Thomas Newsom-Davis:

So we’re going to be talking about all things genomics this afternoon. Andy, first of all, when we are talking about doing genetic testing, genomic testing, whatever you might call it, what are we talking about? Could you tell us a little bit about, I guess tissue biopsies and what that entails?

Alastair Greystoke:

So for every patient first presenting with lung cancer now, and it’s includes in the earlier stage testing as we’ll talk about a element of that tissue should be sent for genomic testing to sequence the DNA and ideally RNA. Maybe come back to that later on for at least eight key genes that we have potentially therapeutic options for. Ideally that should be done within what’s called the genomic laboratory hub structure. But not all hospitals are using that, but all patients should have those tests done.

Thomas Newsom-Davis:

Okay. And now we’re talking non-small cell lung cancer and not including small cell and e are talking advanced stage disease, but also some locally advanced and even early-stage cancer as well. I think we’d agree everyone with advanced stage, locally advanced.

Alastair Greystoke:

Just to go back to the advanced stage, one area of controversy you may find differences between hospitals is the issue about testing for squamous patients. So the national funding just says non-small cell lung cancer guidelines, say non-squamous lung cancer should all be tested. And they say that squamous cancers that fit certain key categories such as under 50 or under 55, depending which guidelines you read, light never smokers, whether it’s a small biopsy, should also be tested. Some places will test everyone, some places will test non squams and ideally test those squams with the key characteristics. But it’s difficult to remember if you’re in an MDT, how often do you get a smoking history, et cetera.

Thomas Newsom-Davis:

Okay. And in a locally advanced, we’d also be testing patients because some of our locally advanced strategies like adjuvant immunotherapy, you need to know someone is EG FFR wild type to be able to give that. And we’ll also be testing some patients with stage one B to three disease after surgery because we do have access to some adjuvant treatments like adjuvant osimertinib. So I guess in that situation you’ve got to wait for your MDT decision and staging before knowing what you’re going to test.

Alastair Greystoke:

No, no. I would argue that your pathology department should be testing everyone reflexly because

Thomas Newsom-Davis:

Reflex testing.

Alastair Greystoke:

Yeah, because the number of patients where it doesn’t impact on the management now is so small. You’ve got your patients who are going down the curative route. Some of them may be eligible for neoadjuvant treatment that’s not funded and not suitable for patients that have EGFR and ALK abnormalities. And as you say, they may have access to adjuvant osimertinib or adjuvant alectinib if they’re in ALK patient equally, if you’re having a stage three chemo rad, you may not want to be giving you EGFR mutated patients durvalumab, for example. So I think for everyone it makes sense

Thomas Newsom-Davis:

The reflex testing the way forward. And by that we would mean when your pathologist is reporting at adenocarcinoma for example, they just get on and organise it. You don’t have to ask them

Alastair Greystoke:

To Exactly.

Thomas Newsom-Davis:

Now there’s going to be a variation in terms of the technology that people have available. Some people are going to have access to next generation sequencing MGS, some are not, and they’re going to be used using PCR based or other assays. What would you see as be the best, if you could have the best in your medical hospital, what would be the best? And if people don’t have that, what are the alternatives are there?

Alastair Greystoke:

So there is no doubt that the best is what’s called next generation sequencing, which is doing a panel of genes ideally on both DNA and RNA and I’ll pick up the most abnormalities. So why is that not done routinely? So there’s some technical issues. So lung cancer biopsy is often small if they’re not treated well, particularly on the RNA panel, they may fail. So maybe 10, 20% of lung cancers if not treated well, the biopsy might fail on you technically, and you might need to use a simple PCR test. The other issue is this issue around turnaround times. So the problem is that most of the next generation sequencing panels are done in big central laboratories within the, what’s called the genomic laboratory hub structure. And for example, in Newcastle, mine is in Leeds, yours will be somewhere else in London. And so if somebody is having a biopsy in Northumbria, it may need to travel first to Newcastle, then down to Leeds, and then the analysis gets done in Leeds that may take a week and then the result needs to feed back up. And that leads to delays, it leads to clunky pathways because there’s multiple trusts, multiple transfer points. And this is where we start to see some of the longer turnaround times and people’s frustration building out the process. And they say, well, why can’t I just have a simple gene test done point of care device in my local pathology lab, gives me my answer 12 hours later, job’s a good one.

