Elsevier

Analytica Chimica Acta

Volume 996, 15 December 2017, Pages 1-9
Analytica Chimica Acta

Review
Review of recent developments in determining volatile organic compounds in exhaled breath as biomarkers for lung cancer diagnosis

https://doi.org/10.1016/j.aca.2017.09.021Get rights and content

Highlights

  • Methods for determination of volatile organic compounds (VOC).

  • VOC as potential markers for early diagnosis of lung cancer.

  • Review of sample pretreatment and analytical methods used.

Abstract

Lung cancer is the most common cause of cancer deaths, its global incidence is rising, and continuing rises are predicted. The potential to diagnose lung cancers based on the determination of volatile organic compounds (VOCs) in human breath has been attracting increasing attention with the development of new techniques and methodologies. However, despite many reports of VOC profiling in lung cancer patients, little is known about how specific biomarkers relate to the biochemical pathways involved in lung cancer development, and there is still no reliable method for diagnosing lung cancer at the early stages. This review summarizes some of the latest methods used for monitoring biomarkers in lung cancer patients, which could be applicable for clinical diagnosis. Techniques for capturing and pre-concentrating biomarkers, and the technologies used for subsequently determining them, are also discussed.

Introduction

Due to its high, and rising, morbidity and mortality, lung cancer has become the leading cause of cancer deaths globally [1], [2], [3]. Approximately 14.1 million people were diagnosed with cancer in 2012, with 8.2 million deaths worldwide [4], [5]. Of these 14.1 million cases, 1.8 million (13%) were lung cancer. Increases in various environmental risk factors are expected to induce rises in annual numbers of new cancer cases and associated deaths to 24 and 14.6 million, respectively, by 2035 [6]. Therefore, there is a clear need to develop new methods for preventing, detecting, and treating cancer [7].

Cancer screening is important for detecting the disease at early stages, to avoid metastatic spread, thereby increasing the rate of successful treatment. New screening methods that are highly sensitive, specific, and fast are needed for early diagnosis, prognosis, monitoring pathogenesis, and targeted therapy [8], [9], [10], [11], [12]. The search for new diagnostic methods and tools that can meet these needs is increasingly attracting the attention of researchers in interdisciplinary fields, such as biomedicine, biophysics, and analytical chemistry [13].

Lung cancers are usually categorized as one of two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter representing a large majority (85–90%) of cases [14]. Regardless of histopathological subtype, 88% of lung cancer patients die within 5 years of diagnosis, suggesting that delayed diagnosis is a significant problem [15]. Currently, various combinations of multiple techniques, including radiology, endoscopy, and molecular biotechnology, are used to detect lung cancer at early stages [6]. These techniques, and their diagnostic applications, are briefly listed and described in Table 1.

All these methods are useful at various stages of diagnosis and have specific merits. However, in early stages of the disease it remains difficult to distinguish lung cancer from benign nodules based purely on morphological criteria. This results in frequent false positives and unnecessary surgical resection [10], [11], [17], [20], [21]. Detecting volatile organic compounds (VOCs) in the exhaled breath of patients may offer a rapid, noninvasive, inexpensive and more specific alternative [37]. However, the success of VOC-based diagnosis depends on the identification and validation of one or more chemical species that can serve as accurate biomarkers of lung cancer [38], [39].

Recent developments in sampling techniques and detection methods have been discussed extensively in review articles written by Sun et al. and Saalberg et al. [40], [41]. Techniques for determining VOCs, including gas chromatography (GC) or mass spectrometry (MS) based and sensor-based techniques, have been described in detail [40]. In contrast, this review primarily addresses the identification of VOCs, and we aim to highlight research focused on the discovery of biomarkers for early screening and diagnosis of lung cancer. Literature published up to the end of May 2017 is included, and the main compounds considered relevant to lung cancer diagnosis are listed. The reported sensitivity and specificity of these compounds are also summarized.

Section snippets

Determination of VOC as a tool for disease diagnosis

The smell of human breath has been for used for diagnostic purposes since ancient times. The possibility of using it for detecting lung cancer has also been investigated for many years, and greatly boosted by rapid recent developments in metabolomics as a new branch (together with genomics, transcriptomics, and proteomics) of systems biology [38]. Metabolomic analysis of exhaled breath generally focuses on the quantitative determination of metabolites with low molecular weights (less than 1000

Conclusion and perspectives

Lung cancer is one of the most prevalent forms of cancer worldwide, with a high mortality rate. Therefore, screening for lung cancer at an early stage is vital for improving survival rates, as well as improving patients' quality of life. In the past 50 years, breath analysis has developed into an established tool for the clinical detection of early stage lung cancer, based on known molecular pathways contributing to the progression of the disease. The development of new techniques and

Acknowledgements

The authors thank Dr. E. Jane Maxwell for important discussions and editing of this manuscript. This work was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, and JZ and ZH acknowledge fellowships from the Canadian MITACS Accelerate Program.

Jiemin Zhou obtained her MD in Clinical Medicine from Nanjing Medical University in 2011, and completed her residency at People's Hospital of Jiangsu Province, Nanjing, China, in 2012. Currently, Dr. Zhou is an MSc student in the Faculty of Pharmaceutical Sciences at the University of British Columbia, Vancouver, BC, Canada.

References (112)

  • G. Song et al.

