The ABCs of colorectal cancer

What do you know about the ABCs of colorectal cancer?

In 2008 roughly 450,000 new cases of colorectal cancer were diagnosed in Europe – but with the ABC-Cancer project, a state-of-the-art screening tool may be on the horizon.

Professor Frederik-Jan van Schooten and Dr Agnieszka Smolinska tell Health Europa how the ABC-Cancer project will lead to a non-invasive, cost-effective and reliable screening tool for colorectal cancer.

Colorectal cancer – or bowel cancer, rectal cancer and colon cancer, as it sometimes known – is the second leading cause of cancer-related death in both men and women in Europe. It is second to only breast cancer as the most common type of cancer in women, and is the third most common type of cancer in men, behind lung and prostate cancer. Roughly 450,000 new cases of colorectal cancer were diagnosed in Europe in 2008, and more than 230,000 people died as a result of the disease.1

Thankfully, colorectal cancer deaths are in decline across Europe: according to the WHO, mortality fell from 20.36 per 100,000 population in 1995 to 18.86 per 100,000 in 2009.1 Nonetheless, recent research suggests a worrying rise in the disease among young people. Data from 20 European countries shows that incidence rates increased by 6% each year between 2008 and 2016 among adults aged 20-39 years.2 This is especially alarming given that colorectal cancer is traditionally thought to be a disease of older people.

A wealth of evidence supports the claim that screening for colorectal cancer reduces incidence and improves outcomes; however, screening programmes are typically offered to people over a certain age (the European Commission recommends routine screening for men and women between the ages of 50 and 74) and have a number of limitations.

For instance, immunochemical faecal-occult-blood-tests (iFOBTs) – which check for hidden human blood in faeces – often lead to a high number of false positive results, and colonoscopies – which use a thin, flexible tube and built-in camera to examine the colon for abnormalities – are invasive, burdensome and costly. There is thus an urgent medical need for less expensive, more accurate and less invasive screening tools.

It is here where Airborne Biomarkers for Colorectal Cancer (ABC-Cancer) comes in. The EU project has the ultimate long-term goal of delivering point-of-care devices for the accurate, low-cost and non-invasive diagnosis and monitoring of colorectal cancer.

Towards this end, ABC-Cancer – which combines partners in the Netherlands, Germany and Poland – focuses on the potential use of volatile organic compounds found in biological fluids such as blood, urine, faeces and breath as a biomarker for bowel disorders, among them not just colorectal cancer but also inflammatory bowel disease, irritable bowel syndrome and colonic adenomas.

The use of volatile organic compounds as biomarkers of disease has already been explored in previous studies and altered breath volatile organic compound profiles have been linked to several biological processes, including changes in cellular metabolism and increased presence of reactive oxygen species.

ABC-Cancer notes that volatile organic compounds in faeces and breath appear to reflect alterations in host metabolism, dysbiotic gut microbiota and inflammation, all of which are associated with pre-cancerous stages, advanced adenomas and colorectal cancer.

The project will build on this promising evidence base by making use of state-of-the-art mass spectrometry-based technologies to analyse the volatile organic compounds found in the faecal headspace and exhaled breath of multiple patient cohorts drawn from outpatient clinics and national colorectal cancer screening in the three partner countries. Following this analysis, machine learning will be applied in order to identify a unique colorectal cancer-specific volatilome that can be translated into an effective and easy screening tool and point-of-care device for early-stage and pre-malignant colorectal cancer.

In the future, such an outcome could play a vital role in reducing the morbidity, mortality and healthcare costs associated with colorectal cancer and improving patient quality of life.

To find out more about the project, Health Europa spoke to co-ordinator Professor Frederik-Jan van Schooten and assistant professor Dr Agnieszka Smolinska, both of the Department of Pharmacology and Toxicology at Maastricht University (UM) School of Nutrition and Translational Research in Metabolism. Here, they discuss the limitations of present colorectal cancer screening measures, the success they have already achieved studying volatile organic compounds, and their plans for the future of the project.

ABC-Cancer is aimed at the delivery of an alternative colorectal cancer screening method; in what way do you believe current procedures are limited?

Van Schooten: We began this project because it is very hard to diagnose colorectal cancer. The current tests lead to many false positives. So, at the moment, colorectal cancer is screened for using faeces which is collected using a certain kit, and via that method, blood material is detected that could be an indication for cancer but could also easily be the result of a different process, for example inflammation.

Every false positive has to be followed up by a colonoscopy, which requires trained endoscopists, time, money and other resources. That is of course a problem. More or less everyone is searching for technologies that can be applied to improve this situation, and breath research is very interesting because it is non-invasive and it can be specific. There are indications that the colon can be monitored by compounds that are exhaled in breath, which is how we arrived at this project.

Could you outline in more detail how exactly the volatile organic compound method works?

Smolinska: What we are doing in the project is we are sampling the content of exhaled breath, containing so-called ‘volatile organic compounds’. Volatile organic compounds are the products of host and microbial metabolism that enter the blood and are excreted from the body. They are related to inflammatory processes occurring in the body and some of them are for instance directly produced by the gut microbiome.

The method is quite straightforward: what we do is we ask a patient to breathe normally for about five or six minutes, and then we capture a sample of their breath in a special tube.

The tube is filled with suction material so that it works basically as a sponge. Those tubes are then closed and can be stored for a few weeks before any analysis is performed.
In the project, we do not collect just one sample of exhaled breath, but we collect four, using a specialised sampling device, ReCIVA. That way, we can distribute the samples among our partners.

