June 4, 2026 | A prominent urologic oncologist has helped develop a urine test found to be strikingly predictive of bladder cancer recurrence among patients undergoing surgery followed by BCG therapy, the current gold standard treatment regimen. The liquid biopsy also tends to identify recurrence risk that is missed by routine cystoscopy exams.
The inspiration for the research is drawn from the patients he sees in the clinic, says Joseph Liao, M.D., professor of urology at Stanford University. “These are some of the most motivated patients out there, because the current standard of care is suboptimal.” If possible, they’d like to avoid both the therapy and the endoscopic procedure and “by and large they would very much prefer to keep the bladder they were born with.”
BCG (Bacillus Calmette-Guérin) is an immunotherapy that is administered topically by instilling it into the bladder via a urinary catheter, he explains. It is used to treat non-muscle invasive bladder cancer, the type accounting for about 70% of patients at the time of presentation.
The procedure itself can be unpleasant, and BCG can cause significant urinary discomfort as well as flu-like symptoms. BCG is also subject to recurrent global supply shortages, and the overall cost of the treatment process is very high, says Liao.
“Most patients do respond [to BCG], but certainly a subset of patients do not,” he adds. And the cancer often returns or requires alternative treatments. Lifelong endoscopic surveillance, roughly every three months, is therefore required. “There is a lot to be said for a noninvasive urine test that could be done in both a screening ... and surveillance population, as well as in assessing treatment response.”
That potential was explored in a study that was published recently in Cell (DOI: 10.1016/j.cell.2025.12.054). Notably, the novel liquid biopsy test gets its ultra-specific detection capabilities by applying a statistical method that filters out noncancerous field-effect background mutations that naturally accumulate with age, which in the context of urine the researchers have termed “clonal cystopoiesis.”
Bladder cancer is the fourth most common cancer in men, and the sixth most common cancer overall, with 70 being the average age of diagnosis, Liao points out. Like most cancers, it does not have a large inherited genetic component but is instead caused by DNA mutations acquired during a person's lifetime, often due to environmental exposures and lifestyle choices.
Some of these mutations may in fact be precursors to cancer, he adds. When an age-related somatic mutation will transition over to a precancerous lesion remains “a bit of an unknown.”
But cancers of the bladder, like those in the lung, involve a large surface area that’s exposed to the environment. In the case of bladder cancer, potential carcinogens such as tobacco smoke and diesel exhaust as well as contaminated water are present in the urine, says Liao.
This is not the only urine tumor DNA (utDNA) assay ever developed, says Liao, but it is believed to be the first one to remove the field-effect mutations. In the latest study, he and his team applied their minimal residual disease approach to 261 samples from non-muscle-invasive bladder cancer patients undergoing surgery and adjuvant BCG to identify three molecular response classes: surgical responders, BCG responders, and non-responders.
The BCG responders, but not the surgery responders, had pre-existing immune activation and higher mutation burden, he reports. Findings suggest the new liquid biopsy method could guide personalized therapy as well as reveal biomarkers for tracking, predicting, and evaluating the impact of each distinct therapy within a combined regimen.
When applied to the prospective group of patients undergoing standard-of-care treatment, the urine test proved to be remarkably predictive. Patients with detectable tumor DNA after completing BCG had an almost certain risk of recurrence, while those whose tumor DNA cleared had excellent outcomes.
Clonal cystopoiesis, the somatic mutations being erased here, is a parallel concept to clonal hematopoiesis observed in blood cells that can sometimes render people more susceptible to different types of diseases, including cancer, says Liao. This is the first time the concept has been observed in the urine as it relates to bladder cancer, highlighting a way to enhance diagnostic signals by “subtracting out” all the background noise.
As a urologist who treats patients with bladder cancer, Liao says he thinks a lot about how to risk-stratify patients beyond analyzing their tumor's stage and grade. “One size doesn’t really fit all, and I think that’s why you can have a great therapy but it’s maybe ... [given to] the wrong patient, or ... has a lot of side effects. Being able to deploy the right treatment at the right time [precision oncology] is a big challenge.”
‘Precision Diagnostic’ Approach
Non-muscle-invasive bladder cancer can usually be managed endoscopically for both diagnostic surveillance and treatment purposes, he continues. If there’s a tumor recurrence, it can be removed through endoscopic surgery.
For patients with muscle-invasive bladder cancer, the first-line treatment is removal of the entire bladder, says Liao. “It’s a big deal [because] we have to reconstruct a different mechanism for the urine to be drained out.” About 5% of patients present with metastatic disease, which is when systemic therapy is the way to go.
