ESMO 2012, Vienna, Austria

Putting the theory of personalised medicine into practice

Professor Gordon McVie – ecancer and European Institute of Oncology, Milan, Italy

Professor Fabrice André – Institut Gustave Roussy, Paris, France

Dr Ramesh Ramanathan – Scottsdale Healthcare Research Institute, US

Professor Peter Harper – Guy’s and St Thomas’ Hospital, London, UK

Professor Robert Leonard – Charing Cross Hospital, London, UK

GM:      I’m Gordon McVie and I’m here with some good friends to talk about personalised medicine. If you’re as confused as I am about personalised medicine then join the club. There are at least 140 definitions that I’ve seen and I suppose the first thing I have to say, as the eldest in the panel, I thought that we were doing personalised medicine already but of course we’re not. So, how did MOP come to be, how did DaVita choose MOP then, Robert Leonard?

RL:       From memory, I think it emerged after fifteen, maybe longer, years of trial and error with individual drugs being put together in different combinations and repeated disappointments and finding eventually that combination chemotherapy in the liquid tumours seemed to be doing something more than single agents were. They put together, as far as I recall it to be the case, the drugs they thought they could tolerate and then went from there and found some early successes.

GM:      And Bonadonna put ABVD together because Pharmitalia made Adriamycin?

PH:      Adriamycin, almost certainly that’s true but in fact it’s a wonderful drug in the treatment of breast cancer, it happened to be Italian and it happened to go to Bonadonna, but putting together the regimens for breast cancer with an anthracycline that are still in use today. So, serendipity but it worked.

GM:      But we didn’t know how it worked.

PH:      No.

GM:      And I remember the first topoisomerase conference that Franco Muggia organised in New York and it was suddenly announced that anthracyclines and topoisomerase got together and also that we had a whole family of drugs that we didn’t even realise we had which attacked topo 1. So what’s happened then, Fabrice, from Gustave Roussy? Personalised medicine is based on what?

FA:       I think the important point is to define what we are speaking about. We need to make a difference between personalised medicine and stratified medicine. Stratified medicine is what we are doing now; we have HER2 positive breast cancer, it’s 10% of breast cancer, a defined stratus of patients. Personalised medicine is really individualising treatments meaning that the patient is unique according to the molecular alteration. This is the second point that is important in the definition, actually we are speaking about personalised medicine according to molecular alteration but you are right, we are already doing personalised medicine according to their weight, their height and many other things, their social life, many things. We are already individualising treatment, here we are speaking about personalised medicine by molecular analysis.

GM:      And Ramesh, you and Dan Van Hoff have being doing this with prediction of cytotoxic effect for some time now?

RR:      Correct.

GM:      And it works?

RR:      We think some patients do get benefit. Cytotoxics are here to stay for at least, I would think, for the next ten years and the vast majority of patients get cytotoxics, sometimes in combination with targeted therapy so I think it’s important to pick the right cytotoxic for the patient.

GM:      So the old ideas of growing the cancer then giving them some medicines to see whether they died, à la bacteriology, that’s moved on and we’re now looking at genomics?

RR:      That’s moved on, I think there’s something to be said for that. I think it did help, or set the foundation, for what we do now. Now we look at the tumour cells either from biopsies or sometimes we grow them in mice, xenografts, I think that also has a role to play.

GM:      And you’ve got some personal experience from patients that you talked about here at ESMO today.

RL:       Yes, the mouse link is a good one actually because, of course, patients aren’t mice, biologically or psychologically. Yes, we’ve seen some good successes with this approach but we are also dealing with people who have their own prejudices and sometimes it doesn’t quite accord with our selection of medicines, even if it’s in the patient’s best interest as we perceive it. So we’re always going to have that debate, if you like, as to what the benefits are against the costs.

GM:      So if you’ve got a technology, and there are several around at the moment, how do you choose the patient to try this test on?

