Ecancer.tv would definitely like to congratulate you on being the AACR Distinguished Lectureship Awardee. You have chosen to talk about a topic that’s very close to your heart, molecular evolution, specifically here molecular evolution under neoadjuvant chemotherapy. So I’m going to ask you all about this: what is the context of this in breast cancer and what are the exciting areas that you’ve been looking into and that you want to tell the world about?
Yes, I think that evolution is extremely important in breast cancer progression and what is ongoing when you are on any kind of chemotherapy, for example. We know that breast cancer is so many heterogeneous diseases and we were among the pioneers in sub-classifying them into these five subtypes. We have been asking the question, is the evolutionary path different in the different subgroups?
And is it?
It looks like it definitely is. How does that alter during the treatment and can you move from one phenotype to another phenotype?
And can you predict this evolution though?
Not today but that’s some of the aim that we really would like to predict the evolution. I think that having one snapshot of the sample you cannot predict, so then when you have three samples, for example, when the patients are under treatment, then you may be more able to predict than just having one snapshot.
Now, we tend to initially categorise patients according to the initial biopsy testing but now you’re proposing serial testing. What’s happening during the period of neoadjuvant treatment that you’re particularly addressing today?
One of our aims is also to do classification and follow the molecular evolution at many different levels, not only at the DNA level but the DNA copy number, the sequence alterations, the methylation. But then also on the microRNA level, the mRNA level, protein and the metabolic level. So that’s what we have been doing, to really do it at six different levels to put that together. That can tell us more about the dynamics between the different subclasses and what is changing during this treatment.
Now, is it the presence of different clones or is it the ambiance created by the therapy that’s the main driver of this evolution?
Without any treatment the tumour will evolve anyway but it’s under larger stress and you have more selection when you have a stress on the tumour cells. So you eradicate some of the most proliferating ones, that gives room to the less proliferating that may come further in the next stage. So then of course we would like to see if you change therapy during this course can you eradicate the next subset of clones that you didn’t eradicate in the first round.
And part of the success of doing this could well be in the sheer mathematics of what you’re doing, couldn’t it?
Exactly. So we are working closely with mathematical modelling to really model this evolution of the tumour cells and the co-operation between the different clones.
Could you hypothesise for me a successful scenario where you do check up on the genetic composition initially then you follow it and then you change? What kind of thing would you like to see happen with different therapies evolving with the clonal evolution of the cancer?
First of all if we know about some signatures that can highlight which way the evolutionary route is going and then if we can transfer that to some, for example, in situ technology so you can do it in situ and look by cell by cell, are they close by. Then you can do that on the sections as you go along and then you can immediately follow that patient, take the biopsy, look at the section, look at the clonal composition and then change the therapy because then you can see which clone has been dying and which is still left and can you target that one. That’s the sort of scenario that I hope to see. In addition to that, of course, if we can follow circulating tumour DNA at the same time you have two really highly powerful technologies that we can follow and do changes in the patient much, much earlier.
So you need both the biopsies and the circulating tumour DNA do you?
I think that that would be absolutely the best to have both at the same time.
But you could monitor more frequently with the circulating DNA?
You could do and of course that’s non-invasive so you can do that more frequently and then you can take the tumour biopsy. But for the time being we know what happens actually also in the tumour itself.
What do you think doctors should make of this technology and this science and this mathematics right now? Is it a distant hope to be able to get ahead of the game and halt the cancer despite the proliferating number of subspecies that are happening there?
It’s a hope. Because we still have some work to do to really find the right profile in the right patients where we can start to intervene. But I think we need to start to do some trials in this to really follow it and to see how much benefit it will be to the patient, and be allowed to change the therapy more frequently than we do.
And what kinds of innovative intervention could be used, do you think?
First of all we need to do more combination therapy because one single target is not so we need to have more targets at the same time. Of course then we have to rule out the toxicity and then maybe a new combination in the next round.
And the impact of things like radiotherapy on all of this, does that have any impact at all?
I think it will. We know too little about that for the time being, how much of the radiation is impacting the clonal evolution. But that’s another study that we really would like to take on.
Of course the trade-off between more immunological approaches and more chemical approaches to anti-tumour, how does that play?
For example, if you can monitor also because when you’re really looking in situ, and that’s the advantage of having the biopsy, you also see the infiltrating cells, you see the macrophages and the TILs that are coming in there and you can see how they act. And if you can stain which type of TILs are there you can also use that as a marker for are you going to do now immunotherapy in response.
A very exciting field but what is the take home message for practical cancer doctors who have patients right now?
The practical, from my view, is collect samples. Biopsy, biopsy, biopsy and we need to do investigation to do that.