- A new urine-based test can detect minimal residual bladder cancer after surgery and BCG treatment by analyzing tumour DNA in urine.
- The test can distinguish between those likely to be cured by surgery alone, those who could benefit from BCG immunotherapy, and those who do not respond and are at high risk of recurrence.
- Participants with detectable tumour DNA after completing BCG were highly likely to experience cancer recurrence, while those whose tumour DNA cleared had excellent outcomes.
- The approach may enable more personalized treatment by identifying who needs additional therapy, who can safely avoid BCG, and who may require earlier intervention.
Approximately 70 to 75% of newly diagnosed bladder cancers are non-muscle invasive bladder cancer (NMIBC). This describes an early stage in which cancer cells are confined to the inner layers of the bladder and have not yet grown into the muscle layer.
Initial treatment typically involves the removal of the tumor. It may then be suitable to receive medications placed directly into the bladder to destroy any remaining cancer cells and reduce the risk of cancer recurrence or becoming more aggressive.
Now, a study published in Cell suggests that a simple urine test may help identify which people with bladder cancer are likely to benefit from BCG immunotherapy and those who will not. The findings could mark a step toward more personalized treatment.
However, even after seemingly successful surgery, NIMBC often returns. This is likely due to the “field effect,” where the bladder lining is susceptible to forming new tumors, or because microscopic cells remain.
“In this context, the field effect refers to the presence of somatic mutations in normal-appearing bladder epithelial cells surrounding or adjacent to a tumor,” Max Diehn, MD, PhD, the Jack, Lulu, and Sam Willson Professor of Radiation Oncology and co-senior author of the study, explained to Medical News Today.
“These mutations arise from carcinogenic exposures and early clonal expansions and create a subpopulation of normal urothelial cells with increased cancer susceptibility,” said Diehn.
“Mutations arising from these normal cells can lead to false positive results in urine DNA-based tests. Additionally, these cells could also give rise to multiple independent tumors in the same patient,” he added.
To reduce this risk, clinicians may offer intravesical immunotherapy using BCG to those with higher-risk disease.
But, there is currently no reliable way to predict who truly needs additional therapy after surgery, or who will still experience recurrence despite receiving it. This uncertainty can expose patients to side effects, contribute to treatment shortages, and delay more effective interventions for those whose cancer persists.
Led by researchers at Stanford University, new research explores the potential of urine-based liquid biopsies, which detect tumour DNA fragments shed into bodily fluids. In bladder cancer, urine is particularly useful because it comes into direct contact with tumour cells in the bladder lining.
These tests may offer a noninvasive way to monitor disease at a molecular level, and could detect signs of remaining cancer after treatment for NMIBC, while also accounting for age-related genetic changes that previously made results difficult to interpret.
“Our new liquid biopsy method works by detecting mutations in DNA molecules found in the urine of bladder cancer patients,” Diehn told MNT.
“We and others previously observed that in a substantial subset of these patients, mutant DNA molecules can also come from non-cancer cells lining the bladder due to a phenomenon called the ‘field effect’,” he continued.
“Our method was designed to focus on mutations that are unique to tumor cells and not found in non-cancer cells affected by the field effect. As a result, we are more accurately able to identify if an early stage bladder cancer patient has likely been cured or has microscopic tumor cells left behind that can give rise to recurrences.”
– Max Diehn, MD, PhD
However, the Stanford team identified an important complication, in that healthy bladder tissue can accumulate cancer-like genetic alterations with age. The researchers describe this phenomenon as “clonal cystopoiesis.”
“Clonal cystopoiesis is a term we coined to describe the age-related accumulation of somatic mutations in cells lining the bladder of individuals without bladder cancer,” Diehn explained to MNT.
“This process is analogous to clonal hematopoiesis in blood, where mutations accumulate in hematopoietic cells with aging,” he added.
“Clonal cystopoiesis poses a major challenge for urine DNA–based tests because these assays detect mutations without distinguishing their source. As a result, mutations arising from normal cells could be misinterpreted as tumor-derived, leading to false-positive results and the incorrect suggestion that a patient has bladder cancer.”
– Max Diehn, MD, PhD
These background variations can release altered DNA into urine, potentially leading to false-positive results in highly sensitive tests. To help overcome this, the researchers developed a statistical correction method to filter out age-related signals and isolate DNA more likely to originate from active cancer.
The study tested the refined urine assay in patients undergoing surgery and BCG therapy. It found that those with detectable tumor DNA after completing BCG therapy were highly like to experience bladder cancer recurrence.
Additionally, the test suggests those whose tumor DNA disappeared had excellent outcomes and could identify recurrence risk even when standard cystoscopy results appeared normal.
In many cases, the molecular changes in urine appeared to predict relapse earlier than conventional surveillance methods.
By analyzing the urine samples taken before surgery, after surgery, and following BCG treatment, the researchers were able to identify three biological response patterns.
These included surgery responders, where tumor DNA cleared after surgery alone, BCG responders, where tumor DNA decreased after immunotherapy, and non-responders, where tumor DNA persisted or increased despite treatment.
The researchers suggest that different biological mechanisms may drive response to surgery versus immunotherapy.
The study also shows that tumours resistant to surgery tended to exhibit gene activity associated with growth and invasion. Additionally, those responding to BCG were more likely to exhibit higher levels of gene alterations and pre-existing immune activity.
The findings also suggest that earlier liquid biopsy methods may have been affected by age-related variations in normal bladder tissue. By correcting for the ‘field effect’, the researchers improved the accuracy of urine-based tumour DNA testing, enabling better distinction between the effects of surgery and those of immunotherapy.
The researchers add that separating these treatment responses also helped reveal biological differences that may predict which tumours are more likely to respond to BCG.
If validated in larger trials, the study findings could have several clinical implications. This could include avoiding unnecessary BCG treatment, and prioritizing BCG for those most likely to benefit.
Additionally, it could help identify high-risk patients earlier and escalate treatment sooner, reduce reliance on invasive monitoring procedures, and improve use of limited BCG supply during global shortages.
“Our findings could have significant clinical impact,” Diehn said to MNT. “Non-muscle invasive bladder cancer (NMIBC) patients are often treated with surgery followed by an immunotherapy called BCG. We observed that patients with negative test results after surgery (i.e. before BCG) had excellent outcomes, suggesting that many of these patients may already be cured and may not require additional treatment.”
“Furthermore, we found that patients with positive test results after BCG had a very high risk for developing recurrence. This suggests that these patients likely could benefit from additional treatment in order to try to prevent recurrence,” he added.
“Thus, our test could facilitate personalized treatment of NMIBC. Importantly, before such personalized treatment strategies could be routinely performed in the clinic, they will need to be tested in clinical trials.”
– Max Diehn, MD, PhD
If confirmed through larger clinical studies, the approach of more precise biomarkers could help ensure patients receive treatments tailored to their individual cancer risk.
