Around 14,500 people are diagnosed with malignant melanoma each year in the UK. And while many are successfully treated, when the disease spreads it’s far harder to treat.
Thankfully, in recent years, there’s been a big increase in the number of new drugs available to help people with advanced melanoma – both so-called ‘targeted’ therapies, and immunotherapy drugs. With each of these being the cause of much excitement.
And for some patients, these treatments have led to some truly impressive responses.
But the sad truth is that some patient’s tumours don’t respond, while others see their disease return and spread. And scientists can’t yet predict why this might happen – much less get detailed information on which drug to use next, if and when the previous one stops working.
As well as the disappointment of a treatment failing, it can also mean a frustrating wait for the results of scans to find out if treatments are actually working, or whether a tumour’s growing again.
So to try to make a difference for these patients, and offer them more personalised care, it’s imperative that researchers find new ways to better monitor how these patients are responding to treatment.
And it lies in patient’s blood samples.
It’s in the blood
Tracking cancer’s development by studying DNA or rogue tumour cells floating in the blood has been an area of huge interest in recent years.
In lung cancer, for example, our scientists have been isolating and studying circulating tumour cells to uncover the disease’s hidden complexities.
And, building on early research from other teams, the researchers, led by Professor Richard Marais, alongside Professor Caroline Dive, are now applying similar analyses to melanoma, homing in on tumour DNA in the bloodstream of patients with the disease.
This DNA arises as the cells that make up a tumour die – something they do constantly as a tumour develops and grows. The resulting chunks of their DNA are shed into the patient’s bloodstream, carrying with them clues about the disease.
Scientists now know how to isolate this DNA and study its genetic code for faults, while also monitoring how the levels of these faults change within a patient over time.
In the latest study, published in the journal Cancer Discovery, the Manchester team applied this DNA analysis to blood samples from seven melanoma patients, who were part of a number of different clinical studies.
And it was by analysing this DNA that they were able to spot reliable changes linked to how the patient’s tumours were responding to therapy.
Spotting a response
Around half of melanomas carry a faulty version of a gene called BRAF. And these faults provide the cues that tell melanoma cells to keep growing.
Over the years, Marais and his colleagues have been instrumental in piecing together how faulty BRAF affects cancer cells. And their discoveries have paved the way for the development of drugs that target these faults – bringing with them some much-needed survival improvements for patients.
But eventually, most patients stop responding to these drugs. So the challenge for their doctors is spotting when and how this might happen, as soon as possible.
Fortunately, the faulty genes that fuel a cancer’s growth can also act like a fingerprint – allowing researchers like Marais and his team to fish them out of blood samples and study them.
In four of the seven patients on the study, the team focused their attention on particular faults in the BRAF gene, along with faults in another gene called NRAS. And they tracked how the levels of these circulating DNA markers changed in the blood over time as patients received both ‘targeted’ drugs and immunotherapy.
At the moment this is just a snapshot of what we might learn from these blood samples
– Professor Richard Marais, Cancer Research UK
Interestingly, they found that in many patients changes in the DNA levels mirrored how their tumour was responding – something that was confirmed by looking at scans of the patients’ tumours.
When tumours stopped growing or shrank, the DNA levels dropped. Conversely, when a tumour started growing again or came back, the team saw spikes in the faulty DNA levels within the blood.
This suggests that the team’s DNA blood analysis could be used as a test to monitor patients. But it’s still early days, as Marais points out: “At the moment this is just a snapshot of what we might learn from these blood samples.”
But they’re already extending their analysis further, looking at what can be learnt about drug resistance.
Tracking drug resistance
A huge challenge when trying to understand why tumours stop responding to drugs is gathering information about what’s actually going on inside a tumour – something that normally needs a tissue sample or biopsy. But when a patient has advanced disease, it’s not practical – or fair – to ask them for multiple tumour samples.
And that’s why there’s lots of excitement around what scientists can learn from the blood. Many believe it could offer a less invasive way of gathering crucial information about how tumours change during treatment.
How do they work?
And the Manchester team found some early evidence that tracking tumour DNA may offer useful insights for people with melanoma.
On top of monitoring the levels of faulty BRAF and NRAS, they were also able to pick up increases in several other faulty chunks of DNA that emerged as tumours stop responding to those ‘targeted’ drugs.
The analysis was based on previous research on the myriad ways tumours can get around these treatments. And it suggests that these changes could be responsible for the drug resistance seen in those few patients.
The team is now following up on this by studying how tumour cells and models of drug resistant melanoma behave. And they hope that blood samples will offer important information about how to tackle this challenge.
But in the short term, Marais believes this type of ‘real-time’ DNA analysis has the potential to help doctors planning scans.
“There are important considerations around when to do scans,” explains Marais. “Doctors need to limit a patient’s exposure to radiation from the scans themselves, and they’re also expensive.”
Because of this it isn’t feasible to regularly scan patients to monitor their disease. But Marais believes the team’s DNA analysis could get around this challenge.
Crucially, they were able to spot signs that a patient’s tumour was responding to drugs in advance of scheduled scans.
It’s too early to say whether blood analysis is better than a scan, as they’ve only studied seven patients, and the two methods haven’t been tested head to head in a trial. But Marais’ findings do offer an early indication that regularly monitoring changes in tumour DNA in the blood might help track the disease, and plan the timing of scans.
For example, if there’s a rapid increase in tumour DNA levels then doctors may want to bring forward a planned scan. Or if the DNA suggests a tumour is responding, this could boost confidence in waiting for a planned scan a few weeks away.
It’s obviously early days, but as Marais says: ”This lays the groundwork for what we hope will be a promising way of learning more about the biology of melanoma from blood samples, and then using this to help patients”.
If we’re to achieve truly personalised care, having a reliable way of regularly monitoring patients will be vital.
And a simple blood sample could be one way of getting there.
Girotti, M., et al. (2016). Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma Cancer Discovery, 6 (3), 286-299 DOI: 10.1158/2159-8290.CD-15-1336