TRACERx – a new era in lung cancer research

Ceri with her daughter Leoni, before Ceri passed away

At the turn of the millennium, Bill Clinton stood in front of the White House to announce a milestone in scientific and human history.

Scientists had produced a map of our DNA, a breakthrough that was set to revolutionise medicine, and our understanding of diseases like cancer.

Nobel prizes were awarded. Progress was promised.

Eight years later, Tracey and Heidi’s sister Ceri was diagnosed with a form of lung cancer. She was just 34. She had an 11 year-old daughter. She died the following year.

For all the promise, fanfare and hype – to say little of the billions of dollars spent on molecular cartography – the map of human genome had done precious little to save her.

Lung cancer is a terrible disease. It develops covertly, is usually diagnosed late, and rapidly develops resistance to treatment. As a result, it claims nearly 35,000 lives in the UK each year (and an estimated 1.4 million worldwide). Survival rates have only improved fractionally in forty years.

This needs to change.

Today we’re announcing a multi-million pound research project – TRACERx – that will exploit the map of the human genome to explore, in unprecedented detail, what makes lung cancer tick.

Our researchers will be analysing how the genetic changes inside the lung cancers of more than 850 patients change over time, from their point of diagnosis and throughout their treatment.

On top of this, they’ll be throwing a whole suite of cutting edge analytical techniques at these patients’ tumours samples, to understand what’s going on inside them as their cancers grow and spread.

At £14 million, it’s the biggest single investment in lung cancer research we’ve ever made, and the start of a strategic Cancer Research UK-wide focus on the disease. And the end result will be – we hope – a transformation in understanding the disease, and real progress for patients.

Cancer – a moving target

Researchers have known for several decades that cancers contain regions of variation – so-called ‘heterogeneity’ – that allow them to evolve in response to treatment. But it’s only in recent years that we’ve had the technological know-how to study this phenomenon in detail.

Researchers have now published a plethora of studies looking at how cancers evolve inside a patient. One in particular caught the public eye in March 2012. Cancer Research UK-funded researchers mapped out the changes in different parts of a patient’s kidney tumour. No two areas were identical. The study shone a spotlight on cancer’s formidable complexity.

The brains behind the study was Professor Charlie Swanton from Cancer Research UK’s London Research Institute – a practicing oncologist at UCLH as well as one of the UK’s leading cancer researchers.

Swanton is determined to map out and understand this heterogeneity in patients’ cancers – not just because of scientific curiosity, but because he wants to make a difference to his patients.

“Understanding the genetic complexity within a tumour and what we call their ‘clonal architecture’ – in other words, the way different groups of cells in a tumour adapt and compete with each other – really is the next frontier in cancer medicine,” he told us. “It’s the explanation for why we generally can’t cure cancer after its spread, and it’s why cancers can foster resistance to even the most cutting edge treatments we have.”

This led him to set up the TRACERx study – a hugely ambitious national collaboration between six clinical centres and four centres of scientific expertise to try to crack lung cancer.

“Lung cancer places a terrible burden on our society, and outcomes are depressingly poor, especially compared to other major cancer types. In terms of ‘unmet medical need’, it’s right up there,” he says.

A journey through time

TRACERx – a journey through space and time

Drawing on the ancient pharmacists’ symbol for a prescription or treatment, ‘Rx’, TRACERx stands for Tracking Cancer Evolution through Treatment (Rx) and will recruit patients with an early stage diagnosis of the most common form of lung cancer – non-small cell lung cancer.

All of these patients will have an operation to remove the tumour in their lungs, which will be sent to the TRACERx team for detailed analysis. At this point the patients may also be offered chemotherapy or radiotherapy.

Then, if and when the patients’ cancer comes back – which it tragically will in many cases – they will be asked if surgeons can take a sample of the recurrent cancer. This too will be analysed – meanwhile the patients will receive further treatment.

And if the cancer comes back after that round of treatment, the patients will again be asked if they will donate tissue samples for further analysis.

And in parallel with all of this – because we now know that signs of cancer DNA can be spotted in the bloodstream – the patients will give blood every three months, which will be stored for analysis at a later date.

