A new study may pave the way toward more personalized treatments for patients with high‑risk bladder cancer, according to a study published in European Urology.

High‑risk non–muscle‑invasive bladder cancer returns after treatment in roughly 30 percent of patients and leads to death in about 10 percent within two years, even after tumor resection, intensive surveillance and treatment with the standard immunotherapy known as bacillus Calmette‑Guérin (BCG).

The situation has become more urgent in recent years due to a global shortage of BCG, forcing hospitals to delay or modify treatment, said Joshua Meeks, ‘05 MD, ‘03 PhD, ‘06, ‘11 GME, the Edward M. Schaeffer, MD, PhD Professor of Urology, who was senior author of the new study.

“We have this drug, BCG, that’s been around as our standard of care for 50 years. It works pretty well in about three‑quarters of people,” said Meeks, who is also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “We had the question: Why do some tumors respond and some do not?”

In the study, Meeks and his collaborators set out to more precisely understand why some patients respond well to immunotherapy while others relapse — and whether molecular profiling could help guide therapy.

Using a “multi-omics” approach that combined transcriptomic profiling, targeted genomic sequencing, single-cell RNA sequencing and spatial transcriptomics, the team analyzed tumor samples from patients with high-risk bladder cancer. Their work revealed that these tumors are not biologically uniform. Instead, they fall into four molecular subtypes, each defined by unique patterns of gene expression and immune activity.

They found that one cancer subtype demonstrated the strongest response to BCG immunotherapy, suggesting that tumors with preexisting immune activity may be primed to benefit from immune-based treatments.

“The microbiome within the bladder kind of sets up its baseline level of inflammation, but there’s mounting evidence that there’s a correlation there with response,” Meeks said. “If you have a microenvironment that’s more inflamed, it’s likely to have a better response to an immunotherapy.”

Next, the investigators also developed a machine‑learning model that integrates genomic and transcriptomic features of bladder cancers to predict recurrence risk. The model performed strongly, according to the findings, suggesting it may be useful for guiding patient care.

Although more work is needed to validate the model, such a tool could help clinicians identify patients most likely to benefit from BCG immunotherapy and those who may need alternative or intensified treatment strategies, Meeks said.

“This is really a great example of the benefit of having close collaboration between research and clinical teams, as we do at Northwestern,” Meeks said. “We had insights from our patients treated here and were able to go to the lab and figure out why they were responding to therapy or not.”

Although larger, multi‑center studies will be required to confirm the molecular subtypes and validate the model before it can be used in routine clinical practice, Meeks said the new study represents an important step toward precision medicine in bladder cancer.

The study also suggests that matching therapy to tumor biology could improve outcomes for patients with a disease that has stubbornly high recurrence rates. Future studies will further test these approaches, Meeks said.

“Now we want to go back to the bedside with prospective clinical trials and see if we can alter that tumor microenvironment to get a better response,” Meeks said.

Source – Northwestern University