Susan Galbraith: when cancer DNA circulates
Susan Galbraith, image courtesy of AstraZeneca
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Kat: If you follow the science news - which, being a listener of this podcast, I’m sure you do - you can’t have failed to notice regular headlines promising a ‘simple blood test for cancer’. There have been many stories about such tests over the years, and it’s easy to see their appeal. Rather than painful surgical biopsies, expensive scans or complicated screening tests, what if we could simply take a small tube of blood and discover a wealth of information, such as whether or not you have cancer in your body, where it started, how to treat it, and whether that treatment is actually working. Many of these blood tests, often referred to as liquid biopsies, rely on the detection of tiny fragments of DNA shed from tumour cells that float about in the bloodstream, known as circulating tumour DNA, or CT DNA. And as the technology improves year on year, these tests are coming closer and closer to becoming a reality, moving from the arena of research into clinical practice or widespread screening. I caught up with Dr Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca to find out more about where CT DNA comes from, and what it can tell us about cancer.
Susan: Well, many different cells will release DNA as they break down. So the cancer cells aren't vastly different from normal cells in that regard. It's just that because the cancer cells contain a range of different mutations and other changes that you can detect in these small amounts of cancer cells. You're just being able to pick that up on the background of all of the normal DNA that's coming from normal blood cells, normal epithelial cells, as they go through their cycles of cell division, growth and death. You know, there've been advances in technologies such as next generation sequencing, which have made it possible to measure and analyse very small amounts of the DNA within the bloodstream with increasing sensitivity. And we can use these technologies to measure the absolute amount of circulating tumour DNA and also to sequence it and identify specific cancer mutations.
Kat: When we think about cancer, we think about cells that have a lot of genetic changes, so just changes in their DNA code, but we're also starting to understand that cancers have a lot of these epigenetic changes, sort of changes that affect how genes are active. So can we find those and is that useful information as well?
Susan: Yes, we can find those and it's incredibly useful information. Yes, we do know that the mechanism by which cells are switching on and off different segments of genes, that those control mechanisms or epigenetic controls are also quite abnormal in cancer cells compared to normal cells. You know, those abnormal changes in the epigenetic profile are highly detectable and they can increase the sensitivity by which you can detect abnormal DNA within the blood.
Kat: So what can studying this circulating tumour DNA tell us about cancer in the body? Is it just like, OK, there's some cancer in there. What kind of picture can we paint of what's going on in these processes inside the body, by looking for these fragments of DNA?
Susan: Well, one thing that the epigenetic program tells you is the tissue of origin, where the cancer has come from. So if you take, for example, one of the most common mutations is P53 mutation, which is, you know, is called the guardian of the genome. And once that's mutated, you've got the increased likelihood of getting a large number of other mutations that are happening. But you can have a P53 mutation in many, many different cancers. So just detecting a P53 mutation in the peripheral blood doesn't tell you where that cancer's likely to arise. And so by looking at the epigenetic changes, it can tell you which tissue the abnormal DNA has come from. And that's much more useful information for then subsequent imaging tests to try and identify the cancer and identify whether surgical intervention would be appropriate, or thinking about the different treatments that might be available in the event that you identify the cancer.
Kat: So that's clearly very useful that if you think that someone has cancer, to be able to tell where it is based on this information, but what about, you know, looking at what's actually going on with the growth of cancer. Can we get information about that as well?
Susan: You absolutely can. You can get a quantitative measure of the amount of cancer that is around. At the moment we measure response to treatment through quite often imaging tests, and the imaging tests quite often, don't tell you very clearly whether all the cancer is disappeared after a certain treatment. Circulating tumour DNA offers the opportunity to give more precision around how much cancer is around and that can improve the monitoring and then the adjustment of treatments based on that change in the circulating tumour DNA.
Kat: I think this is so exciting and so important because the more I research about cancer, we understand that you give someone a treatment and it looks like it's working and on a scan, all the cancer seems to have gone, but then the cancer comes back. And we now understand that it's because we've got these tiny little pockets of cells that are left, that are now resistant to the treatment and they're growing again. So is this the kind of thing that we should be able to monitor using blood tests rather than having to have lots of scans or having to have even lots of surgical samples taken?
Susan: Yeah, I think that's exactly right. We need some more data to understand how the changes in circulating tumour DNA correlate with the imaging changes. But I do think there's a future where you can have more monitoring tests done by blood tests using this kind of technique rather than having to have repeated CT scans or MRI scans, and certainly cut down on the number of those. And I also see that we can switch treatments at an earlier point. Once we know whether the drug isn't working anymore, you can switch treatments and give people more appropriate treatment. And that means that you're more likely to have a better, longer term outcome because you can work out whether a drug's not just working in a population of people but for an individual patient.
Kat: So it sounds like we've got a lot of uses for this kind of technology. We can detect cancer in the blood. We can figure out where in the body it has come from. We can look at the mutations that are in there and see whether particular treatments are likely to work. And then we can monitor the cancer as it's growing and as it's responding to treatment and potentially coming back or not responding to treatment. So what are your interests as a drug company in this kind of technology? Are there particular projects that you are applying this kind of technology to improve treatments?
Susan: So we are applying this technology in many different ways across our portfolio. One of the most exciting that I think has the potential to make the biggest difference to long term outcomes is this use of early detection. And we've got a collaboration with a company called GRAIL - using their test we'll identify patients at an earlier stage and then having identified them, we can potentially give them a treatment at an early stage of their cancer where it's more likely to work. And by linking together with this company, I think it offers a possibility of moving drugs that are currently being used in the late stages of cancer into the early stages of the disease, where cure is more possible, more rapidly than we've ever done before. I do think this is a fundamental part of what will help us to build more effective treatment regimens.
References:
Siravegna G et al. How liquid biopsies can change clinical practice in oncology, Annals of Oncology, 2019; 30:1580 – 1590
Cancer Research UK. How cancer starts
Zhong Y et al. Application of Next Generation Sequencing in Laboratory Medicine, Ann Lab Med. 2021, Jan; 41(1): 25-43.
Herceg Z & Hainaut P. Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis, Mol Oncol. 2007 June; 1(1): 26-41.
Rivlin N et al. Mutations in the p53 Tumor Suppressor Gene. Genes Cancer. 2011 Apr; 2(4): 466-474.
National Cancer Institute. Biomarker Testing for Cancer Treatment
Cancer Research UK. Why some cancers come back.
Weaver C H. Ask The Experts About Circulating Tumor DNA in the Management of Cancer. Cancer Connect. April 2022.
GRAIL. (2022, June 2). GRAIL Announces Strategic Collaboration with AstraZeneca to Develop Companion Diagnostic Tests to Enable the Treatment of Early-Stage Cancer [press release].
