Liquid biopsies for cancer

We are delighted to present Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.

In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.

In the first episode, Dr Joanna Janus explains the basics of liquid biopsy, its role as an alternative to solid tissue biopsies, and its potential as a tool for monitoring the success of treatments

If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

If you have any further questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: 0:08

Welcome to making science work for health, the PHG Foundation's podcast, exploring developments in genomics and related emerging health technologies. Social media, and the many digital news outlets now mean more of us than ever are aware of the progress being made by teams of intrepid scientists and researchers around the world. Many of the latest advances feature genomics and 'omics related technologies, the field in which the PHG Foundation has 25 years of experience, helping policy makers get to grips with practical on the ground delivery. Making science work for health aims to strip away the gloss and explain what new science means for you as patients, health professionals, and as members of society. My name is Ofori Canacoo part of the communications team at the PHG Foundation and host of making science work for health. For this episode, we're discussing the use of liquid biopsies in cancer. Recently in national press, liquid biopsies have been making headlines concerning the promising developments in their utilization. Joining me for this episode is Dr. Joanna Janus, policy analyst at the PHG Foundation. Hello, Joanna.

Joanna: 1:23

Hello.

Ofori: 1:23

Would you like to tell us a little bit about yourself?

Joanna: 1:26

Yes. So I've been a policy analyst in the science team at the PHG Foundation for about three years now. And in the science team, we're constantly scanning for new innovations and new technologies. Especially genomics based ones. We look at how those can be used in healthcare to make science work for health and make a difference, hopefully, to patient outcomes. One of my favorite topics has been circulating tumor DNA testing, and that's the subject of today's podcast. And I've been working on that over the last few years. And it's a particular favorite of mine because I did my PhD in cancer biology, but that was very research focused. And it's now really rewarding to work in an area related to cancer. Where research and science is actually being translated into real world benefits and tools to help patients.

Ofori: 2:14

Great. Let's get into it. For anyone that doesn't know could you explain to us what a biopsy is?

Joanna: 2:20

Yeah. First of all, a biopsy is normally a medical procedure where a small piece of tissue or a sample of cells, so we'd call that a solid sample, is taken from a patient for further examination in a lab. And that's typically done to gain further information about a patient's disease or their risk of a disease developing. And for example, if you have a suspicious mole on your skin, you could have a skin biopsy taken in order to find out if it is a cancer or not. Or for example, if you have symptoms of liver or kidney disease, you might need to provide a sample of kidney or liver tissue. So you need... that tissue has to be physically removed and that's normally done using a needle and in some cases require surgery. So it can be quite invasive depending on the location of the tissue.

Ofori: 3:07

So what would a liquid biopsy entail?

Joanna: 3:10

So liquid biopsies are currently being explored as an alternative or an additional option to these solid biopsies. Our tissues naturally release bits of themselves, so fragments of themselves, into the blood or other fluids like saliva or urine, a liquid sample such as those, will then contain tissue derived materials like DNA, proteins, or even entire cells. And those materials can be used to provide information about the tissue that they originally came from. And then you don't need those invasive procedures, like the needle biopsies to obtain a solid tissue sample. So simply, instead of taking a solid piece of tissue for analysis, you can take a sample of fluid, which is often blood instead.

Ofori: 3:53

What sort of thing would we be looking for in a liquid biopsy?

Joanna: 3:56

So there's several things you could look for, but one of the most promising and actively researched types of liquid biopsy, is the analysis of circulating tumor DNA. All tissue is made up of cells and those cells release fragments of their DNA into the bloodstream. And that's where it circulates and we call that DNA released from the cells cell-free DNA. If someone has a tumor, that tumor is also made up of cells and so those cells also release cell-free DNA but this time from the tumor. That DNA that specifically originates from the tumor, we call circulating tumor DNA or ctDNA for short. A liquid biopsy, or this blood sample can be taken and used to identify and analyze that circulating tumor DNA, in order to gain information about the cancer without taking a solid biopsy. For example, that could be genetic information such as which mutations it contains or other information such as it could be used to predict how large or aggressive the cancer is based on how much ctDNA there is present.

Ofori: 5:02

In terms of cancer, why would we use a liquid biopsy?

