Volatile Organic Compounds in Breath Can Serve as a Noninvasive Diagnostic Biomarker for the Detection of Advanced Adenomas and Colorectal Cancer

Kelly E. van Keulen; Maud E. Jansen; Ruud W. M. Schrauwen; Jeroen J. Kolkman; Peter D. Siersema


Aliment Pharmacol Ther. 2020;51(3):334-346. 

In This Article

Abstract and Introduction


Background: Colorectal cancer (CRC) is the third most common cancer diagnosis in the Western world.

Aim: To evaluate exhaled volatile organic compounds (VOCs) as a non-invasive biomarker for the detection of CRC and precursor lesions using an electronic nose.

Methods: In this multicentre study adult colonoscopy patients, without inflammatory bowel disease or (previous) malignancy, were invited for breath analysis. Two-thirds of the breath tests were randomly assigned to develop training models which were used to predict the diagnosis of the remaining patients (external validation). In the end, all data were used to develop final-disease models to further improve the discriminatory power of the algorithms.

Results: Five hundred and eleven breath samples were collected. Sixty-four patients were excluded due to an inadequate breath test (n = 51), incomplete colonoscopy (n = 8) or colitis (n = 5). Classification was based on the most advanced lesion found; CRC (n = 70), advanced adenomas (AAs) (n = 117), non-advanced adenoma (n = 117), hyperplastic polyp (n = 15), normal colonoscopy (n = 125). Training models for CRC and AAs had an area under the curve (AUC) of 0.76 and 0.71 and blind validation resulted in an AUC of 0.74 and 0.61 respectively. Final models for CRC and AAs yielded an AUC of 0.84 (sensitivity 95% and specificity 64%) and 0.73 (sensitivity and specificity 79% and 59%) respectively.

Conclusions: This study suggests that exhaled VOCs could potentially serve as a non-invasive biomarker for the detection of CRC and AAs. Future studies including more patients could further improve the discriminatory potential of VOC analysis for the detection of (pre-)malignant colorectal lesions. (https://clinicaltrials.gov Identifier NCT03488537)


Colorectal cancer (CRC) is the third most common cancer diagnosis and a major cause of mortality in the Western World.[1–3] CRC usually develops from focal changes within benign polyps via a multistep process involving a series of genetic, histological and morphological changes that accumulate over time.[4] This dwell time allows for early detection and removal of precursor lesions to prevent development of CRC. Moreover, detection of early-stage CRC improves survival rates which is why screening programs for CRC are increasingly adapted worldwide.[5,6]

Nowadays, several CRC screening modalities are available, and each test has its own performance characteristics and acceptability profile. Preferably, a screening test should be affordable, non-invasive and precise to achieve a high rate of cooperation from asymptomatic individuals. Faecal immunochemical testing (FIT) is currently the most commonly used non-invasive screening test for CRC. This stool-based test is relatively cheap and easy to perform, but population screening with FIT results in missed cancers and unnecessary colonoscopy procedures due to suboptimal sensitivity and specificity of 56%-89% and 92%-97% respectively, for detection of CRC.[7–9] Furthermore, ideally a screening test should detect treatable precursor lesions to prevent development of cancer, but sensitivity of FIT for advanced adenomas (AAs) is low, only 39%-57%.[7,8] These suboptimal test characteristics of FIT and sometimes disappointing adherence rates to FIT screening programs (37%-62%) illustrate the need for a new, more accurate, non-invasive diagnostic test for CRC and its precursor lesions.[10–13]

Analysis of volatile organic compounds (VOCs) might be a promising new technique for early detection and surveillance of various diseases, including CRC. VOCs are gaseous carbon-based end products of physiologic and pathologic metabolic processes which can be detected in all biological specimens (eg breath, saliva, urine, faeces, blood).[14,15] It has been shown that VOC concentration profiles and/or VOC composition differ between patients with and without certain diseases, ranging from infectious diseases[16,17] to malignancies.[18–20] Some potential CRC-associated VOCs have already been identified in small pilot studies,[21–35] but the VOCs identified differed among studies and (external) validation of the results is lacking. Data on VOC's associated with colorectal polyps is even more scarce.[25,29,32,33]

Thus far, most studies that evaluated the potential of VOCs to serve as a non-invasive biomarker for CRC used faecal samples and gas chromatography-mass spectrometry (GC-MS) for VOC analysis. We hypothesised that breath analysis with electronic nose (e-nose) technology may be more suitable for clinical practice since breath sampling may be more acceptable for (asymptomatic) individuals. In addition, contrary to GC-MS, e-nose technology is relatively low-cost, easily operated and it allows for point-of-care diagnosis.

Therefore, the objective of this study was to evaluate if exhaled VOCs can serve as a non-invasive biomarker for CRC and its precursor lesions using e-nose technology. In this study, breath analysis was performed with Aeonose devices (The eNose Company). This specific type of e-nose allows for datasets of multiple devices to be combined which facilitates the generation of large data sets to develop disease models. Furthermore, once-developed models can be transferred to new e-noses which will further aid in clinical implementation of e-nose technology.[36]