COMMENTARY

What The ESMO Translational Research Award Means to Me

Prof Charles Swanton

Disclosures

September 29, 2019

This transcript has been edited for clarity.

I'm Professor Charles Swanton. I work at the Francis Crick Institute and University College London [UCL] Hospitals.

The ESMO Translational Research Award means a lot to me. It's a reflection of all the work that my team have done. And what they've achieved over the last 10 years is remarkable and a real testament to them.

They've been supportive, they've come up with ideas when I've been bereft of them. And all in all they have been the brains and the hard work behind everything that's responsible for this prize today, from the times when we first stumbled upon branched evolution in kidney cancer through to our developments of the minimal residual disease assays that I presented today.

Tell us more about the research that led up to the award. What's been the biggest achievement?

About 2 decades ago when I first started training as a medical oncologist, the problem of drug resistance was really forefront in my mind.

And of course having had a scientific background and having done a PhD at university on the UCL MBPhD Programme, I felt very strongly at the time that science would be able to contribute to addressing this problem of drug resistance to targeted therapies in the clinical setting.

The models of cancer evolution that we'd been taught at medical school didn't explain this problem of acquired resistance to common targeted drugs that we're used to seeing in the clinic now.

The way I explained this problem of resistance to patients was through Darwinian evolutionary phenomena, with very little evidence to support that contention. Indeed, papers from Peter Nowell and others in the 70s postulating Darwinian evolution, tumour heterogeneity and natural selection driven by genome instability, or genome lability as he called it, was really a foundation, or the bedrock explanation, that I used to explain to patients why resistance was happening so quickly to the targeted drugs that we were using. But there wasn't any foundational evidence really for that at the time, in the early 2000s. 

When I set up my own laboratory, one of the first questions we tried to address using the new era of next generation sequencing technologies was to sequence tumours at considerable depth to see if there was evidence of natural selection and Darwinian evolution in tumours. And we took clear cell carcinoma of the kidney as our disease model, simply because firstly, this was a disease nobody else was working on. So there was plenty of tissue and secondly, the tumour tissue was prodigious in nature by virtue of the nephrectomies that patients would undergo, and the residual tissue the pathologist wouldn't need for their diagnoses. 

So we have plenty of tissue to work with, and to analyse. And we have the advent of next generation sequencing technologies on our doorstep to use. And so we essentially put the two together and sequenced multiple regions from several tumours over about a 3 year period. And we found that really branched Darwinian evolution and natural selection was the norm, rather than the exception. 

And this gave us the confidence to really explain to patients that resistance really is occurring in real time as a function of this genomic diversity that we had observed in tumours. And I should also say it's not just us, but many others around the world at the time, friends, collaborators, other scientists stumbled upon exactly the same phenomena in other disease entities, including breast cancer and ovarian cancer.

Many other examples of branch evolution came out at the same time or even before our examples. For me, that really gave us the confidence that we should now dedicate our entire laboratory programme to understanding evolution. It was clearly important. It was startling, quite how diverse these tumours were.

And what is referred to as parallel evolution in the literature, that is, the same gene been targeted on multiple occasions in different regions of the same tumour, gave us confidence that selection was playing out within the life histories of these tumours. It was clear to us and to many others that this was a new field that deserved to be studied and deserved to be invested in at scale. 

And as a result of those early investigations, we set up the TRACERx programme, which stands for TRAcking Cancer Evolution through therapy (Rx), to try to understand, or begin to understand, potential evolutionary rule books, or patterns in evolution, if you like, that might begin to inform therapy and outcome.
 

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