Australian research shows circulating tumour DNA is there to be found in early prostate cancer.
Early diagnosis and prognosis for recurring localised prostate cancer is set to improve with the discovery of circulating tumour DNA that can provide early indication of a new tumour and its size, enabling more informed, personalised decisions about treatment.
Liquid biopsy, taken via a fluid test (often a regular blood test), can identify DNA circulating in the bloodstream that has been shed by a tumour. But unlike breast, colon, brain, metastasised prostate cancer and others, localised prostate cancer has not been a cancer that was thought to be able to benefit.
Now, for the first time, DNA has been picked up by using a very sensitive method of detection, the INtegration of VAriant Reads (INVAR) pipeline, that uses data from thousands of patient-specific tumour mutations.
“Contrary to previous research, there is strong evidence of circulating tumour DNA in localised prostate cancer. It’s there. It’s just that you need very sensitive methods to detect it – much more sensitive than had previously been applied. And it is significantly associated with poor outcomes if you do detect it,” Associate Professor Bernard Pope, bioinformatics lead at Melbourne University, told Oncology Republic.
“You can use the information for diagnostic purposes, to determine the presence or absence of disease. And you can use it for prognosis. The volume of CtDNA might be indicative of the stage of the disease. More volume means it’s likely to be a larger tumour that’s shedding more DNA and growing more rapidly,” said Professor Pope, who discussed his team’s recent findings at the International Congress of Genetics held in Victoria last month and at an American Association for Cancer Research meeting in Denver earlier in the year.
The study sequenced the primary tumours of 128 people with localised prostate cancer who had undergone radical prostatectomy. There was also a control group of 27 participants without cancer. The pre-treatment blood plasma ctDNA in the cancer group was analysed using the most sensitive method available, INVAR, which used data from targeted sequencing of over 280,000 patient-specific mutations. Mutation-based ctDNA was found in just under 10% of the participants in the cancer group. Where it was found, there was a significant association with relapse (p=0.01) and shorter metastasis-free survival (p less than 0.0001).
“A small percentage [of those with localised prostate cancer] go on to have disease recurrence and later stage disease and they have very poor outcomes. In prostate cancer, one of the key challenges is not over-treating, and trying to identify the small number of individuals that have aggressive disease and need to have much more intensive treatment, much more early on,” said Professor Pope.
Current methods, such as MRI, detect recurrence when the tumour is already large enough to be seen, whereas liquid biopsy can possibly find one out of 100,000 molecules, meaning detection can take place much earlier, he said. And because tumour DNA circulates for just a few hours, a liquid biopsy provides a real-time snapshot of disease progression, and in some cases can be used to monitor real-time response to treatment, he said.
Liquid biopsies have several advantages over tissue biopsies. For starters, “it’s the least invasive way you could imagine of taking a sample,” said Professor Pope. They are usually taken using a regular blood test, which has the added benefit of being easily sent away for analysis, rather than requiring the patient to travel.
And while tissue biopsies can only provide a partial picture of what’s taking place in the prostate, circulating tumour DNA potentially samples the entire tumour, he said.
One limitation of the method used in the study is the need for access to the primary tumour. “We have to have a biopsy (needle biopsies in prostate tumours are regularly done) or a prostatectomy to get the tissue sample to do the sequencing,” Professor Pope explained. That’s because only one molecule in 100,000 or more in the blood stream will provide evidence of a tumour, so finding them by chance is unlikely. Looking at areas where the mutations are likely to exist will vastly narrow the search.
“For metastatic disease, that’s a different story altogether. We see orders of magnitude more DNA molecules from the tumour circulating, probably because there are more sites, often in lymph nodes and other places where they’re close to vasculature and shed DNA into the bloodstream more rapidly, and they are probably also growing faster.”
There is currently no method for using liquid biopsy in localised prostate cancer that does not need a tissue biopsy, said Professor Pope.
“But the good message is there is circulating tumour DNA. It’s there to be found. Maybe someone will come up with another very sensitive method, and they may be inspired to do it now because we know the ctDNA can be found, rather than thinking, we might do this and never find anything. We’ve shown that it is there.”