Finding the Full Spectrum of Genetic Variants in Advanced Prostate Cancer - Rosalind Eeles

In this conversation, Alicia Morgans and Rosalind Eeles discuss how patients should be selected for genetic counseling and testing. This discussion highlights several important questions including: What is the spectrum of genetic predisposition that we currently know? How should we use this? Who should be tested? Are there international discrepancies in the guidelines? How do we manage men who are at higher risk? What will the future look like? Emphasizing "smarter screening", Rosalind shares ongoing work at the Institute of Cancer Research and the Royal Marsden, where the BARCODE 1 study is underway, a study undertaking this profile of smarter screening.  It is a 170 gene saliva test for the snip profile in 5,000 men in London. This test is undertaking a more intensive prostate screening in those men, and looking at what the results are to test those patients or people who are more likely to then have the disease, taking this normal curve of distribution and highlighting that highest risk population to use screening in a smarter way. In conclusion, Ros also shares details on a protocol which is being developed with hopes to be able to take into primary care, to look at more extensive genetic profiling as part of potentially overall health screening in the future. 

Biographies:

Rosalind Eeles, FMedSci PhD FRCP FRCR, Professor of Oncogenetics, Honorary Consultant in Clinical Oncology and Oncogenetics, The Institute of Cancer Research

Professor Eeles has both a private and an NHS practice at The Royal Marsden. She trained at the University of Cambridge and St Thomas’ Hospital Medical School. She then underwent higher medical training and is a fellow of the Royal College of Physicians of London. She trained in clinical oncology at The Royal Marsden and is a fellow of the Royal College of Radiologists (Clinical Oncology Faculty), UK.

Alicia Morgans, MD, MPH is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi, I'm thrilled to be here today at APCCC 2019 with Professor Ros Eeles, who is a professor of Oncogenetics at the Institute of Cancer Research in London. Thank you so much for being here.

Ross Eeles: It's a pleasure.

Alicia Morgans: Wonderful. So you gave a lovely talk, trying to help us as clinicians, put into context how we should think about which men should be tested for genetic abnormalities with prostate cancer, and helping us try to think through which are the most important genetic mutations that we need to think about that are most clinically relevant, and how we think about screening populations to really identify those patients at highest risk. Can you give us a little bit of an overview of your talk?

Ross Eeles: Thank you. So when we think about an increased risk of prostate cancer, then in the genetic makeup there can either be common variants which occur in many people in the population, but each of them have a very small increased risk. But they add together, they add together actually in a log additive way, or a multiplicative way and they can end up giving quite large risks if you carry many of them. And then there are much rarer variants that have a much higher risk. So when we think about how we might develop a genetic test to identify men that are at increased risk of the disease, we have to think about both these components.

So as an example, if you think about a hundred men in a room, we now have a snip test, or a profile test, for genetic variation that tests for 170 variants that can actually distinguish, in those hundred men, the man at the top 1% of the risk level. He's at about 40 fold risk compared with the man at the bottom 1%. And about 5.7 fold risk compared with the man in the average, in the middle of the genetic distribution. And there are also these rarer variants, may be carried by about one in a hundred, to one in a few hundred individuals, that have much higher risks. The ones that are well known about already are the mutations in the breast cancer predisposition genes, BRCA1 and BRCA2. But we now know, from other studies, that there are other genes that also carry variation and we're trying to determine, in targeted screening studies, such as the one that's about to be published shortly from the IMPACT trial, what the exact levels of risk are and where the PSA screening will help to identify more aggressive disease.

Alicia Morgans: So I love the idea of smarter screening and I'm just wondering with this 170 gene test that you've mentioned, is that something that people could use in their clinics at this point in time? And if so, what is it? Where would they get it? And how would they think through that? And would that really be in a primary care sort of a population? Or is that's not the testing we would want to do for men already diagnosed with prostate cancer, is it?

Ross Eeles: You're absolutely right. The development of the test really is nearly here. The development of a test that might include both common and rarer variation. But the use this in the clinic is not quite here yet, because we need to do the studies which are actually ongoing in London. So at the Institute of Cancer Research and the Royal Marsden, we have a study called BARCODE 1, which is undertaking this profile, this saliva test for the snip profile in 5,000 men in London. And then undertaking more intensive prostate screening in those men, and looking at what the results are. We anticipate that BARCODE 1 should have results by the time of the next consensus APCC conference.

Alicia Morgans: That'll be wonderful. So, and that'll be really interesting to see how that could be implemented more in either urology clinics before a biopsy. Or primary care, I think most effectively, to make our testing actually test those patients or people who are more likely to then have the disease. Like you said, taking this normal curve of distribution and highlighting that highest risk population to use screening in a smart way. So that's wonderful.

Ross Eeles: Yes. And it's interesting that you mention primary care because we are at the moment have developed a protocol, which we hope we will be able to take into primary care, to look at more extensive genetic profiling as part of potentially overall health screening in the future. At the moment this is quite futuristic, but it is the way that the field is going. And as a component of that, the prostate cancer genetic profile will be a very important part, trying to identify men that would really benefit from more intensive screening.

Alicia Morgans: Wonderful. And so what is that looking at exactly? It's looking at these patients and then trying to help define how to better screen them. Is that-

Ross Eeles: Yes. Because until recently, quite rightly, screening of the general population, say with a single PSA value in a man of 55, wasn't improving survival and it wasn't finding more aggressive disease. So we're hoping that if we can identify individuals that are at higher risk because of their genetic profile, maybe that will help us identify men that would benefit from such screening, and we can target to all screening resources to those that are most likely to benefit because we would find more aggressive disease.

Alicia Morgans: So I think, at least in the United States, we absolutely need this smarter screening approach. I think that general screening has led to so much controversy, in the US, about whether we should be doing PSA screening at all. And so any efforts that we can make to ensure that we're screening more effectively, I think will be helpful in the UK, certainly, but worldwide. And so I really do look forward to seeing that publication.

Ross Eeles: Thank you. And then I think the other cautionary tale we would say is that it's possible that not all populations are the same.

Alicia Morgans: Yes.

Ross Eeles: So the data that we have so far are mainly in the Caucasian population. And we're doing a lot of work within a consulting pool practical. Where one of our collaborators, Chris Hyman at USC, is leading on the analysis of multi-ethnic populations, to see if the profiles that we find in Caucasians, also apply to black men, and people from Hispanic and Asian subgroups. And we look forward to seeing his results.

Alicia Morgans: Absolutely. And it's not just, I think understanding the prevalence of these variations that we already know about, these mutations that we already know about, but potential future work in determining whether there may be other drivers in those ethnic populations, that we haven't picked up, because we actually just don't have a database with large numbers of samples from those patients. So that's really, really important.

Ross Eeles: That's where this so called team science is so important. And the exciting thing about these large consortia is, first of all, people from all over the world, like in this conference, come together and work together. And we've developed very good data-sharing agreements and agreements that work across boundaries and frontiers, whereby it's very much an international effort.

Alicia Morgans: Wonderful. Well, thank you so much for sharing this practical guidance and your thoughts on where things are going in the future. And I really look forward to having the ability to use some of these tests in my clinical practice and to hear in your talk, probably in another two years, at the APCCC, where you can tell us where we're going next even from here. So thank you so much for your time.

Ross Eeles: Pleasure.

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