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Blood test

A blood test could provide a simple way to monitor cancer

Cancer is a wily enemy. It mutates and spreads within the body and becomes resistant to treatment. Understanding and counteracting this tricksy behaviour is the greatest challenge for researchers and doctors, and is the key to bringing forward lasting cancer cures.

Thanks to advances in technology, we’re now starting to map out cancer’s underlying genetic landscape. In theory, if doctors knew exactly which gene faults were driving a patient’s cancer, they could give them the most appropriate targeted treatment.  

And as well as selecting the therapy with the best chances of working, it’s also important to know whether the disease is responding to treatment or not as fast as possible, so doctors can decide on the best course of action – for example, whether to continue with a particular drug or switch to a different one.

But there’s a problem with this approach. Monitoring how well a patient’s cancer is responding is not a simple job. At a minimum, it requires regular scans or other tests.  On top of this, analysing a tumour’s genes requires having a sample of it, usually taken as a biopsy with surgery, as well as access to tests that can provide meaningful results in a short timeframe. And if the cancer has spread to a multitude of locations in the body, it’s simply not possible to biopsy them all.

As an extra kicker, we now know that a single tumour can house cancer cells with a range of different gene faults – a characteristic that scientists refer to as “intra-tumoural heterogeneity”, but could also be described in rather more unpublishable words. And secondary cancers that have sprung up elsewhere in the body also have differences in their genetic makeup compared to the initial tumour.

The problems seem almost insurmountable – it’s a bit like trying to attack a shape-shifting army that we can’t properly see. But, as you might hope, research is coming to the rescue.

Building on work we talked about last year, scientists at our Cambridge Institute have made a significant step forward in developing a relatively simple genetic blood test that can monitor breast cancer as it progresses.

They’ve published their results in a paper in the New England Journal of Medicine, and although the title – “Analysis of circulating tumor DNA to monitor metastatic breast cancer” – may not set your heart racing, the contents are certainly inspiring for all of us hoping for progress in cancer research.

In the blood

This new work relies on the fact that cancers reveal traces of their presence into the blood in several ways:

  • Cancer cells can break away from a tumour and travel in the blood, where they can be spotted using sensitive detectors.
  •  Tumours also produce various molecules, usually referred to as biomarkers, which escape into the bloodstream and are relatively easy to measure.
  • And when cancer cells die, they release tiny fragments of DNA which can also be detected in the blood and ‘read’ using new genetic technology (for more details about how this works, have a look at our previous post).

Led by Professor Carlos Caldas and Dr Nitzan Rosenfeld, the scientists set out to test which of these three tell-tale signs most accurately reflects how a woman’s breast cancer is responding to treatment. This was a small study, involving just 30 women who were having chemotherapy for cancer that had spread.

The researchers collected blood samples from the women on a regular basis over two years, then matched up the results of the three different blood tests with CT scans showing whether tumours were growing and spreading or shrinking.

Using the best techniques available, the scientists managed to detect a specific biomarker protein (called CA 15-3) in the blood of 21 out of 27 women tested, while they could spot whole cancer cells in 26 out of 30. And they could detect tumour DNA in the blood of 29 out of the 30, suggesting that this is the most sensitive method of the three.

In particular, the researchers were looking for fragments of tumour DNA carrying faults in two key genes – PIK3CA and TP53 (which encodes the infamous ‘tumour-suppressor’ protein p53) – which they knew were present in all 30 women.

Crucially, these faults are only found in DNA from the cancer cells and not in DNA from healthy cells, which can also be found floating around in the bloodstream.

Because the proportion of DNA from cancer cells is very small compared to amount of DNA from healthy ones, the scientists used two sensitive techniques called digital PCR and TAm-Seq (described in more detail here) to accurately measure and track the tumour DNA in the blood.

Charting a course

To find out how well each of these three markers – cancer cells, tumour DNA or CA 15-3 protein – reflected what was happening within the body, the scientists compared the results of the blood tests with CT scan data from 20 of the women, which revealed how many tumours they had and how big they were.

Here’s where things get interesting.

For women who had a reasonably large number of escapee cancer cells in their blood, the number of these cells mirrored their response to treatment reasonably well – the number of cells fell after chemotherapy, and slowly climbed back up again as the cancer returned.

But for women who only had a relatively small number of cancer cells in their blood to start with (reflecting the fact that they have fewer and/or smaller tumours) there was no match.

They found a similar effect for the levels of CA 15-3 – if women had relatively large amounts of the protein in their blood to start with, then the changes in their CT scans matched up with fluctuations in the marker, although the shifts weren’t very big. But again, this didn’t happen for women whose levels of the CA 15-3 were pretty low to start with.

But measuring the levels of tumour DNA in the blood provided an even better match in most of the women, tracking the changes in their cancer through several cycles of treatment. Even more intriguingly, it looks like tumour DNA can reveal how a patient’s cancer is changing and evolving on the genetic level – something which is vital if we’re to make progress in ‘personalising’ treatment. For example, the scientists were able to find faults in specific genes in some patients’ cancers that weren’t there when their tumours were first biopsied up to a decade before.

