Sometimes it feels like cancer research is progressing at a dizzying speed.
Just last year, we reported how Cancer Research UK scientists had reconstructed the evolution of a patient’s kidney tumour during treatment – one of many studies over the past few years illustrating cancer’s fearsome genetic complexity and adaptability.
This phenomenon, known as ‘intratumour heterogeneity’, led many to predict a long, hard slog to fully understand it – let alone get a handle on its implications for treatment.
One key concern was that patients would need to undergo a series of small operations (biopsies) to take repeated tissue samples to track how their cancer develops – and that this could be painful, costly and risky – especially for cancers deep in the body. And even then, because of the genetic variation within each patient’s cancer, there would be no guarantee that the biopsy results would represent an accurate picture.
Others also pointed out that such heterogeneity was a blow to the optimism around new-generation ‘targeted’ therapies, designed to treat cancer cells driven by individual mutations.
But recent discoveries have renewed this optimism. It turns out that tumours release DNA into the bloodstream, and that this seems to contain signals about what’s going on inside it. Consequently, there’s been a growing hope that analysing these DNA fingerprints could provide a quick, simple ‘liquid biopsy’ to track tumours’ progress.
And last month, researchers at our Cambridge Institute published compelling evidence that circulating DNA could indeed be used to take a snapshot of the DNA errors (mutations) in a patient’s breast cancer.
Today they’ve gone one step further proving, in a beautifully detailed paper in the journal Nature, that blood samples can be used to monitor genetic changes in a patient’s disease over time.
This has the potential to be a game-changer, and rapidly accelerate research into what makes cancers tick, in real patients, in timeframes that can impact on clinical decision making.
Let’s look at what they found.
It’s in the blood
The research followed six patients – two with breast cancer, three with ovarian cancer and one with lung cancer. All of the patients’ cancers had spread to other parts of their bodies.
While they were undergoing treatment, these patients donated regular blood samples to a team of doctors and researchers led by three of our leading experts – Professor Carlos Caldas, Dr James Brenton and Dr Nitzan Rosenfeld.
The research team analysed the samples using a technique called ‘exome sequencing’, which looks at the composition of each of our 20,000 genes (which make up a small fraction of the entire human genome).
Using this technique, the researchers were able to look at the proportion of the DNA in each patient’s blood that came from their tumour, and how the genes from the tumour differed from their normal DNA.
But crucially, since they had samples from before and after the patients had different treatments, the researchers were able to look at how the DNA from the tumour differed before and after treatment – including types of genetic differences it contained.
What did they find?
Each patient’s blood contained large numbers of mutated genes, coming from the cancer’s DNA. But the exact mutations, and their levels, subtly changed in response to treatment.
By comparing their findings to previous published studies on cancer drug resistance genes, the researchers were able to pinpoint the likely culprits. They highlighted several of these in their Nature paper.
One of the breast cancer patients was originally treated with a drug called epirubicin, then switched to a second drug called paclitaxel.
After paclitaxel treatment, the researchers spotted higher levels of a mutation in a gene called PIK3CA in the patient’s blood. Previous lab studies have implicated this mutation in paclitaxel resistance.
So it’s likely that the appearance of this mutation showed that the patient harboured cancer cells that were resistant to paclitaxel, which were now growing in response to the treatment.
The second breast cancer patient was treated with tamoxifen and trastuzumab (aka Herceptin). This resulted in increases in levels of a mutation in a gene called MED1, also previously linked to tamoxifen resistance. The patient was switched to a second drug combo – lapatinib and capecitabine – and very quickly, a second mutation in a gene called GAS6 became apparent as the cancer adapted to the treatment.
Again, this mutation has been previously linked to resistance to drugs like lapatinib.
Similar pheonomena were observed in the ovarian and lung cancer patients. For example, after she was treated with cisplatin, a mutation in a gene called RB1 became much more common in the blood of one of the ovarian cancer patients.
And studying the blood of the lung cancer patient, who was treated with gefitinib but didn’t respond, showed why: a new mutation had appeared in the EGFR gene (the target of gefitinib), causing the drug to stop working.
How does this help patients?
The search for ‘biomarkers’ – reliable ways to measure a tumour’s response to treatment – has been a long and tricky one – and has tended to look for proteins secreted by tumours.
This new research opens the door to using DNA – rather than proteins – as a much more reliable biomarker for a cancer’s growth. This has long been talked about, but never before demonstrated so elegantly. “It’s the missing piece of the jigsaw puzzle,” Professor Brenton told us. “We can now understand what happens during treatment, and how that affects the development of drug resistance.”
On top of this, its simplicity should allow the test to be used in a whole raft of clinical studies. “This is a test simple enough to be scaled up to 100s or 1000s of patients,” he said.
