Genome sequencing and prostate cancer: U of T researcher hopes to deliver precise and personalized care to men

Men diagnosed with localized prostate cancer have different risks of dying. In many men with "intermediate” risk, the disease appears localized and is curable with radiotherapy or surgery. But for about a third of these men, initial treatments will fail due to hidden metastasis outside the prostate. This “miss” in staging the disease can lead to further spread and therapy resistance and in some cases, death.

But which men have the hidden spread and which don’t? That’s a key question in prostate cancer research these days.

Dr. Robert Bristow is a professor in the departments of medical biophysics and radiation oncology at U of T's Faculty of Medicine and a clinician-scientist at Princess Margaret Hospital in the University Health Network. Bristow and his colleagues recently found a way to determine which men with intermediate-risk prostate cancer will likely do well with local therapy alone and which men may benefit from intensified treatments. 

The journals Nature and Nature Communications published the results this month based on studies by Bristow, Paul Boutros from the Ontario Institute for Cancer Research who is an associate professor in the departments of medical biophysics, and pharmacology and toxicology at U of T and Gail Risbridger at Monash University in Australia.

Bristow spoke with U of T's Jim Oldfield about the team’s novel findings, how they plan to bring them to the clinic and how science is rapidly changing the prognosis for every man with prostate cancer, which kills about 250,000 men worldwide each year.  

How are men with prostate cancer assessed now, and how might your research improve that process?

Right now, once we’ve diagnosed a man with prostate cancer, we run tests to determine roughly how aggressive the cancer is and how far it’s spread. We use the PSA blood test, pathologic grading (the Gleason score) and staging with CT scans and bone scans. These clinical parameters allow us to provide a probability or risk of dying from the disease as low, intermediate or high.

Many men will have intermediate-risk prostate cancer. But we know that within this group, about 30 per cent will fail with local treatment alone following surgery or radiotherapy. And within that subset, up to 10 per cent will fail rapidly within two years after the first treatment. These latter men are especially at risk for death and need intensified therapy from the get go. But we haven’t been able to parse out who those 10 or even 30 per cent of men are at the initial diagnosis.

So in our research, we pieced together an individual genetic fingerprint for each cancer, which in future could help us decide if a cancer is curable with surgery or radiotherapy alone, or whether it also requires chemotherapy, hormone therapy or molecular therapy – in other words, it would mean personalized and precise care for men with prostate cancer.

How did that discovery come about?

For our studies, we used whole-genome sequencing. Like it sounds, we sequenced the entire genomes of these cancers, the coding and non-coding parts, and that allowed us to look at which genes were methylated (turned on or off), translocated (re-arranged) and mutated, and where there was loss or gain of a chromosome.

These and other genetic factors are usually looked at in isolation, but for the first time we were able to put them together to form a comprehensive genetic signature with predictive accuracy better than 85 per cent in the roughly 500 cancers we tested.

How can you move these results to the clinic?

There are two main things we need to do next. The first is to prospectively validate our results in men who face the greatest risk of dying within two years – that roughly 10 per cent I mentioned. We need to show that we can identify them right away and invite them to partake in clinical trials that could offer them a different course of treatment and better outcome.

Second, we need to develop a high-grade, clinical-quality test that’s reliable and fairly simple to use in the clinical setting. Ideally, we want a chip or a single machine that will provide all or most of the multi-modal genetic signature for each cancer.

We're now working hard to start a company in the next year that can develop this technology for the clinic. And it's important to stipulate here that all the way along this has been a team effort. Paul Boutros has been instrumental in driving the bioinformatics associated with these studies, along with basic scientists, oncologists, pathologists and the DNA sequencing team, with financial support from Prostate Cancer Canada and the Movember and Princess Margaret Cancer Foundations. 

If you can move this advance into the clinic, what impact could it have?

It could change the way we talk to patients. Every man with intermediate-risk prostate cancer wants to know if he’s one of the 30 or the 70 per cent. In the new version of the molecular urology clinic, we’ll be able to tell them.

How many men could this affect? Based on current rates of prostate cancer in North America, we could probably find the 5,000 to 8,000 men who aren’t getting cured now and offer them alternative and intensified treatments within new clinical trials based on the unique genetic make-up of each man’s cancer. We’re developing those trials now. And, we may finally be able to alter the course of prostate cancer for a rare subset of men with a bloodline BRCA2 mutation, who have a very aggressive form of the disease.

In a related study we did on 14 men who had this germline, or inherited mutation, we found their cancers shared genetic qualities with cancers that spread and were resistant to hormone therapy in the larger group of 500 men. This in part explains why BRCA2-linked cancers prove fatal within five years, in half the men who have them – even before these men get treatment, molecular pathways resistant to treatment are activated. And so we could target those pathways with a PARP inhibitor or other drugs to offset their risk of dying.

Have we reached a watershed in prostate cancer research?

Yes, I think so.

Five or six years ago, we didn’t understand why some cancers spread and some didn’t. We now have a much better picture of local disease versus metastatic and treatment-resistant prostate cancer.

We can approach patients very soon from a molecular standpoint and determine the genetic architecture of each tumour. In the next three to five years, we’ll see treatments based on that architecture: molecular targeted drugs, immunotherapy, and more effective hormone and chemotherapies. It’s really an exciting time, and it should provide hope for all patients with aggressive prostate cancers. We’ve recently come a long way in a short time, and we’re on the cusp of a major shift in how we practice.