurs within 5 years and has a 20% risk of tumor progression to advanced disease and high mortality 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,” Dr. Theodorescu stressed. “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,” he noted.
Study Methods and Results
In the new study, the researchers examined the cases of 132 patients with non–muscle-invasive bladder cancer who had never received BCG immunotherapy, and 44 patients whose cancer recurred following BCG treatment using molecular profiling. They identified three distinct subtypes among these tumors and matched them with patients’ clinical outcomes to determine whether the subtypes were linked with cancer recurrence.
The researchers discovered that one of the subtypes called BCG Response Subtype 3 was associated with reduced progression-free survival compared with the other two subtypes. Further, BCG Response Subtype 3 was found to be the dominant subtype among patients whose cancer recurred after BCG immunotherapy.
Conclusions
As a next step in their BCG Response Subtype 3 assessment, the researchers have initiated a follow-up study analyzing the outcomes of patients with high-risk non–muscle-invasive bladder cancer over time.
“The aim of this new trial is to further determine whether BCG Response Subtype 3 can help us predict patients’ response to treatment,” Dr. Theodorescu detailed. “We believe that this marker can also help us investigate alternatives to BCG treatment and ultimately improve outcomes and survival rates for [patients with] non–muscle-invasive bladder cancer,” he highlighted.
In addition, the researchers emphasized that a commercially available test may accurately identify BCG Response Subtype 3 tumors. They noted that a larger follow-up study is currently underway to further validate these findings.
“[We] 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,” Dr. Theodorescu concluded.
Disclosure: The research in this study was supported by grants from MRACE, the Anschutz Foundation, the FICAN Cancer Researcher by the Finnish Cancer Institute, and the National Institutes of Health. For full disclosures of the study authors, visit science.org.