Thomas Newsom-Davis:

Okay. And we should say, this isn’t not a UK problem, this is an international problem. Everyone’s ISS battling with that problem. So if you decide you don’t have access to nng S because of those complexities, or maybe it’s not funded, people sometimes using PCR based assay, they’re quicker. What’s a disadvantage? Why aren’t we all doing PCR?

Alastair Greystoke:

So A PCI, you can do one, two more genes. The more genes you do, the more tissue you use up. But also you’ll start to miss abnormalities. So for example, for EGFR, yes, you’ll pick up your 80, 85% of your common abnormalities, but you will miss some key abnormalities where we have treatments going forward with. So it’s not ideal. And certainly once you get up to beyond five or six genes, it’s far more cost effective, but it’s also a better use of tissue to get that full profile on the eight genes that we actually need for NHS care, never mind clinical trials or anything else, which we can come on to talk about. If you just want your eight NHS genes, the best way to get it is through a next generation sequencing panel.

Thomas Newsom-Davis:

And people might have heard of Adilla that’s doing the rounds. What is Adilla? Why do people use it? It seems to be a bit of a hot topic. Are there disadvantages to it? Presumably there must be.

Alastair Greystoke:

Well, there are disadvantages. So a dealer is what’s called a point-of-care device. So it’s a bench that sits on a box that sits on your bench top. So you can have it in your pathology laboratory and it will spit out a result very quickly. And if you’re going to do those eight genes, you need to use either three or four separate cartridges of tissue. So the issues then are cost, who pays for it? So it will have to be paid for by either your pathology or your oncology department or some people are using alliance money, but also it is not next generation sequencing. And you may miss some abnormalities

Thomas Newsom-Davis:

When we’re talking about missing abnormalities either by the Adilla or PCR. Can you tell me a couple of those? For example, it can or may miss EGFR Exon 20 insertion, that’s an important one. What other things might people have missed if they’re not using a proper NGS based assay?

Alastair Greystoke:

Yeah, so the ones I worry about are the fusions because these are complicated abnormalities. Can you really pick it up on a chip? And the MET exon 14, skip lesions, there’s over 200 different MET abnormalities. And I am concerned that not all of those, and I have had cases where they have not been picked up by an NAD technology or another point of care device, but they have been picked up in their formal genomic laboratory structure.

Thomas Newsom-Davis:

So you talked a minute ago about the test directory and you talked about these regional genomic laboratories. What is a test directory and who’s arrived at that? And second question is, what’s the significance of it? Why do I care what’s on a test directory?

Alastair Greystoke:

So this is just for NHS England. There are separate processes which we should probably touch on for Scotland, Wales, and Northern Ireland. But in England the national test directory is a list. It’s in the public domain. It’s a big spreadsheet of the tests that are approved and funded by NHS England centrally and have to be delivered by the genomic laboratory hubs. How they were divided, how they were reached at was by, they’re basically for lung cancer, pretty much aligned to the nice appraisals. So when we have an ALK inhibitor come through, ALK testing goes on the national test directory. So it is a bit clunky and it only includes genes that we have therapies associated for. Increasingly there will also be a move for important diagnostic genes for lung cancer, some of the rarer lung cancer subtypes to go on it. And we’re also trying to future proof it because at the moment it can take quite a long time to get a test on the national test directory. So for example, MET testing, we had access through NICE to positive a met inhibitor about six months before we had the test approved. So myself and some colleagues are trying to future proof the test directory. So some people may start to see extra genes coming onto their reports. So for example, now we are reporting MET Amplifications where we don’t have a drug. We are reporting HER two insertions where we don’t yet have a drug, but there are drugs coming forward to try and future proof so that when we do have a drug, we’ve already identified the patient population.

Thomas Newsom-Davis:

So if it is on the test directory, all of our colleagues listening in England should be able to get access to that different situation north of border in Scotland. Do you know the situation in Scotland?

Alastair Greystoke:

So in Scotland it is a bit more piecemeal. They are trying to centralize their laboratory and the genomic testing in Glasgow, but it hasn’t yet happened. And so there’s no prescribed list of genes that have to be done. It’s very much done on the clinicians giving advice to their pathology labs and there may be differences from one center to another

Thomas Newsom-Davis:

Is Wales following England.

