This week a study by dr. Christiaan de Jong, PhD student and dr. Tahlita Zuiverloon, urologist was published in Science Translational Medicine. Both Zuiverloon and de Jong are affiliated with the Bladder Cancer Center of the Erasmus MC Cancer Institute.
Immunotherapy
1 in 3 patients with bladder cancer have high-risk non-muscle-invasive disease. Treatment consists of surgical removal of the tumor followed by regular intravesical instillations with inactivated tuberculosis bacilli (BCG) for 3 years. This form of immunotherapy has been used since the 1970s, but there have been multiple instances of BCG shortage globally and treatment can cause unpleasant side effects.
For these patients, Zuiverloon and De Jong’s findings mean good news. ‘If we can predict which patients will benefit from BCG, this will allow correct use of limited resources and prevent unnecessary exposure to toxicity of the treatment,’ says De Jong.
Overactive genes
Here’s the thing: treatment with BCG does not work adequately in 40 percent of patients. These patient will have recurrent tumors, which are often more aggressive and more difficult to treat. Zuiverloon and De Jong discovered that bladder tumors that do not or insufficiently respond to BCG have a specific set of overactive genes. They called that gene pattern BRS3:an abbreviation of BCG Response Subtype-3.
We are recruiting patients with high-risk non-muscle-invasive bladder cancer follow-up study
De Jong and Zuiverloon’s PCR test can determine with 87 percent certainty whether the tumor tissue contains the BRS3 gene pattern. Zuiverloon: ‘For years there has been a need to improve patient stratification by being able to predict which will benefit from BCG. So with this test, that seems possible.’
Immune cells
They also found that these gene patterns correlate with higher numbers of certain immune cells. These immune cells prevent BCG from doing its job properly. Also, genes were activated with stem cell characteristics, allowing the tumors to grow faster. ‘We can now also start investigating whether we can develop new drugs against these overactive genes,’ De Jong said.
The findings are also important for a small subgroup of patients with very high-risk non-muscle-invasive bladder cancer. ‘In this subgroup, the advice is to remove the bladder immediately. Because by the time it turns out that BCG does not work, you are often too late and the tumor invades the bladder wall,’ Zuiverloon explains. ‘We have found a gene pattern in a subset of these patients who still benefit from BCG, with this we could prevent direct bladder removal.’
Time-consuming
Zuiverloon and De Jong used next generation sequencing and immunofluorescence for their study. Because these laboratory techniques are complicated and time-consuming, assistance was sought from the company InnoSign. InnoSign developed the PCR test, called OncoSignal, which can measure specific gene patterns.
To validate that the PCR test works well, Zuiverloon and De Jong have initiated a follow-up study in high-risk non-muscle invasive bladder cancer patients nationally: the IMPASSE study. We still need a lot of patients for this study. People who have recently been diagnosed with high-risk non-muscle invasive bladder cancer by their urologist and who will be receiving BCG are our target study population. These patients can ask their urologist how to participate in the IMPASSE study.
Want to know more about Zuiverloon and De Jong’s study? Email: blaaskankercentrum@erasmusmc.nl
About bladder cancer
Bladder cancer is a common form of cancer with 7,000 new cases per year in the Netherlands. Smoking significantly increases the risk of bladder cancer.
A bladder tumor is treated by transurethral resection of the tumor after diagnosis. The cancer is then examined by the pathologist. If it is found to be non-muscle-invasive bladder cancer, the tumor is classified into 1 of three risk groups: low, intermediate or high risk. These groups reflect the risk of recurrence and disease progression.
About two-thirds of people with bladder cancer have non-muscle-invasive disease. This means that the tumor has not grown into the muscle layer of the bladder.
Zuiverloon and De Jong conducted their research in collaboration with Dr. James Costello of the University of Colorado Anschutz Medical Center in Denver and Prof. Dan Theodorescu of the Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai in Los Angeles. The study included patients from multiple Dutch urological centers and Norwegian bladder cancer patients at Stavanger University Hospital.
Check out the paper here for all the information and the full list of co-authors and collaborating institutions.