Joanna: 5:05

Firstly, just as an alternative to these solid tissue biopsies to obtain genetic information needed to make treatment decisions, but through a less invasive process, because obtaining a solid tissue... sample of tissue, as we said earlier, can be invasive and complicated for many cancers and that could cause further harm, potential complications for someone who may already be quite ill. And so, liquid biopsies could provide an alternative for those patients simply too ill or unable to provide a solid tissue biopsy. And also sometimes even when a solid biopsy sample is taken, it can't be used to provide good quality genetic information for various reasons. So a liquid biopsy can be used as an alternative in that case too. And in both cases, identifying the genetic profile of the tumor is important because that can allow access to personalized treatments that match the genetic profile of the cancer. Without the liquid biopsy, some patients might not be able to access those treatments and they would be effectively missing out. And then on top of that, we've got other features of ctDNA and liquid biopsies that open up completely new ways to manage cancer. Which solid tissue biopsies were never suitable for at all in the first place. For example, ctDNA is released and cleared up by the body in a constant process, literally within hours, any ctDNA analysis performed gives you this snapshot, this real time picture of a patient's cancer status at that point. And that means you could use it to perform regular blood tests because blood tests are also quite easy to perform. And that means that we could use these liquid biopsies to monitor patients. For example, after surgery or during treatment to regularly get status updates on their cancer, which you couldn't do with solid biopsy process.

Ofori: 6:54

Is this being used in practice at the moment?

Joanna: 6:58

Today, it's being used for a type of cancer called non-small cell lung cancer, and patients with this type of cancer can have a specific variation in a gene called EGFR, and that makes them eligible for a specific targeted therapy. And so a few years ago, NHS labs had started to implement ctDNA testing in order to make this therapy more accessible to patients where a solid biopsy sample wasn't possible for the reasons we just mentioned before. Liquid biopsies, on top of that, were also being used for patients whose cancer occurred after initial treatment and this allowed those patients to benefit from a further targeted therapy, without having to undergo another solid biopsy procedure after their cancer occurred. This was great but the problem was that although a few pioneer labs were using this technology at the time, many other NHS labs were not. So across the country, patients weren't getting equitable access to this testing. And at PHG, we wanted to understand why this was and if anything could be done about it. We did what we do at PHG, which is to bring a range of stakeholders together, to understand some of the reasons why this was happening. And it turned out those reasons were multiple, including a lack of awareness of ctDNA testing by doctors, as well as the lack of infrastructure, to be able to physically do the testing, as well as changes to sort of the clinical pathways that doctors use, that had to be properly thought through to see where the test really fit in as well as funding, which is often a problem. So since then the test has been added to the national test directory or genome test directory. Which means that officially this test should now be available across the whole country as a standard of care tests that clinicians can order. Today this test is much more widely used for non-small lung cancer. Hopefully, additionally, we hope this, this work will have paved the way for ctDNA testing to also be used in for, in similar ways for other cancer types in future.

Ofori: 8:58

So would this mean then that we would start to see liquid biopsies replacing solid biopsies?

Joanna: 9:05

I think that's unlikely. And that is because liquid biopsies provide really useful genetic information, but, at least circulating tumor DNA liquid biopsies, don't provide all the information that you would get from analyzing an actual piece of tumor tissue. For example, by looking at a section of tumor tissue from a cancer biopsy, you can use that to identify the subtype of the cancer or how aggressive and advanced the disease is. As well as that, this complete tissue sample can provide other non-genetic information, for example, information on proteins present, and that can also be useful for diagnosis and making treatment decisions. ctDNA analysis basically only provides you with part of the information that you need. So I think it's more likely that a liquid biopsy would continue to be used alongside solid biopsies to provide that alternative method when needed. There are also these other new ways that circulating tumor DNA could be used to improve cancer management where you would never have used the solid biopsy in the first place. So in that case, the ctDNA analysis would be used by itself.

Ofori: 10:14

You mentioned monitoring for cancer patients. How would that work?