“There are, of course, still unanswered questions, and we don’t know 100 per cent whether this applies to every patient, but certainly for most of the main cancer types – breast, bowel, lung ovarian etc – there’s good evidence that monitoring tumour DNA is feasible.”
So… what happens next?
“We’re looking to get this out of the lab and into the clinic as soon as possible, and run clinical trials where we monitor patients’ DNA at the high quality levels in NHS hospitals – so-called CPA-standard testing. We want to work out how we can exploit changes in their tumour DNA to make solid clinical decisions that will help them,” he added.
The important leap forward, he says, is that DNA blood tests represent a test that won’t hurt or inconvenience the patients. “It’s a tremendously powerful technique.”
Professor Charlie Swanton, the London-based Cancer Research UK researcher whose kidney cancer heterogeneity study caused a big splash last year, is similarly excited.
“It’s a fabulous study,” he told us. “I have no doubt this is really game-changing for cancer biomarker development.” He thinks the paper will lead to a much deeper understanding of how different ‘sub-clones’ inside tumours evolve through treatment.
“Undoubtedly, this is a major step forward in overcoming the tumour sampling problems we are facing,” he says.
The Cambridge team are now working on a number of new studies to exploit the power of tumour DNA testing. There’s a long way to go before it becomes routine for all cancer patients, but given the resources being invested in gene testing, and the avalanche of molecular knowledge emerging from labs around the world, there are certain to be new advances before the year is out.
- Murtaza M. et al (2013). Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA, Nature, DOI: 10.1038/nature12065
Biopsija July 5, 2013
Blood test can’t show the real situation… Biopsy is better way to get information about the cancer.
debasis May 30, 2013
The technique called ‘exome sequencing’, found very interesting , I am going to explore more on it.
Janet R Edwards May 23, 2013
Surely any form if preventative treatment should be tried, rather than waiting for a cancer to develop. Annual full blood counts should be routinely offered to all.
carol taylor May 11, 2013
Why do we not have yearly blood tests on every nhs paitient? It would cost so much less than the treatment for patients who are diagnosed with this horrible disease.
Margaret Chappell May 8, 2013
Not sure that the cancer becoming resistant to a treatment is the right way of looking at it – as suggested in some of the comments. As indicated by some of the main text, it seems more likely that although most of the cancer cells respond to a drug some of the cells already have a mutation which makes them resistant to the drug even before treatment. This clone will have an advantage over responding parts of the tumour and so become more prominent with more of their DNA in the blood.
derek May 5, 2013
If oxygen is present then cancer cannot evolve so maybe a pill that emits oxygen molecules to all areas of the body would be the answer to all cancer.
Janis Hall May 2, 2013
It is amazing to hear that a simpler, less intrusive method for identifying when tumor cells mutate in response to chemical treatments has been discovered. I can only imagine the lengthy process still to be followed to move from where we are now to identifying a method of “second guessing” how these cancer cells will mutate and preventing such action. Funding research …. the way forward.
Sandra May 2, 2013
Its brilliant news however I have Inoperable Thymic Carcinoma & there appears in this country to be No Research what so ever being done on it.Also in your info section on this Cancer you say its found in ages 40 to 60.I am on a TC Forum
there is people has young as 23.There is people from around the world on this forum,America are doing some Trials but on Operable cancer patients.
Richard Da'Casto May 2, 2013
I think someone has sort of asked this above, is this something that will be refined so that people who have a family history of cancer related deaths could use this (at hospital or surgery) to identify if a person potentially could get one of the cancers? Any work related to finding the cause, cure or best treatment for incurable cancers is very worthwhile and researchers deserve everyone’s thanks and support for the work they do – it touches all of us in one way or another at some point in our lives.
Sam Shoetan May 1, 2013
It is just amazing and we thank all these researchers for the brilliant work they do helping to making treatment of this dreadful disease.
Anne Marie May 1, 2013
Having metastatic BC myself, this is very interesting. Will CRUK be recruiting volunteers for the trials?
Harold May 1, 2013
I hope patients that are in remission can give blood samples for this Biomarker research so that the doners can be monitored.
Antonio Leonardis April 20, 2013
can we do this with patients at risk for developing ovarian, lung or breast cancer, before it becomes resistant to drug treatments? it seems like we cannot stop it from happening, but maybe prevent it or identify what factors are present while it is developing that could be removed or eliminated?
shahrin ahmed April 11, 2013
its a great discovery by scientist and I am proud to be studying in cancer studies…we all hope it a best process to tracking cancer.
Facing Cancer Together April 8, 2013
So often people are left wondering “did it really work?” after treatments. I hope this leads to a more certain resolution & tracking for patients.