RL:       Well, I think we’re at a stage at the moment where we’re not quite mature enough with the technology to say this is the first thing we should be using in the patient. Maybe it should be, but it’s not at the moment, we haven’t got enough evidence. If we have evidence of there being an effective medicine or medicines, combination, out there that, say, we have for breast cancer, by and large, we have very good data for early stage disease, OK we have failures but we have very good data based on large numbers of patients as the Oxford overviews repeatedly tell us, we wouldn’t be using these drugs at that early stage of treatment until we’ve proved with far bigger numbers than we have at the moment that they are actually more effective because they target the right targets.

GM:      Peter Harper from London Clinic, you are convinced, I think, by the approach of analysing the tumour in depth and then looking at what lessons you can learn in terms of the therapeutic management. Having come from an ivory tower, you’re concerned about how we can afford to get this out, this technology out, so that more patients can benefit from it.

PH:      Yes, so all treatments are a judgement of the doctor based on clinical trials – what’s the evidence, does it work, will it work in the majority of patients? We all know that there are patients who do spectacularly well and patients who, to our great surprise, do spectacularly badly. What we’re trying to do always is to refine that selection of the patient and I think that there is evidence that you can do that both for cytotoxics  and absolutely for targeted treatment. Now how you’re going to get that out there, at the moment it’s certainly out there as a result of phase III clinical trials, but I think that the evidence is now saying that the patient and their tumour are unique and even if in that tumour type this isn’t a drug you would commonly use or frequently use, you should think about it if you’ve got the evidence. We are seeing, I think, as examples today from José Baselga, that in certain tumours it’s magical and for us, who have been using targeted drugs since they first came in, we have eight year, nine year survivors from our first trial in metastatic lung cancer. That’s not common and, for instance, in kidney cancer equally very, very good responses and survival. But these are stratified, they’re stratified by the tumour type, they’re not selected for the patient.

GM:      Now you’ve got an astonishing set-up in France where you’ve got government funding to set up these genomics clinics or these diagnostic clinics – 22, or something, all over the country? Tell us about that, we certainly don’t have it in many other places in Europe.

FA:       Yes, it’s quite a unique project. So the project is the following: the French NCI has decided to develop 28 genomic centres and the goal of each genomic centre is to provide genomic tests for each French citizen. So it’s a unique project, the goal is to provide equal access to genomic medicine for all French citizens and it’s working well. They succeeded to make the scale up in terms of number of tests done; for example, in 2010 they performed 144,000 genomic tests for clinical use that is. It’s very high.

GM:      So you’re an expert in this area, how do you advise the France NCI which tests are valid and how do you validate, because there is a choice?

FA:       Yes, I think the key point is, of course, to provide tests based on level 1 evidence. There are two difference evidence that support the use of a test, first is when a drug has been developed and approved in a very specific genomic segment, that is the approval of the drug is conditioned by the test. Then there are other tests, like KRAS in colon cancer, where several retrospective analyses of randomised trials consistently report that the genomic test can predict resistance to treatment and that we can select patients based on this genomic test to avoid additional costs and additional toxicity. So there are the two different situations where a test can reach the level 1 evidence and implementation for patients.

GM:      Ramesh, how do you pay for it in the United States?

RR:      In the United States I think that there are a number of sources. One is certainly grants, clinical trials and, for some of the new ones, profiling studies. A lot of the clinical trials that we have done in our programme are from foundation support. Increasingly this can be reimbursed by insurance; we have a number of clinical assays, profiling assays, if there are clear certified and the test is FDA approved, most insurers in the US will pay for it.

GM:      And you would use the same sort of criteria, level 1 evidence, as they do in France?

RR:      No, I think a lot of the profiling in the US, it’s evidence but not level 1 evidence; level 1 evidence, I would say a randomised clinical trial but for most profiling I would say we don’t have level 1 evidence so it may be retrospective or prospective phase II studies.

GM:      Bob, the case reports from you and from Baselga were really quite instructive and José Baselga was saying let’s put all these responders on iCloud. Is this something that ecancer should be doing? Should we be taking all these genomic patterns associated with unexpected responses, make it available?

