Test helps detect signs of bladder cancer that don’t show up on imaging scans

Brazil is expected to record 13,100 new cases of bladder cancer per year between 2026 and 2028, according to an estimate from the Instituto Nacional de Câncer (INCA), Brazil’s National Cancer Institute. The disease is more common among men, who are expected to account for about 9,000 diagnoses a year. In 2024, 5,483 people died of this type of cancer in the country.

Bladder cancer begins in the cells that line the inside of the organ and may remain confined to the most superficial layers or reach the muscle. In the latter case, it is called muscle-invasive bladder cancer and carries a higher risk of spreading to other parts of the body.

“In the innermost layers, it behaves more locally. When it reaches the muscle and gets into the lymphatic circulation, the disease becomes more lethal,” explains Fernando Korkes, coordinator of the Uro-Oncology Department at the Sociedade Brasileira de Urologia (Brazilian Society of Urology).

For some patients with muscle-invasive bladder cancer, treatment includes surgery to remove the bladder, followed by monitoring to detect possible signs that the disease has returned.

“Even when all visible disease is removed with surgery, these cells can remain in the body and later cause a recurrence. That’s why treatment today shouldn’t focus only on the tumor we’re able to remove, but also on possible microscopic disease,” says urologist Renato Mariano, who specializes in uro-oncology.

CT and MRI scans are used in this follow-up and can identify suspicious changes or lesions. However, the number of tumor cells remaining after surgery may be small and may not form a lesion that can be seen on imaging.

Tumor DNA can be found in the blood

Cancer cells can release small fragments of their genetic material into the bloodstream, carrying characteristics of the tumor they came from. This material is called circulating tumor DNA, or ctDNA, and can be detected through a blood sample.

The analysis is a type of liquid biopsy, the term used for tests that look for tumor-related components in body fluids. After surgery to remove bladder cancer, detecting ctDNA in the blood may indicate the presence of a very small number of tumor cells in the body, a condition called molecular residual disease that is associated with a higher risk of recurrence.

“A positive ctDNA result doesn’t necessarily mean there is already a visible metastasis. Above all, it indicates that the patient is more likely to have a recurrence,” explains Mariano.

The absence of ctDNA is usually associated with a more favorable prognosis, although it doesn’t completely rule out residual disease, since the amount of DNA released by the tumor may fall below the test’s detection limit.

“It’s a very favorable result, because it means we didn’t find signs of residual disease at that point. But it doesn’t mean zero risk. The tumor may be very small or release little DNA, leading to a false-negative result. That’s why a negative ctDNA doesn’t replace traditional follow-up,” adds urologist Mariano.

In addition to providing information about the risk of the disease coming back, ctDNA analysis is being studied as a way to guide treatment decisions after surgery and identify patients who may benefit most from additional therapy.

Study evaluated using ctDNA to guide treatment

This possibility was evaluated in IMvigor011, an international phase 3 clinical trial that followed 761 people with muscle-invasive bladder cancer who had undergone bladder removal and showed no signs of disease on imaging.

Published in the New England Journal of Medicine in 2025, the study included Brazilian centers. Oncologist Ariel Kann, head of the Centro Especializado em Oncologia at Hospital Alemão Oswaldo Cruz in São Paulo, took part in the research and is one of the authors of the scientific paper.

“The study’s main question was whether serial monitoring of circulating tumor DNA (ctDNA, a type of liquid biopsy) in the blood after bladder removal surgery (cystectomy) can identify patients with molecular residual disease (MRD) who benefit from adjuvant treatment (also called ‘preventive’ treatment) with the immunotherapy atezolizumab compared with placebo,” explains Kann.

Among participants who tested positive for ctDNA and met the study’s other criteria, 250 were selected for the comparison between treatments. Of this group, 167 received atezolizumab, an immunotherapy, and 83 received placebo.

The treatment reduced the risk of recurrence or death by 36% and the risk of death by 41% over the period analyzed. Median time without disease recurrence or death was 9.9 months among patients who received atezolizumab and 4.8 months in the placebo group.

Among 357 patients who remained ctDNA-negative and received no systemic treatment after surgery, 95.4% were alive and free of recurrence after one year and 88.4% after two years. About 11%, however, had a recurrence, which means a negative result cannot be interpreted as a definitive absence of risk.

Test complements imaging follow-up

Identifying molecular residual disease through ctDNA does not eliminate the need for the tests already used to monitor bladder cancer, because the methods provide different information. While the blood test looks for changes at the molecular level, imaging can locate lesions that are already visible.

“CT shows where there is an abnormality; cystoscopy lets us look directly inside the bladder; and ctDNA looks for molecular signs of the disease. So today, ctDNA should be seen as complementary, not as a replacement for conventional tests,” explains Mariano.

