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New Bladder Cancer Molecular Classification Predicts Response to Common Immunotherapy

NEW YORK — A team of researchers in the US and the Netherlands has identified three distinct molecular subtypes of high-risk non-muscle-invasive bladder cancer, one of which is likely to recur after treatment with a common immunotherapy called Bacillus Calmette-Guérin (BCG).

The new classification, published in Science Translation Medicine on Wednesday, could help clinicians select alternative treatments for patients unlikely to respond to BCG. "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," co-corresponding author Dan Theodorescu, director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, said in a statement.

After non-muscle-invasive bladder tumors, which make up about 75 percent of all bladder cancers, are surgically removed, most patients receive BCG, an infusion of the bladder with inactivated tuberculosis bacteria that stimulate the immune system.

While most patients show an excellent response to BCG treatment at first, 50 percent end up with recurring disease within five years.

These patients are unnecessarily exposed to the toxicity of the BCG treatment and often face a delay in receiving more aggressive treatments. "BCG treatment failure is a major risk factor for progressive disease and death from bladder cancers," the authors wrote.

Thus, they wanted to understand if it was possible to identify patients who were most likely to respond to BCG before they receive the treatment.

For their study, they conducted whole-transcriptome sequencing of non-muscle-invasive bladder cancers from 132 patients who had never received BCG treatment and 44 patients whose cancer recurred following BCG treatment.

Based on the results, they identified three unique subtypes among these tumors — BRS1, 2, and 3. Patients with BRS3 showed increased epithelial-to-mesenchymal transition pathway activity and were enriched for mutations associated with the extracellular matrix, compared to the other two subtypes.

By matching each of the subtypes with patients’ clinical outcomes, they also found that patients with the BRS3 subtype had a higher risk of recurrence compared to BRS1 and BRS2 groups. BRS3 was also the most dominant subtype among patients whose cancer recurred after BCG therapy.

The team validated its findings in a second cohort of 151 BCG-naïve patients and found that a commercially available test named OncoSignal could identify BRS3 tumors.

"Identification of BRS3 tumors may be a critical step for implementation of more aggressive therapeutic regimens, such as an early radical cystectomy or recruitment into clinical trials," the authors concluded.

As a next step, the investigators have initiated a follow-up study to track high-risk non-muscle-invasive bladder cancer patients over time. "The aim of this new trial is to further determine whether BRS3 can help us predict patients’ response to treatment," Theodorescu said.

Highlighting the study's limitations, the authors said that tumors from BCG non-responders were overrepresented compared with a real-world situation. This reiterates the need to have clinical trials in a bigger patient group before clinicians adopt the findings in practice, Theodorescu told GenomeWeb.