And a journey across space

As well as tracking patients through time, TRACERx will also bring together expertise through space – in the form of the UK’s enviable network of cancer researchers.

The samples collected throughout the project will be analysed in multiple different ways by different teams around the UK. As well as detailed DNA analysis (of which more below), Dr Sergio Quezada in London and Professor Gary Middleton in Birmingham will look at the involvement of the patient’s immune system in each sample.

And Professor Caroline Dive in Manchester, and Dr Jacqui Shaw in Leicester, will analyse the blood samples for signs of circulating cancer cells or DNA respectively.

All of these researchers are supported by Cancer Research UK. “It’s a pan-CRUK dream protocol,” enthuses Swanton.

And to the depths of the genome

But the centrepiece of TRACERx will be the genetic analysis Swanton’s collaborators will be performing.

Rather than analysing the entire 3 billion ‘letters’ of the human genome in each sample, they’ll be using a technique called ‘exome sequencing’, and homing in with precision on  the 1.5 per cent of our DNA that encodes our genes – something that wouldn’t have been possible without the human genome project back in the 90s.

But that still amounts to some 51 million ‘letters’ of DNA for each tumour sample.

On top of this, to ensure the results are accurate (after all, one wrong letter is a big deal in genetic terms), they’ll analyse each sample not once, but 500 times over – about 510 million DNA letters in all.

But – uniquely – they won’t just be analysing a single sample. They’ll be analysing six different regions of each patient’s tumour, as well as a sample of their normal tissue for reference. And then even more regions at a later date, if their cancer comes back or spreads.

When you add up the total amount of DNA sequenced for each patient, it amounts to nearly 223 billion letters of DNA.

And they’re doing this for 850 patients.

All in all, TRACERx will be running about 195,075 billion letters of DNA through the DNA sequencing machines at UCL and our London Research Institute, over a nine year period. That’s the equivalent of more than 65,000 human genomes.

No research team has ever looked at lung cancer in this sort of detail before. This is using the map of the human genome to explore completely uncharted territory.

The resulting data will allow Swanton and his collaborators to reconstruct the genetic architecture of each patient’s disease, spotting commonalities and differences, and providing a template for future progress. They’ll be able to answer questions like:

• How quickly does genetic variation develop?
• What processes drive it?
• How is it related to how patients fare?
• Can we target variation with drugs?
• How does treatment affect the development of variation?
• Are there different ‘types’ of non-small cell lung cancer? (as we’re now finding in breast cancer)
• Can we predict how a patient’s tumour will behave?
• What role does the immune system play in the disease?

Bringing benefits to patients

Tracey and Heidi raise money in Ceri’s memory

The primary aim of TRACERx – which will begin recruiting later this year – is to understand what lung cancer is – how it adapts and responds to treatment, and where its Achilles heels are (since there are sure to be different vulnerabilities in different patients).

At the outset, no patient will receive any different treatments on the study other than what’s routinely offered on the NHS.

But the data generated will help identify patients who could benefit from existing drug trials – particularly of newer, targeted treatments.

Indeed, the study has already gained the attention of several drugs companies, interested in setting up more trials in the UK. TRACERx will provide a valuable resource to identify patients who could benefit from such trials.

Ultimately, this is about cracking open our understanding of a disease for which there’s an urgent need for progress. That’s something Heidi and Tracey can readily identify with.

As someone who takes part in Race for Life, and has even climbed Mount Kilimanjaro to raise money for research in Ceri’s memory, Heidi told us; “Much more urgently needs to be done to improve treatment for people with this disease, and so we really welcome this £14 million investment from Cancer Research UK.

“Cancer doesn’t care who you are or who you might leave behind. Our family has experienced first-hand the devastation that it causes, and things have to change. And it’s only by doing research that we can beat this terrible disease.”

More than a decade after the publication of the first draft of the human genome, the huge promise offered by that scientific breakthrough is now starting to make its way into studies that will bring real benefits to lung cancer patients – and it’s not a moment too soon.

Henry

• Information for people affected by lung cancer
• Current UK lung cancer trials