A single sample is also not enough to track the molecular course of the disease, since the result may turn positive only months after surgery.

“It’s still too early to completely abandon imaging and rely exclusively on liquid biopsy. In addition, 40.8% of positive patients only turned positive on subsequent tests during follow-up. So confidence in early detection depends on serial monitoring (samples every 6 weeks in the first year), not just a single isolated test right after surgery,” says Kann.

Urine is also being studied as a source of tumor DNA

In addition to blood, urine is being studied as a source of molecular information about bladder cancer. Because it stays in direct contact with the inner surface of the organ, it may contain DNA fragments released by the tumor. This material, called urinary tumor DNA, or utDNA, is being investigated mainly as a way to identify changes related to disease located in the bladder itself.

“In the blood, we look for tumor fragments that have reached the circulation. In urine, we look for DNA released directly by the tumor in the bladder. Since bladder cancer is in direct contact with urine, urine analysis is very interesting and may play an important role in the future, especially in bladder surveillance,” explains Mariano.

The possibility of combining information from blood and urine was one of the topics presented at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in 2026. An analysis of the NIAGARA trial evaluated both types of samples in patients with muscle-invasive bladder cancer who received treatment before having the organ removed.

The results showed an association between tumor DNA found in urine before surgery and the response observed after treatment. Among patients who tested negative for both ctDNA in blood and utDNA in urine, 73.6% reached surgery with no residual tumor in the bladder, lymph node involvement or metastases. Among those with negative ctDNA in blood but positive utDNA in urine, that proportion was 24.2%.

The difference reinforces the possibility that the two samples provide complementary information. A negative blood result, for example, does not necessarily rule out disease confined to the bladder, which may be identified by other methods.

This limitation also appeared in an analysis of the RETAIN trials presented at the same meeting. Negative ctDNA in the blood was associated with control of metastatic disease, but did not reliably identify recurrences that remained confined to the bladder. The researchers noted that future studies on organ preservation may benefit from combining serial ctDNA monitoring in blood with testing for tumor DNA in urine.

For now, the findings do not allow the result of a blood or urine sample alone to be used to decide whether a patient can avoid bladder removal.

Broader use faces limitations

The information obtained through these tests may help distinguish patients with different risks of recurrence and, in specific situations, guide the choice of additional treatments. The available evidence does not allow a molecular analysis alone to be used for every decision related to bladder cancer.

IMvigor011 itself evaluated a specific group of patients, all with muscle-invasive bladder cancer, who had undergone bladder removal and had no evidence of disease on imaging. Other possibilities, such as using molecular information to monitor treatment response or to help evaluate bladder-preservation strategies, remain under investigation.

In Brazil, access is also an obstacle. Performing the tests depends on specialized technology and may involve shipping tumor tissue and plasma, in addition to high costs. “These tests arrive in Brazil much more expensive,” says Korkes.

Kann cites regulatory review, coverage by the public and private systems, and training laboratories to perform the tests with standardization and analytical rigor among the challenges to expanding the use of ctDNA in the country.

Brazil brings together different strategies for treating bladder cancer

Bladder cancer treatment in Brazil includes different approaches, which may involve surgery, chemotherapy, radiation therapy and immunotherapy, chosen according to the stage of the disease and each patient’s characteristics. The country also takes part in international research investigating new ways to treat and monitor these tumors.

In 2026, the first Diretrizes Brasileiras Conjuntas para o Tratamento do Câncer de Bexiga (Joint Brazilian Guidelines for the Treatment of Bladder Cancer) were published, developed by specialists from the Sociedade Brasileira de Urologia, Sociedade Brasileira de Oncologia Clínica, Sociedade Brasileira de Radioterapia and Sociedade Brasileira de Patologia, with participation from Instituto Oncoguia. The document brings together recommendations for different stages of the disease and considers the treatment options available in the SUS (Brazil’s public health system) and in the private health insurance sector.

According to Korkes, coordinator of the Uro-Oncology Department at the Sociedade Brasileira de Urologia and of the guidelines’ development, the number of available treatments has grown in recent years, making it necessary to have a reference that helps doctors and patients understand the options recommended in different situations. The document organizes this information according to the clinical picture and also the health system in which the patient is treated.

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Credits

Dr. Fernando Korkes -  coordinator of the Uro-Oncology Department at the Sociedade Brasileira de Urologia - CRM-SP (Regional Council of Medicine registration) 108697 | RQE (specialist registration) 64083

Dr. Ariel Kann - head of the Centro Especializado em Oncologia at Hospital Alemão Oswaldo Cruz - CRM: 112002 | RQE 45030

Dr. Renato Mariano - urologist specializing in uro-oncology - CRM 132086 | RQE 154043