Our clinical or research question being answered was could we use urinary cell-free DNA in order to measure minimal residual disease in the bladder for patients who had non-muscle invasive bladder cancer. To answer that question we designed a prospective study on patients with high-risk, non-muscle invasive bladder cancer undergoing standard of care repeat TURBT.
What was the methodology?
In non-muscle-invasive bladder cancer we had patients who came in with a diagnosis of non-muscle invasive bladder cancer beforehand. Standard of care in those patients - because of their risk category, size of tumour, grade of tumour - is to undergo another resection in the operating room, which is another general anaesthesia, another risk of complications after surgery, catheter placement, complications etc. So we collected urine from them beforehand, and then we took them for their standard of care procedure. We sent that tissue to pathology to determine if there’s any residual disease in the bladder. If there was tumour present, that tumour also was sequenced with whole exome sequencing, similar to the index tumour. Then for the urine, we ran a cell free DNA analysis, which was a custom panel of up to 50 genes based on the original index TURBT tumour.
What were the findings?
So, looking at the index and the repeat TURBT tumour, we found a high concordance between the two, on average it was about 83% of similar genomic alterations between those two time points in the same patient. In the urine, we found that we could detect tumour-specific alterations in ten of the eleven patients, so it was highly sensitive and, depending on the definition which you use for utDNA positivity, extremely sensitive – up to 100% - meaning that all patients who had residual disease on their repeat TURBT were positive for the utDNA of the tumour in the urine.
How could this impact the future treatment of bladder cancer?
There are multiple implications, not necessarily just for treatment of patients, that’s certainly the goal, but I think to deviate from the current standard of care we have a lot of work to do to establish utDNA. Looking forward, some of our aspirations, things we hope to do, is to use it in clinical trials, to use urinary tumour DNA as a surrogate for a biopsy to monitor disease on and off therapy. We still have tremendous work to be done to validate this as a surrogate for MRD, but in terms of patient care and standard of care, one day, with the supporting data behind it, we could potentially be risk stratifying patients prior to repeat TURBT to see which patients we could save from having to undergo another general anaesthesia and invasive surgery.
What are the next steps?
Specifically we’re looking at the urinary tumour DNA across a longer period of time, so these patients that we have, the data that we’ve presented, is a small fraction of the large ongoing prospective study. We’re monitoring them throughout surveillance periods so that we can monitor if they have a utDNA positive time event, what is the time to recurrence, and will they recur shortly after that. So a longer follow up in these patients primarily, with a larger cohort, will continually answer the immediate questions we have now.
Secondarily, we hope to look at standard of care intravesical options which includes chemotherapy and BCG, and monitor the utDNA on and off therapy. For example, if we have a patient who’s getting BCG therapy we have a baseline urinary tumour DNA level, we can monitor it to see if it increases, decreases, or does not change, to serve as a surrogate for their pathologic clinical response.