Alastair Greystoke:

So Wales has a centralized test. In fact, Wales is probably head of England, it just had one sequencing facility. It’s very forward thinking. They’ve been reporting a large number of genes based around next generation sequencing for several years.

Thomas Newsom-Davis:

Brilliant. So we know who we’re going to test, we know we’re going to do reflex testing, we know what we should be testing. Our colleagues have done that. They’re lucky they have access to NNG S, they get the report through. It should say in there, the other mounty found and there should be an interpretation. It should tell you, supposing our colleagues are reading that and they say, I don’t really understand that or I’m not quite sure, there is no interpretation. What would you do in that situation? How would you advise them?

Alastair Greystoke:

Yeah, so there’s a couple of things. So number one, most of the reports will have an email or something like that on the report where you can query it. But also all the genomic laboratory hubs will have a genomic tumor advisory board associated with them.

Thomas Newsom-Davis:

GTAB

Alastair Greystoke:

A GTAB, yes, we love our acronyms, love our NGS GTAB. So what does that mean? Well, that’s different in different places in the northeast. That’s a virtual meeting once every two weeks, which I chair and you send an email through saying I want this case discussed and why you want it discussed. There’s about 20 of 30 US and we sit down and we look at it with clinical scientists, cancer geneticists, lab scientists, and we try to answer your question and feed it back to you. It is an advice on the genomics. It is not an advice how to manage your patients. That is an MDT job. Okay. So you may then need to take your advice back to the MDT and say, well the genomics people have told me this. How do I now change the management of my patients? But

Thomas Newsom-Davis:

The important thing is to also reassure patients. No one’s going to take their patient away. This is saying to them this is a significance. And I guess the other thing they could do if they don’t have access to a GTAB or they don’t want to use that, you can always phone up your molecular biology department whose number will be on the report. Exactly. And there’s no shame in saying I don’t quite know what it means. Or you can use Google or other search engines are available and I think people aren’t sure. I think the trick is be absolutely certain what the significance of the finding is. Don’t just assume it’s not significant.

Alastair Greystoke:

Yeah, no, I think that’s exactly the right thing. I wouldn’t maybe advise Google. There’s a couple of really nice websites out there that you can use. There’s one called Civic, which is a bit like the Wikipedia for genes. There’s onco kb, which is the MD Anderson database where you can put your genetic abnormality in and they’ll try to, they will give you an interpretation. The problem with onco KB is that you have to pay if you want full access, but you can get a superficial analysis for free.

Thomas Newsom-Davis:

So that’s tissue NGS. Now you and I have been part of a ctDNA circuit consumer DNA or cell-free DNA pilot liquid biopsy. It’s also called, before we talk about that particular pilot and what might happen to it, tell me a little bit about this technology and when we should be ideally using it.

Alastair Greystoke:

Okay, so liquid biopsy is looking for small amounts of circulating tumor DNA in a bloodstream. And it’s based on the fact the technology, so it’s an NGS same as on new tumor, but it’s based on the technology’s got so much better that we’re starting to be able to pick up abnormalities in the blood at about 1% or half a percent of the circulating tumor DNA. So circulating free DNA. So we’ve all got DNA going around our bloodstream. It is mostly made up of broken up white cells, stuff like that. But if a cancer patient has cancer active in their body, they start or can start to release tumor DNA into the bloodstream and we can pick it up with our new technologies. So with metastatic lung cancer patients using present technologies, not academic, but commercially available, it’s about 80% of patients that have metastatic disease. You will be able to pick this up and you will be able to do an analysis on the circulating tumor DNA and the specificity. So if it says that there is something there, it is basically a hundred percent correct.

Thomas Newsom-Davis:

And how does it know it’s from the tumor and is not from normal cells? The white blood cells you mentioned.

Alastair Greystoke:

So the short answer is it doesn’t. It will just give you a read on mutated DNA. But if you see an EGFR classic EGFR mutation and a patient has metastatic lung cancer, that’s going to be coming from the tumor. So most of the genes, it’s very clear that it’s coming from the tumor. They’re very classic lung cancer abnormalities. There are some genes that are known to be released by white blood cells as we get older. This is the type of thing you should be sending to your GTAB. But then none of the genes that we use for treatment at present time. So you don’t need to worry about it too much,

Thomas Newsom-Davis:

But it will therefore has the potential to pick up inherited disorders.

