ESMO 2010

Dr Kevin Davies - Bio-IT World, Massachusetts, USA

The impact of mapping the human genome on cancer therapies

Kevin, thank you very much indeed for coming and spending a couple of minutes.

Thanks for having me, sure.

Kevin, this is yours, right? I will just get the maximum publicity for this book, The Thousand Dollar Genome. You know, even a year ago that was crazy. So what’s made that all come together?

Well let me first off say that we’re not quite at the thousand dollar genome price point just yet. But three years ago Jim Watson, the man who co-discovered the double helix, was given a portable hard drive with his digital genome, his digital DNA on it. The cost of that was $1 million. So from 2007 $1 million to 2010, what can you get for $10,000 or $20,000? Anybody watching this video segment could go to their doctor, get a note, send it to a company in the US called Illumina, and get the same level of sequence that Jim Watson got and the price is just going to keep coming down as more companies reach the market.

It’s one of the strategic aims of the European Institute of Oncology in Milan, to my astonishment, and I think it’s going to be the way that we’ll all go. What puzzles me a little bit, because I’m a bit old you know now, and I wonder about how we’re going to deal with the knock-on effects of this in terms of clinical practice. What’s your take on that, Kevin?

So the technology is coming fast and furious down the train tracks, so the people watching this, particularly the oncology community, have really got to wake up and see this is coming. There are pockets of groups around the country, I can probably give you a couple of anecdotes, where people are not just using whole genome sequencing to identify cancer mutations, this has been done for the last couple of years in the New England Journal of Medicine and elsewhere, but they are now starting to use it on individual patients to guide treatment decisions.

So the debate is still open as to whether you would do a whole genome or maybe just look at the genes, the coding regions, you can probably just do 10% of the genome if you wanted to do that. And still people may favour doing targeted genes and I think there’s going to be a long-ranging debate in the industry, in the community, for the next few years as to whether we should just target known hot spot genes, or whether there is time and money to be saved in the long run by just sequencing the whole genome and seeing what you get out.

Who’s driving it?

The field is driving it, I mean there are groups.

Science.

Science is driving it.

Or industry or both. Governments are not driving it.

Technology is a huge driver. You cannot ignore the fact that we can now sequence a human genome in a week, for less than $10,000. Many institutions around Europe, around the world, are doing this right now. Companies that want to sequence human genomes can send samples to a company in California called Complete Genomics and get them for perhaps even $5,000.

So, this technology is really what’s driving it. And we’ve been talking about personalised medicine for a decade or more, and a lot of people were starting to think, well we’ve had the Human Genome Project, when are we going to see our genome actually make sense, make a difference for the man on the street and we’re now just beginning to see the first examples of that.

We hear dissonant noises from the United States in terms of what we have achieved so far with the Human Genome and what we have not yet translated into human benefit. Where do you sit in that dialogue?

I think the payoff has been delayed because we completely underestimated the difficulties of drug development. Just because we now have the human genome on a computer with a complete sequence of reference genomes with many, many dozens, indeed hundreds of other individual genomes, that doesn’t really change the equation of the fifteen years and a billion dollars to bring the successful drug to market. You know this better than I do.

So more and more studies are leveraging the Human Genome, not just in target selection but I think increasingly in patient stratification. You can see a lot of examples here at the ESMO Congress where the more you can pass your patient population as you begin to do clinical trials, the faster those drugs are going to move through because you’re targeting on the most at-risk population.

The whole definition of rare cancers has shifted in within two or three years from the neuroblastomas or the neuroendocrine tumours, to breast cancer. Suddenly breast cancer became not one rare cancer but a series of very rare cancers and lately, of course, non-small cell lung cancer, suddenly we’ve got a couple of little groups of people in there, whom you’d better find because they’re getting 60, 70, 80% response rates from targeted drugs. Is this the way it’s going to go?

I do think it’s going to go and there are certainly companies, a company called Ion Torrent was just bought by Life Technologies for $375 million. They’re not going to do a whole genome sequence but they’re going to provide a bench-top machine that in principle could allow any pathology lab in any medical centre in the world to just focus in on the genes you know are mutated, the genes that if you have a KRAS mutation or you don’t, or an EGFR mutation or you don’t, that’s going to change the pattern of therapy you’re going to prescribe for that particular patient. So that technology is entering the clinic as we speak.

And is that foolproof? I mean, we’ve had real problems, let’s say, with trastuzumab and now lapatinib targeted to people with HER2 over-expression and immunochemistry and FISH, even in the best hands, in the best labs, are still sometimes misleading.

Good point. I wouldn’t claim it’s foolproof, I don’t think anybody would, I mean you can always find exceptions. I was very struck, though, by a case presented at Cold Spring Harbor just a few weeks ago from the group at the Genome Center in Washington University, St Louis, who sequenced the first whole genome sequence of a cancer patient in 2008. They sequenced a leukaemia patient that wasn’t responding to therapy and the fusion protein that they discovered as a result of whole genome sequencing, which may seem overkill but that’s what they felt they needed to do to get to the bottom of this patient’s tumour, that turned out to be a novel rearrangement, a novel fusion protein, it completely changed the way they thought about what they should be prescribing, and that patient is now doing fabulously well.