Joanna: 10:18

Because taking a blood sample is relatively noninvasive and simple, that means you can repeat it regularly as a procedure, which you couldn't do with the solid biopsy procedure. So that means that you could do regular tests to monitor patient's outcomes over time. An example that you might have heard of is prostate specific antigen or the PSA test, which are commonly used to check the status of patients after prostate cancer surgery, to see if their prostate cancer is recurring based on this biomarker, PSA, being present or not. Basically, liquid biopsies, to measure the amount of ctDNA, could be used in a similar way. For example, after surgery or even during treatment. If the cancer is returning, you would expect to see ctDNA present in the liquid biopsy. However, if there was no ctDNA detected that would mean that that cancer was likely still in remission.

Ofori: 11:17

And why should that be useful for patients?

Joanna: 11:19

The main hope is that ctDNA testing could be used to detect signs of cancer recurrence much earlier than current methods. Some studies show that ctDNA tests might detect cancer recurrence actually months earlier than imaging tests that are currently used to check the status of a patient's cancer. And that earlier detection could mean that treatments could be started earlier, and that's at a point when they may be more effective. Similarly for patients already on therapies, the same approach could be used to understand if that therapy is still working or if it's no longer effective. That could mean, for example, that the cancer has developed resistance to the treatment and that treatment should be stopped and replaced with an alternative treatment.

Ofori: 12:03

Okay. So it sounds promising, but do we know whether it actually works?

Joanna: 12:08

So the question is, even if we do have a good test, and that still has to be established, what do we actually mean when you say the test works? Typically, for a test to be considered good and useful, it means that it has to change a patient outcome. In this case, it might seem logical and common sense that if you manage to detect cancer recurrence earlier, then you can switch to a new treatment and the patient will likely have a better outcome. Currently, all of this is still unclear and there is still uncertainty even over what actions to take and if they benefit patients. So we need more work to understand all of this.

Ofori: 12:48

Based on everything we've discussed so far, where would we go from here?

Joanna: 12:53

As we've just been talking about, I think one of the main real needs at the moment is to demonstrate that ctDNA tests of all kinds have that potential to be clinically useful and can be used to improve patient outcomes for any use of ctDNA, not just monitoring. We need evidence from clinical trials for this.

Ofori: 13:14

Are there any trials that you are particularly excited by then?

Joanna: 13:18

Yes. So one example is one of the first trails that was launched to look at the use of ctDNA to guide treatment decisions after surgery, in this case for colorectal cancer, and that study was called the DYNAMIC trial, and that has just recently completed. It's really exciting because it's provided some of that first solid evidence that we need. That ctDNA can be used to better select those patients who need additional chemotherapy following their surgery, to remove all traces of the cancer. But at the same time, it can be used to identify those patients who don't need this additional treatment. So that's sparing them from unnecessary chemotherapy. However, this trial has also taught us some important lessons to consider for further trials and use of ctDNA in practice. For example, just performing the ctDNA testing in the trial resulted in several weeks delays to those patients, receiving the therapy. It didn't seem to have an impact in the trial, but it is important to reduce those timelines as much as possible. So practical lessons like that could be useful for informing future trial designs. So, of course that's just one trial and alongside that there are many other trials ongoing to develop this evidence base further, as well as generating this evidence of clinical utility for the field in general, there is also an ongoing need for technology development. For example, making these tests more sensitive to detect these really small amounts of ctDNA present. And finally, we should remember that ctDNA testing is just one type of liquid biopsy, and we haven't even mentioned other types. For example, you could also analyze whole cells present in the bloodstream rather than just the DNA or even liquid biopsies that look at other body fluids, such as saliva and urine, which present exciting opportunities for this test in their own right. So all of these have their own strengths and limitations and will be really interesting to explore in future. And overall, I think it's fair to say this is a really fast pa.., fast paced, sorry, and exciting field at the moment. It has loads of potential to improve cancer outcomes across the whole spectrum of cancer prevention and treatment.

Ofori: 15:38

Wonderful. Joanna, thank you for joining us.

Joanna: 15:41

Thank you very much.

Ofori: 15:44

Well, that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org. And if you have any further questions about the topic then you can email us at intelligence@phgfoundation.org. Thank you for listening. My name is Ofori Canacoo and I look forward to bringing you a new topic in the next episode.