Alastair Greystoke:

Correct.

Thomas Newsom-Davis:

How might someone spot those and what should they say ignore it, or should they be doing something about it? Can you pick up a hereditary BRCA mutation for example, in a patient with lung cancer who actually happens to have a hereditary disposition to lung cancer, which they never knew about.

Alastair Greystoke:

So don’t ignore it. Please do not ignore. Very important. So when you get the report, it will give you the percentage of each abnormality in the DNA. Okay. And that’s called VAF or variance allele frequency. You also see this on your tumor as well. So they’ll say that for your tumor, 30% has a mutation with it. And that’s the amount of tumor cells in your DNA. It’ll say half a percent or 1% has an EGFR mutation. If it is inherited, it should be about 50%. Okay. Because if you’ve got a BRCA abnormality you should have inherited from your mom and your dad, it should be about 50%. That’s a bit rule of thumb. We normally say somewhere between 40 and 60%.

Thomas Newsom-Davis:

So it’s really high. Do something about it. Contact your local.

Alastair Greystoke:

So not for everything. Okay. If it’s very high and it’s BRCA, yes. If it’s a known germline abnormality, and we certainly are going to try and produce a list of genes. If you are worried this might be the ones you might want to take to your tumor advisory board rather than ignoring. Okay. Some of the companies and some of the technologies will give you a estimate of how much tumor DNA you have going around your body. And so it might say 50% DNA tumor DNA in the bloodstream. You’ve got a patient who’s riddled with disease, half their bloodstream is tumor DNA, and then if it says 50% KAS or 50% EGFR, that’s not inherited, it’s just coming from the cancer. But if you can see, if it says 1% tumor and 50% BRCA, then yeah, that makes you think germline.

Thomas Newsom-Davis:

So that’s our blood test and there are various platforms to do that. There’s been an NHS England pilot running for, well more than two years now, three years now which has gone through a kind of early phase, not as an early phase trial, but early phase of the project now running routinely. We do it routinely. Do we know whether this is going to be continued indefinitely or are we waiting for some kind of readout for the powers that be to decide?

Alastair Greystoke:

So this was a project that was set up three years ago by a number of us in the community and it was looking at what’s called a liquid first approach. So was patient first having their CT scan showing metastatic lung cancer. You do a blood draw and you’re trying to get the result back early and get them on treatment. So initially started with 700 patients as funded. It’s now funded up to 10,000 patients a year. Every single trust in England should have access to this. We are, and what we were waiting for was analysis of clinical outcomes and some of those will hopefully be shown at BTOG tomorrow.

Thomas Newsom-Davis:

Excellent. Looking forward to that.

Alastair Greystoke:

Yeah, looking forward to it. They look good. Some of it is around the cost effectiveness analysis. So these technologies can be a bit more expensive than doing it on the tumor. And particularly if you’re doing both the tumor and the liquid, that is obviously causing more cost. We’re working with NHS England to say, is this cost effective? And also is this a way for some patients to say, well actually I’ve got the answer with a liquid biopsy. Maybe I don’t need my tumor analysis.

Thomas Newsom-Davis:

So if you are sitting there with your patients, you have done your liquid biopsy earlier, it’s a quicker turnaround time, you get a result saying there is an ALK fusion, you have yet to get your tissue back, even telling you it’s an adenocarcinoma, would you be a happy and B funded to start your A treatment for that patient.

Alastair Greystoke:

So the blue tech forms from NHS England are very clear that you can treat based on a CCF DA report and a MDT call of metastatic lung cancer. So

Thomas Newsom-Davis:

Your answer

Alastair Greystoke:

Yes, you don’t need to wait.

Thomas Newsom-Davis:

Okay. So we now know about the different platforms available. Hopefully people listening have got both available. We hope that CTDNA will continue indefinitely. From the patient point of view, what’s the advantage here? Why do we have to know these results and why is imperative to know them accurately and quickly?