RL:       I think it has to be done, yes, I think it has to be done. I think it’s a novel suggestion, I don’t know whether there’s enough good will out there for it to happen, but yes, the data should be made available. It’s happening in physics, they share the data; it’s happening in all sorts of sensitive areas of science, why shouldn’t it happen in medicine?

GM:      Peter, biobanking – are you of the view that we should be recommending that patients’ tumours are banked, maybe not routinely and maybe not for immediate use but maybe for unexpected recurrence or early recurrence or progression of diseases?

PH:      Yes, it can go by many names, biobanking is one which is where you take a tumour and you lay it down for future use, that can be as fresh frozen tissue or as tissue which is preserved. But more than that I think we are coming to the point when, when patients progress, when patients relapse, they will need to be re-biopsied, that’s quite a shift for the patient to have to go through. They’ve had cancer, they’ve had it treated, they might well have had a remission or response, now it’s come back and we say, “Well, we need another biopsy.” I think that is where the subject is going and that is part of what we’ll be asking patients to do is have a re-biopsy so we can look at the molecular profile of what’s gone wrong.

GM:      And you think that the liquid technology is going to come along, circulating tumour cells or plasma DNA or whatever, as an alternative?

PH:      Yes, we think as an alternative DNA, circulating DNA, is certainly an option. Circulating tumour cells are difficult assays, it’s one of the assays I think I’m personally rather surprised hasn’t become easier and hasn’t become cheaper, it’s very, very dependent on the operator; it’s not really a technology driven subject, the operator is very, very important. If CTCs, circulating tumour cells, could be easier assayed and it could become more reasonable then I think it’s still got a lot to offer but it does look as though circulating DNA will be the way forward.

GM:      So we have a consensus, have we, that personalised medicine is about the individual patient and his or her genome and the individual patient’s tumour and whatever is in there, and then the adaptation of the treatment to that individual profile. That’s the way we’re going?

RR:      Yes, I think that’s correct but I also hope that physician medicine, which is a little bit more precise, I would think, but that’s a good definition.

GM:      You’re not worried about handing over the decision making to the laboratory print-out?

RL:       I don’t think it’s as simple as that, of course, because we’re going to learn a lot about individual patients and it’s going to be hard to put the data together to give confidence that treating Mrs X in ten years’ time is the same as treating Mrs X ten years ago because the technology will have changed, the drugs will have changed, so it’s going to be very hard actually to get the real confidence in the data; however many cases we do put into this cloud, if that’s what we do, there’s still going to be a great difficulty in interpreting it for the individual patients, I think.

GM:      How are we going to tell our colleagues about this Peter, and how are we going to tell our patients about it?

PH:      I think we do need to see, we need to learn about the great successes we’ve had -why has patient Y or Z done so very well? We need to look and see what’s happened and we need to bring that out into the general oncology perspective and to the physicians. My personal view is that they’re wide awake and they’re listening but what we have to have is easy access and no-one is going to be able, or an ordinary physician is going to be able to analyse which of 17,000 genes it is and so we are going to need to have algorithms which help us to choose what is best for that patient.

GM:      And, Fabrice, the technology is not finished yet, is it? It’s really shifting. What is your hope for it?

FA:       No, it’s a permanent evolution. Personally, I think the next interesting technologies are, of course, next generation sequencing, in-depth sequencing, to identify this minority clone that can mediate resistance. There is another kind of technology that is interesting, is assessing the activation of proteins - whether the kinase is activated, is the DNA repair functional? All these functional tests are becoming very interesting because once we have the genomic profile what do we have in front of us? Is it pathway activated? Is the cell going to proliferate? So we need some complimentary information to genomics.

GM:      Gentlemen, thank you very much for being so clear and I think the message is straightforward, that we’re really shifting, really for the first time in twenty years, towards really looking after each individual patient. Maybe in the next meeting in a year’s time, or should I say, the next, next meeting, that’s the technology, I’m told, things will have changed and things are even brighter. So thank you very much indeed, all of you, I appreciate it.