A subset of high-risk, non-muscle-invasive bladder cancer patients progress to the muscle-invasive variety, he notes. Early detection and personalized treatment are therefore extremely important in preserving the natural bladder.
But routine surveillance cystoscopy is a burdensome process which, unlike a colonoscopy or bronchoscopy, is done while the patient is awake, Liao says. “Endoscopy by nature is also somewhat subjective ... if you can’t quite see it, then you can potentially miss it.” It can also be hard to tell if lesions are bona fide cancer, an artifact from the treatment, or a benign inflammatory process, adds Liao, getting back to the promise of his team’s “precision diagnostic” test producing a high-strength signal.
The field effect is highly significant with other utDNA diagnostic tests, producing false positives that subject erroneously flagged patients to unnecessary treatment. “Our approach has that extra edge ... [and] helps with both treatment escalation ... and deescalation,” he says.
Given 100 patients, “what we can tell you is that about a third of the patients are probably going to be cured by surgery alone, a third of the patients are going to be cured by surgery followed by BCG, and a third of the patients are not going to be cured by either,” Liao says. “Right now, every single one of these patients will get surgery plus BCG.”
The hard-to-source BCG could perhaps instead be saved for the patients that stand to benefit from it. Knowing in advance who will get the surgery but ultimately fail, the BCG opens the door to exploring therapeutic alternatives, he says.
Determining the biological drivers for each of the three molecular response classes is currently an active area of research for Liao and his Stanford physician-scientist colleagues Max Diehn, M.D., Ph.D., a radiation oncologist, and Ash Alizadeh, M.D., Ph.D., a medical oncologist and bioinformatics expert. In some of their ongoing work, they are also looking at urine RNA to help distinguish treatment responders and non-responders.
Intravesical chemotherapy is another mainstay treatment for bladder cancer, serving as the second-line agent if intravesical BCG doesn’t work, says Liao. “It may very well be that some patients will benefit from chemotherapy more so than BCG ... [and] some patients may not be as responsive to BCG due to their immune system [being] exhausted,” he adds, noting that the anti-tumor activity of BCG could be boosted through other immunological pathways.
“Our strength is more on the diagnostic side, but we certainly are exploring and collaborating with folks who are working more on the therapeutic side ... to see whether [the utDNA test] could be a way to monitor treatment response from surgery and immunotherapeutics and chemotherapy,” Liao says. His group is additionally developing ways to enhance and augment endoscopic imaging technologies to improve bladder cancer detection and surgery using artificial intelligence and fluorescence.
Diehn and Alizadeh are separately looking at the field effect impact on blood-based liquid biopsies for other cancer types, including those in the blood and lung. Bladder cancer is “uniquely well suited” to a urine-based test given the direct contact between cancer cells and the urine itself, says Liao. “It’s noninvasive ... and no one is ever going to complain about giving you a cup of urine.”
The field-effect-informed urine liquid biopsy will soon be available for guiding enrollment in clinical trials, Liao reports. The test is in the process of being converted into a CLIA-certified test that can be processed by any facility holding a valid Clinical Laboratory Improvement Amendments certificate.
Once his lab is CLIA-certified, prospective escalation and deescalation of bladder cancer treatment trials will begin at Stanford, he says. With the escalation trial, treatment for patients identified as utDNA-positive after surgery and BCG, and therefore harboring minimal residual disease invisible to expert human eyes, would be given something besides BCG ahead of the expected disease recurrence in hopes of decreasing that risk. “The novelty here would be using these urine tests as one of the endpoints to treatment intensify, versus the conventional approach [of waiting and watching for recurrence].”
Approval of the liquid biopsy by the Food and Drug Administration is “on the horizon,” but would be easier shepherded to market by industry than academia. “Some of our patients are already asking us if it is available,” says Liao.
“Bladder cancer is a very common disease, and, in my mind, urine is both the ultimate and the original liquid biopsy,” he says. “What we’re really trying to do is fully harness the diagnostic potential of this noninvasive fluid that we are all so familiar with.”
It took some time to both come up with the clinical unmet need based on the lived experience of patients and apply the most sensitive sequencing and bioinformatics technology to answer that question, says Liao. The journey began more than seven years ago (Cancer Discovery, DOI: 10.1158/2159-8290.CD-18-0825) and “it has been very gratifying to see this coming into fruition.” But much more work lies ahead in transitioning the test into a tool for everyday use benefitting the more than 60,000 patients diagnosed with non-muscle-invasive bladder cancer in the U.S. each year.