Alastair Greystoke:

Okay, so there are a number of these genes where we have first line treatment options, not all of them, but EGFR, ALK re met, et cetera, BRAF, et cetera. And so in that situation, you can give a patient a tablet with potentially a higher response rate and we can talk about what the response rates might be, potentially longer disease control, but also avoiding chemotherapy and immunotherapy. So that means they can start treatment sooner. Certainly in my practise, I will the tablet, I’ll have it waiting for them, which is much nicer than saying you’re going to have to wait 2, 3, 4 weeks for treatment. And we know patients will be deteriorating and suffering symptoms and psychological anxiety during that time, but also at least those treatment options down the line for down the future. The other thing to say is that certainly in NHS England, some of our tablets are only funded in the first line setting. So for example, osimertinib for EGFR mut mutated lung cancer or the dabrafenib and trametinib for the BRAF mutated lung cancer are only available to patients if they have not had chemotherapy. So if you

Thomas Newsom-Davis:

Don’t know at the beginning, you can’t give it

Alastair Greystoke:

Exactly. You can’t give them the best treatment option.

Thomas Newsom-Davis:

And although these are not curative treatments, they are treatments we know are often better tolerated, better efficacy, better quality of life. And that’s why you need to know.

Alastair Greystoke:

Correct. And you can see that with some of these patients. The ALK fusions are the classic example. The average prognosis in the UK real World Series is about five years for stage four disease. And in some series in the states it’s up to like 8, 9, 10 years now. So because of the availability of these targeted treatments for,

Thomas Newsom-Davis:

And we know from data shown by Neil Navani today, the National Lung Cancer Audit, we’ve got the first time from genomics data showing that on by their estimates, 79% of patients with an EGFR mutation first line treatment performance status one or better got an EEG FR inhibitor, which is not high enough. That number perhaps shouldn’t be a hundred percent because not everyone’s going to want it, but it should be north of 90%. So we still have work to do, don’t

Alastair Greystoke:

We? Yeah. To me that should almost be, it should be an event where you are actually working out why did this patient not get a targeted therapy? The default should be that they should be receiving. So

Thomas Newsom-Davis:

We’re not all there yet. Are there some situations where you don’t trust the result? You have your CTDNA saying, I can’t see anything that’s presumably more likely in someone with a low volume of disease? That’s correct. How do people know the difference between this test is not diagnostic and this test has not shown a mutation? They are different, aren’t they?

Alastair Greystoke:

Yeah. So the answer is it’s not always clear. And there is a learning process of getting used to seeing these circulating free DNA tests. The answer is if you do not get your answer from your liquid biopsy, then you need to wait for your tumor biopsy. And we are in the process of developing some guidance for clinicians and other healthcare professionals where they will be able to use a table to say, yes, this is an informative result I can get on with treatment. Or No, this isn’t, and I need to wait for my tumor moleculars and hopefully we’ll get that ratified by everyone and released to the community. It will be, I think it’s the first time anyone’s ever tried that. So there will be teething problems and we’re very happy to get positive informed feedback to get better. Don’t just all shout at me and say, this is rubbish,

Thomas Newsom-Davis:

And tissue biopsy is not perfect either. So you might have a result saying there was insufficient DNA, it might have a result saying that quality DNA, that was lots of it there, but it was poor quality that comes back saying, I can’t give you an answer. Your CDNA hasn’t worked re biopsies. I mean, when do you re-biopsy say, well look, I’ve just got to get on with it. And when would you be saying, I really don’t want to start anything until I’ve had another go?

Alastair Greystoke:

Yeah, I think that’s really challenging. So we know about, again, as I said earlier, about 15 20% of tumor samples are not suitable one way or the other due to necrotic tissue or not getting to the lab or appropriate time in my practice. You have to think about what’s the chance of a, this being a positive pre-test probability. If you’ve got a 40-year-old never smoker female, there’s a high probability they’re going to have something you can target and you should really be trying to re-biopsy. If you’ve got 75-year-old heavy smoker, you’re less likely to be missing something. You certainly want to re-biopsy than maybe in the future, but maybe you should just be getting with some treatment. It is a bit of a judgement call.

Thomas Newsom-Davis:

Okay. So I think that covers all things genomics. Ali, thank you very much for joining me in this discussion. Thank you very much. Thank you.