After the breath is collected, the tube goes through an analytical technique, which, in the majority of cases, is coupled with mass spectrometry, and then the content is measured. The different compounds are separated in the first instance and then they are chemically identified, by which I mean they are given a kind of signature so that later on they can be related to a certain process or metabolic pathway in the body.

What results have you achieved so far using this technique? Can it be applied to conditions other than colorectal cancer?

Van Schooten: We have now been working extensively in this field for around ten years. Initially, we were interested in diagnosing problems in the lungs, in particular COPD or chronic obstructive pulmonary disease. We achieved decent results pretty quickly in that area and so then turned our attention to asthma, which is of course also a lung disease, and we are still working on projects on asthma in children. Again, we have achieved some quite positive results in this space.

We began looking at the colon as well because we were interested in inflammatory bowel disease – which refers to both Crohn’s disease and ulcerative colitis. We thought to ourselves, well, we can detect that these inflammatory compounds are coming into the blood, and once the blood goes to the lungs they will be exhaled. We’ve had strong results with inflammatory bowel disease, and we are still working on that.

We are also doing some work on the liver, because the liver is a pretty big organ in the body, and if something goes wrong with it – for example inflammation – we can detect that. Now we are more oriented towards the major internal organs like the liver and the bowel.

We have seen good results here in Maastricht, and internationally we have also seen examples of certain research groups that have achieved quite positive results. Now we need to take our work to multicentre studies to see whether or not we can replicate these results, and that’s what we will do now in Poland and also in Germany.

How do you hope the ABC-Cancer project will be able to build on these results, and what are its main objectives?

Smolinska: We are not collecting only exhaled breath in the project but also faeces, within which we will be looking at faecal headspace in order to identify which volatile metabolites are excreted. Using these materials, we hope to find a marker of colorectal cancer. That is our primary objective.

As a secondary goal, we want to know more about the relationship between the gut microbiome and the volatile organic compounds – that is, we want to gain an understanding of the role of these compounds in the metabolic pathway of colorectal cancer.

Now that the project has begun, what are your immediate goals in the short-term?

Smolinska: As a next step, we will complete the discovery stage of the project in which we will try to find those markers. Following that, we will enter into the external validation stage of the project, which is a crucial step because if we cannot validate the markers, then they are not specific for colorectal cancer and will be of no use to us. To do that we will use a screening population that is used here in the Netherlands.

People over the age of 55 are invited to take part in the screening programme, during which they are required to deliver faecal samples that are then checked for the presence of blood. If that test comes out positive, those people will have to go for a colonoscopy to confirm the presence or absence of colorectal cancer. We will collect exhaled breath and faeces samples from the same population and use it in our external validation.

Van Schooten: If the results of that are positive, which hopefully they will be, then this biomarker can be used as a screening instrument. That will be very helpful because it would be a less invasive method of treating people with early signs of colorectal cancer and should also result in fewer false positives.

In the future, we hope to also make point-of-care devices that can be used in the doctor’s office or even at home as an early device to detect cancer; however, that is a long way away.

The beauty of this project is that we are collaborating with partners in Poland and also with partners in Germany. We have several patient groups and a number of analytical platforms and so we will be able to combine all the results from these to get a better and more robust biomarker set. The problem with this kind of research usually is that when you do a study here in Maastricht, for instance, and the results are published, you still have to prove that it would work in Munich and the other way around. We are hopeful that we can achieve a set of biomarkers that is more generalisable to other populations and across different centres.

More about ABC-Cancer

The three-year (2018-2020) project Airborne Biomarkers for Colorectal Cancer (ABC-Cancer) is co-ordinated by the School of Nutrition and Translational Research in Metabolism at Maastricht University, the Netherlands, and brings together the Fraunhofer Institute for Process Engineering and Packaging IVV and the University Hospital of Munich (LMU), Germany, as well as Nicolaus Copernicus University, Poland.

ABC-Cancer has received ~€977,000-worth of EU funding under the 2016 Joint Transnational Call for Proposals on ‘minimally and non-invasive methods for early detection and/or progression of cancer’.

It has been awarded this funding under ‘ERA-NET: Aligning national/regional translational cancer research programmes and activities’ as part of the five-year (2014-2019) Horizon 2020 project TRANSCAN-2, which has the specific goal of co-ordinating national and regional funding programmes for research in the area of translational cancer research.

In particular, TRANSCAN-2 is intended to ‘promote a transnational collaborative approach between scientific teams in demanding areas of translational cancer research while avoiding the duplication of efforts and ensuring a more efficient use of available resources, to produce significant results of higher quality and impact, and share data and infrastructures’.3

References

  1. http://www.euro.who.int/en/healthtopics/noncommunicablediseases/cancer/news/news/2012/2/early-detection-of-common-cancers/colorectal-cancer
  2. https://www.ueg.eu/press/releases/ueg-press-release/article/ueg-week-european-colorectal-cancer-rates-in-young-adults-increasing-by-6-per-year/
  3. https://www.era-learn.eu/network-information/networks/transcan-2

Professor Frederik-Jan van Schooten
ABC-Cancer Project
Maastricht University
+31 43 3881100
F.vanschooten@maastrichtuniversity.nl
https://www.maastrichtuniversity.nl/f.vanschooten

Please note, this article will appear in issue 8 of Health Europa Quarterly, which will be published in February 2019.

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