So, the same sort of approach for cardiology, for rheumatology?

Yes, I think oncology is certainly at the leading edge of this. I open my book, The Thousand Dollar Genome, with an anecdote of Jeff Gulcher, co-founder of deCODE genetics the Icelandic company. So they and other companies, like 23andMe, have been offering consumer genomics tests, not whole genomic sequencing now, just looking at about 0.1% of your human genome. But Jeff in his late 40s, a healthy man, did this test, it revealed a high, a doubled increase, risk of prostate cancer. This is still very controversial and his GP wasn’t terribly impressed by this but said, you know what, I’m going to put you in touch with a urologist, we’d better be safe than sorry. Following a biopsy it was revealed that he had the most highly advanced prostate cancer that was possible, it was removed, all because he spat in a tube and sent it off to a lab.

So, a lot of people in the medical establishment frown on this, they really don’t trust the results, but that’s an example where not only did it save his life, it probably saved his insurance company, or what have you, perhaps about $100,000 or more in the prolonged tale of cancer treatments and payments. So, just beginning to see the benefits of this sort of DNA testing.

We’re fussing around still in Europe with the issues of setting up bio-banks and getting them all networked and all these issues about confidentiality and anonymity, it’s all terribly important. Do you think this is all a wasted conversation because actually the tumour blocks are not going to be that interesting in five years time, and we should actually be concentrating on just getting more population, collections of people spitting into test tubes or whatever the simplest possible sample is and then setting that up and then when people get into trouble you’ve got the information then.

Yes, it’s a big issue in the United States as well. George Church from Harvard Medical School has been advocating the Personal Genome Project - getting volunteers to not only be sequenced but to then post their genomic and phenotypic data online. He’s having trouble getting the long-term funding that he needs because this really goes against all kinds of sacred protocols and concerns about privacy and informed consent and so on. So those debates are raging in the US as well. Thankfully now we have some pretty solid federal legislation, GINA is a bill that provides a lot of safeguards about the use of your own genetic information and, when it comes down to it, I think everybody has a right to their genetic information. You know, if you’re going to medically act on it, you’re going to go to your doctor or speak to a genetic counsellor, but if I want that information I should be able to see it and not listen to people who are fretting that everyone’s going to be panicking and jumping off bridges because they can’t handle the truth.

Of course it’s not just the truth for me, but it’s the truth for offspring, cousins, and so on, and there’s another set of discussions. And who do you tell if you don’t particularly get on well with your sibling?

That’s a good point. Jim Watson was the first person to be individually sequenced using one of these Next Gen sequencing technologies, and was asked, did you ask your kids for permission? And he said, no, I didn’t think it was really their business, you know; well yes, it is a little bit their business. So that sort of ethical debate is still going on, absolutely.

And have you had your genome sequenced?

Through the personal genome companies, consumer genomics companies like 23andMe, Navigenics, deCODE, I have a chapter in the book that goes through all of my results, yet there’s still…

Can I ask you, how much did you pay for it?

Well not too much in most cases, most of them were freebies; as a journalist writing a book, I think they were eager to get people to cover it, so a fair number of these kits were given away.

But you know, there are still some inconsistencies between the different platforms and various critics have latched on to this. This is not ready for prime time, if deCODE and 23andMe can’t even agree on the actual lifetime incidence of prostate cancer, let’s say, then how are you supposed to gauge the significance of the results. That doesn’t surprise me, I mean I know where you go to exactly pinpoint the baseline risk and the algorithms that are used to calculate the impact of these genes, the criteria used to decide which genes to use in these calculations to predict the risk for these complex traits all that is evolving. So I’ve no doubt that this is all going to converge in the next few years, as market forces will dictate.

We got a bit of a whiff of it from oncology and the breast cancer gene signatures and what’s been surprising for some is that many of these signatures actually don’t have much in the way of overlapping genes. But it’s because, in my view, the big picture of the big algorithms haven’t actually been developed; we don’t have so many people with mathematic and biological skills to sort of handle this sort of project and it really does require some lateral thinking.

Yes, and I think you are alluding to the expression test on the oncotype and so on. That’s one…

Same issues.

Yes indeed, and, of course, different groups have different algorithms and different approaches, they are going to focus on different subsets of genes. And it doesn’t mean that one group is right and one group is wrong; we could be just approaching this issue from different sides. And I would like to think that in the next few years, looking at gene activity as well as gene mutation and other parameters, protein biomarkers and so on, could all complement each other into perhaps one really definitive ‘at risk’ test.

Kevin, I’ve got a personally signed copy of your book, thank you very much indeed and thank you for the interview.