Charles Swanton: finding hidden tumours
Charles Swanton, image courtesy of AstraZeneca
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Kat: We’ll be coming back to the use of CT DNA blood tests for early detection and cancer screening later on. But before that, I wanted to learn more about how cancer researchers and doctors are using CT DNA to understand more about the progression and evolution of cancer in the body - a topic I’m particularly interested in since writing my latest book, Rebel Cell: Cancer, evolution and the science of life. And who better to speak to than Professor Charles Swanton, or Charlie as I know him - professor of oncology at University College London, and a group leader at the Francis Crick Institute, where he and his team are applying CT DNA technology in research and ultimately in the clinic to improve treatment for patients.
Charles: Well, one of the major problems in oncology is accessing tumour. As you know, Kat, patients with advanced metastatic disease, a disease that's spread beyond the primary site, can have tumour lesions in deep parts of the body, deep organs of the body, like the liver, the spleen, the bone, the brain, and what have you - relatively inaccessible sites that biopsy needles can't get to readily without pain and complications to the patient. So when the CT DNA field first emerged approximately 10 or so years ago, there was huge excitement because this might or at least promise to enable us to profile tumours more readily and understand their genetic underpinnings without having to necessarily biopsy them at regular intervals through a simple blood draw.
Kat: I'd certainly rather take that than a massive needle shoved into a bit of me, for sure.
Charles: Yeah, no, absolutely. Without a shadow of a doubt.
Kat: So perhaps we've conventionally had this idea that cancer, it starts from cells growing out of control. It's a mass of cells. They grow, they spread through the body and then we treat them. But how have we started to get a more sophisticated understanding of what these cells are actually like at a genetic level? And then what they're up to.
Charles: Yeah, great question. So this is an area we've been focusing on really for the last decade and what I think you're alluding to is what the scientists call tumour heterogeneity. tumour heterogeneity essentially means that cells are different within the same tumour. They derive from a common ancestor, a common cancer stem cell, if you like, a cell of origin. And that cell of origin will contain a set of mutations that will continue to propagate through the tumour ever onwards. And we call those mutations, the trunk mutations. So those are the mutations found in every tumour cell. And then there are mutations found in some cells, but not others. And work from us and others back in 2012, showed that depending on where you put your biopsy needle, and depending on which part of the tumour you subject to DNA sequencing, you get a different result. Now, one of the beauties of CT DNA sampling or sampling DNA from the blood is if you like, it's a soup of mutations that gives you a more representative sample of what mutations that tumour contains of both the dominant mutations in the trunk and the branch mutations, those mutations found in some cells, but not others that are present less frequently in the tumour.
Kat: I remember when your paper came out about 10 years ago now, and it was like, ah, this is why cancer is so difficult to treat because all these cells aren't the same. So if you give a drug that will work on some of them, it's not gonna work on necessarily all of them. And those are the cells that are gonna keep growing and then the cancer's gonna come back and then you've got even more of a problem. But now you're saying, so if just taking a simple biopsy is not going to give the full picture and we do need to get a better picture of all the different mutations in a tumour, technically, how does this work from a blood draw? Because like you got 10 mls of blood- how much DNA have we got in there? And how do you piece together the picture of cancer in the whole body, from this sort of soup of DNA and mutations, and you've got normal DNA in there as well. This sounds really hard.
Charles: Yeah. So you've hit the nail on the head again, nothing is perfect. And obviously we cannot sample the entire patient's blood volume. So where does that leave us? Well, it leaves us again with another sampling problem in that for tumours that are small, obviously the amount of DNA they're releasing into the blood is going to be a lot lower. And as a result, our limits of detection for those mutations will be problematic. So the bigger the tumour, the less of a problem this is.
Kat: But presumably as technology improves, you know, we have now incredibly sensitive DNA sequencing technologies. So I guess that is a problem that will get easier to figure out.
Charles: Yeah, that's true to a certain extent, but then there is still the, what we call the stochastic issue, which is, is the mutant DNA even present in your blood tub. And for very low frequency mutations due to this sampling problem, you might just not capture the right 10mls of blood at the right time with the right mutations in. And no matter how sensitive your sequencing technique is, you still may not be able to detect the mutant DNA, because it's just simply not in your blood tube.
Kat: So, those are the limitations, but let's talk about some of the promise now. So given that we can detect mutations, we can build up some kind of picture of the cancer in the body, the heterogeneity, what we're up against, how are you starting to use this in your research and how close are we to getting this kind of technique being used in the clinic?
Charles: So we are using CT DNA in three ways. The first sort of area of huge interest to us and many others is this area of early diagnosis or early detection. So can we use CT DNA to detect tumours in blood before they've presented symptomatically? And you and I know how important that is because we know if we detect tumours earlier in general, they're associated with better prognosis and better clinical outcome. And the second area is in this clinical scenario which we call minimal residual disease. So following surgery, we hope to cure the majority of patients with early stage lung cancer. But we still know that some patients' tumours will come back. The difficulty is we don't know who we've cured and who we haven't cured by surgery alone. So we end up treating almost all patients with stage two and stage three cancer with adjuvant chemotherapy, chemotherapy to mop up any residual cancer cells. We call this a sort of an insurance policy if you like.
Kat: But that is not a nice thing to have to have. And especially if, actually it turns out you don't need it.
Charles: That's right. So, we are hoping that CT DNA may help to illuminate this so that we only treat those patients who really need chemotherapy with those drugs. And then the final area that we're fascinated by that is increasingly important is using CT DNA to offer patients the right drug at the right time in the metastatic setting, that is once the tumour has spread beyond the primary to seed metastatic sites.
Kat: So how does that work? This is about actually figuring out what these cancer cells are really like and the best approach to get rid of them all.
Charles: Yeah. So this is precision medicine or personalised medicine. This is where we sequence the DNA and ask, well, what mutations are driving that cancer? And can we use those mutations to target with new cancer drugs to reduce the risk of tumour progression and hopefully extend survival.
References:
Cheng F et al. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget. 2016 Jul 26; 7(30): 48832-48841.
Fisher R et al. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013 Feb 19; 108(3): 479-485.
Fiala C and Diamandis E P. Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Medicine. (2018) 16:166.
Mayo Clinic. Adjuvant therapy: Treatment to keep cancer from returning.
