Diagnosing cancerous and precancerous oesophageal disease

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Published: 27 Apr 2017
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Prof Rebecca Fitzgerald - University of Cambridge, Cambridge, UK

Prof Fitzgerald speaks with ecancer at the 1st Cancer Research @ Bath Symposium about diagnosing oesophageal carcinoma, and early detection of its precancerous state.

The 'cytosponge' test, which she describes as a cost-effective, low-impact out-patient procedure, was previously reported in The Lancet Gastroenterology & Hepatology.

Prof Fitzgerald goes on to discuss testing for Trefoil Factor 3 (TFF3) as a biomarker of Barrett's Oesophagus, and introduces the BEST3 trial, currently recruiting participants.

I’m going to talk about cancer of the oesophagus; it’s a cancer that often isn’t discussed very much. I’m going to talk about one of the main subtypes which is oesophageal adenocarcinoma and I’m going to talk about some work we’ve done characterising the genome of that cancer as part of the International Cancer Genome Consortium and the implications of that for therapy. That’s the first part of the talk and the second part of the talk I’m going to talk about early diagnosis and a new diagnostic test that we’ve developed.
So one of the big problems with this cancer that has a very poor outcome is it’s detected quite late. So often the common symptoms are weight loss, difficulty swallowing and often at that point the cancer is already quite invasive, usually stage 3 or more. So the natural history of the cancer is actually very slow, it evolves from a pre-invasive stage called Barrett’s oesophagus. If we can diagnose it at that point, and perhaps when it’s a very early cancer, then we can really change those survival statistics around. The standard diagnostic test is endoscopy – straightforward, standard of care test – but nevertheless it’s not feasible to endoscope certainly everybody in the population or even those with heartburn symptoms, it would just completely overburden the service. So it’s not really suitable as a screening test or as a first-line diagnostic test for everyone with reflux and indigestion and that’s the main symptoms of the pre-cancer.
What we’ve been trying to do is to develop something which can be used in the GP surgery which doesn’t rely on endoscopy, that’s very simple, straightforward, cost-effective to do but also as accurate as possible. What we’ve come up with is a test that combines a very, very simple device with a laboratory assay that’s very accurate. The device is very simple, it’s a pill on a string, no camera or anything, just a pill on a string. You swallow the pill down, we call it the cytosponge, it’s a little spherical sponge compressed inside the capsule. When the capsule gets to the top of the stomach and it’s in contact with a warm wet environment the capsule dissolves in just over two or three minutes and out pops that sponge still on the string. The nurse just pulls it back and it comes out in a few seconds and as it comes along the passage of the oesophagus it collects a very big cell sample, so you actually get about a million cells trapped on the outside and within this sponge. From the patient’s point of view the test takes literally five minutes. It’s a bit uncomfortable but compared with an endoscopy it’s really simple to do, you don’t need any sedation, you don’t need a day off work, you just come and have it done. Then the nurse or whoever has done the test just puts it into a preservative pot and sends it to the lab. We spin the cells off and then we can process that sample and look for different proteins expressed or genes mutated.
The test we’ve developed in the lab, the main test which tells you have you got Barrett’s or not, is just a single antibody to look for a single protein called trefoil factor 3. That protein is very specifically expressed in Barrett’s cells and the result is scored yes or no. So it’s really got the right characteristics for a simple triage test. Even if you’ve got one cell positive for this protein we would score that positive. If it does show Barrett’s then we’ve also been working on a second tier test that will tell you is this really cancerous or cancer-prone or not because most people with Barrett’s will never get cancer. Then we can do things like look for mutations in the p53 gene, look for changes in the DNA copy number. So that’s still work in progress.
The have you got Barrett’s or not, we’ve now done two trials to show that this approach is safe and accurate and acceptable to patients and we’re now just starting a very large randomised trial in primary care. We’re literally just recruiting the first patients as we speak. It’s 9,000 patients that we will be contacting, so this is across the UK, it’s called the BEST3 trial, it’s funded by Cancer Research UK, and the whole GP surgery will be randomised, so it’s what we call a cluster randomised design because it would be quite difficult to give equipoise by offering some patients in the practice the cytosponge and some not. So a whole surgery will offer cytosponge to people coming in with reflux symptoms compared with a whole surgery just doing what they ordinarily do for their patients with reflux symptoms which might be give them acid suppressant pills, refer them for endoscopy if they thought it was necessary. In our cytosponge arm they will obviously be given medication for their symptoms but also every person will be offered the cytosponge. What we want to see at the end of the trial is a very simple outcome, the primary outcome of the study is do we diagnose more Barrett’s by systematically offering patients the cytosponge versus ordinary care. Then we’ll also look at acceptability, safety obviously, health economics in some detail.
So that trial is just starting, it should complete patient recruitment in two years’ time, analysis in three years’ time so it will be actually quite a short study to do. We think that that will give us the level of evidence we need to see if this is something that should be rolled out and taken to NICE.