This discovery is really important. It suggests that measuring levels of tumour DNA on a patient’s blood could be a powerful way to track the way the genetic landscape of an individual’s cancer shifts and evolves during treatment. At the moment, the researchers have only looked at faults in a handful of genes, but if this kind of approach could be scaled up to look at a larger range of genes, or even the whole genome, it could be incredibly powerful.

Being able to monitor how the whole cancer ‘ecosystem’ within a person is shifting and changing on a genetic level, rather than relying on one or a few unrepresentative samples, would be a huge step forwards.  

What happens next?

While these results are very exciting, they’re based on samples from a very small number of women. It’s going to take more testing, in a much larger number of patients, to prove that measuring tumour DNA is an accurate and reliable way of monitoring cancer.

And studies like this have only been done in a few different types of cancer – the Cambridge team have tackled ovarian and breast cancer so far – although there’s no reason why their approach shouldn’t work for other types of cancer too.

Blood tests won’t replace the need to take actual tumour samples right now – at the moment, biopsies are still the best, most reliable tool we have for analysing an individual’s cancer.

But hopefully we’ll see ‘liquid biopsies’ based on analysing tumour DNA in the bloodstream coming into the clinic in the coming years. Hand in hand with advances in our understanding of the genetic faults that underlie different cancers and plummeting costs of DNA sequencing, this approach could revolutionise the way that cancer patients are treated in the future. And there are other areas where blood tests are gaining momentum, such as a new trial of a blood test that could diagnose cancer earlier, which we’re funding to the tune of more than £1 million.

We’ve made huge progress in diagnosing and treating breast cancer over the years – today more than eight in ten women in the UK will survive the disease for at least five years, compared to just five in ten back in the 70s.

But despite this improvement, it’s still the leading cause of cancer death for women worldwide. We’re working towards a day when breast cancer is cured for good, and this new research takes us another step closer.

Kat

Reference:

Dawson S.J., et al (2013). Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer, New England Journal of Medicine, 130313140010009. DOI:

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Comments

Kat Arney June 20, 2013

Hi Eraneo,
Thanks for your comment.

With regard to open-access, this paper was published in the New England Journal of Medicine, and it will be made available as open access six months after publication at no additional cost. This is compliant with the policy of all the funders acknowledged in the paper. In the case of other research papers, although we strongly encourage our researchers to publish in journals with good open-access policies, we can’t always enforce this, and it depends on the policies of the particular journal. There is a lot of discussion going on both within Cancer Research UK and the wider academic community about open access to research papers, so watch this space.

And with regard to the technology discussed in the post, although it’s very exciting, it actually combines already-known methods in such a way that it isn’t patentable. This means that it can be freely used by both academic groups and industry, and hopefully won’t be too expensive if it turns out to be suitable for use on the NHS.

It’s worth pointing out more generally that vital medical breakthroughs require significant investment to turn them into treatments or diagnostic products that can ultimately benefit patients. Companies fund the development costs and expensive, large-scale clinical trials, the costs of which can run into many millions of pounds. Because of this, partnering with industry is an important part of turning discoveries into benefits for patients.

Wherever possible, we put legal agreements in place that mean Cancer Research UK gets a share of any royalties from sales of cancer treatments or diagnostic tests. And because we are a charity, this money is ploughed straight back into our research. Finally, through our policy team, we are also campaigning for fairer pricing for cancer drugs. There’s more information about this on our website: http://www.cancerresearchuk.org/cancer-info/publicpolicy/ourpolicypositions/treatment/drug_treatment/drug-treatment

Best wishes,
Kat
Science Information Manager

Eraneo June 20, 2013

Interesting but missing detail. Why aren’t the links to the the full text articles there as opposed links to paid papers?
I thought open access to publicly funded work was a condition for funding!

If this works out I hope it won’t be too expensive for the NHS!

I’d be interested in knowing if this technoligy has anything in place to stop it being sold to the highest bidder as so many before? Those whose main markets are the American insurance industries with their inflated prices. Many hard working scientists are sick of seeing the business people at our institutions sell out to the highest bidder. “The same big players who are expert at milking developments for maximum financial gain” Golfing trips & perks from big industry are scandalous conflicts of interests that someone needs to invest some time & resources looking at!

Bridget Bell April 6, 2013

Big hugs and smiles to all of us battling it in whatever way we have to. KEEP GOING EVERYONE. C U @ Poole festival of Running maybe???!!! Bx

Margaret Barwell April 4, 2013

excellent work bringing really effective knowledge to the field to improve outcomes for many cancer patients. Thankyou!

** Is a greater focus on lung cancer possible yet – 1 GP I spoke to says there are no clinical protocols in place for lung cancer yet – he argues that without treatment pathways there are no benefits in early diagnosis. Indeed he disagrees with the recent advertising encouraging people to go to their GP if they have a cough for more than 3 weeks. There seems to be ambivalence from some clinicians regarding early diagnosis and an acceptance that a poor outcome is inevitable.

jean parker April 4, 2013

I wish i had known about this 2 years ago as last year i was diagnosed with breast cancer.
Its just 12 months ago i had a mastectomy. Last year our daughter was diagnosed with bowel cancer.
At the moment she undergoing chemotherapy treatment. 2 in a family in a year is heart breaking. I already subscribe to your charity and i think you are all doing a fantastic job.
KEEP UP THE GOOD WORK…