    Quantitative breath analysis of volatile organic compounds of lung cancer patients

    Lung Cancer

    (2010)
  • M. Phillips et al.

    Detection of lung cancer using weighted digital analysis of breath biomarkers

    Clin. Chim. Acta

    (2008)
  • M. Phillips et al.

    Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study

    Lancet

    (1999)
  • J. Rudnicka et al.

    Determination of volatile organic compounds as potential markers of lung cancer by gas chromatography–mass spectrometry versus trained dogs

    Sensors Actuators B Chem.

    (2014)
  • N. Peled et al.

    Non-invasive breath analysis of pulmonary nodules

    J. Thorac. Oncol.

    (2012)
  • F.L. Liu et al.

    Single-walled carbon nanotube-based biosensors for the detection of volatile organic compounds of lung cancer

    Phys. E Low-dimensional Syst. Nanostructures

    (2011)
  • M. Phillips et al.

    Detection of lung cancer with volatile markers in the breath*

    Chest

    (2003)
  • J. Rudnicka et al.

    Determination of volatile organic compounds as biomarkers of lung cancer by SPME–GC–TOF/MS and chemometrics

    J. Chromatogr. B

    (2011)
  • E.M. Gaspar et al.

    Organic metabolites in exhaled human breath—a multivariate approach for identification of biomarkers in lung disorders

    J. Chromatogr. A

    (2009)
  • D. Poli et al.

    Determination of aldehydes in exhaled breath of patients with lung cancer by means of on-fiber-derivatisation SPME–GC/MS

    J. Chromatogr. B

    (2010)
  • N. Peled et al.

    Volatile fingerprints of cancer specific genetic mutations

    Nanomed. Nanotechnol. Biol. Med.

    (2013)
  • H. Yu et al.

    Solid phase microextraction for analysis of alkanes and aromatic hydrocarbons in human breath

    J. Chromatogr. B

    (2005)
  • Y. Li et al.

    Serum metabolic profiling study of lung cancer using ultra high performance liquid chromatography/quadrupole time-of-flight mass spectrometry

    J. Chromatogr. B

    (2014)
  • A. Wehinger et al.

    Lung cancer detection by proton transfer reaction mass-spectrometric analysis of human breath gas

    Int. J. Mass Spectrom.

    (2007)
  • N.-H. Kim et al.

    Highly sensitive and selective hydrogen sulfide and toluene sensors using pd functionalized wo3 nanofibers for potential diagnosis of halitosis and lung cancer

    Sensors Actuators B Chem.

    (2014)
  • S. Li et al.

    Ionic liquid-based aqueous two-phase system, a sample pretreatment procedure prior to high-performance liquid chromatography of opium alkaloids

    J. Chromatogr. B

    (2005)
  • J. Kałużna-Czaplińska et al.

    Current applications of chromatographic methods for diagnosis and identification of potential biomarkers in cancer

    TrAC, Trends Anal. Chem.

    (2014)
  • O. Barash et al.

    Classification of lung cancer histology by gold nanoparticle sensors

    Nanomed. Nanotechnol. Biol. Med.

    (2012)
  • M. Caldeira et al.

    Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography

    J. Chromatogr. A

    (2012)
  • P.-J. Chien et al.

    Bio-sniffer (gas-phase biosensor) with secondary alcohol dehydrogenase (S-ADH) for determination of isopropanol in exhaled air as a potential volatile biomarker

    Biosens. Bioelectron.

    (2017)
  • C. Berchtold et al.

    Evaluation of extractive electrospray ionization and atmospheric pressure chemical ionization for the detection of narcotics in breath

    Int. J. Mass Spectrom.

    (2011)
  • B. Bojko et al.

    Solid-phase microextraction in metabolomics

    TrAC, Trends Anal. Chem.

    (2014)
  • S. Khatib et al.

    Analysis of volatile organic compounds in rats with dopaminergic lesion: possible application for early detection of parkinson's disease

    Neurochem. Int.

    (2014)
  • K. Kami et al.

    Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry

    Metabolomics

    (2013)
  • K. Gross et al.

    Cell fate decisions during breast cancer development

    J. Dev. Biol.

    (2016)
  • P.J. Mazzone

    Exhaled breath volatile organic compound biomarkers in lung cancer

    J. Breath. Res.

    (2012)
  • C.L. Sawyers et al.

    Aacr cancer progress report 2013

    Clin. Cancer. Res.

    (2013)
  • O.L. Gobbo et al.

    Magnetic nanoparticles in cancer theranostics

    Theranostics

    (2015)
  • C.L. Arteaga et al.

    Aacr cancer progress report 2014

    Clin. Cancer. Res.

    (2014)
  • M. Orecchioni et al.

    Graphene as cancer theranostic tool: progress and future challenges

    Theranostics

    (2015)
  • A. Jemal et al.

    Global cancer statistics

    CA Cancer J. Clin.

    (2011)
  • A. Amann et al.

    Lung cancer biomarkers in exhaled breath

    Expert Rev. Mol. diagn.

    (2011)
  • I. Taivans et al.

    Breath testing as a method for detecting lung cancer

    Expert Rev. Anticancer Ther.

    (2014)
  • R. Gasparri et al.

    Volatile signature for the early diagnosis of lung cancer

    J. Breath. Res.

    (2016)
  • A. Ulanowska et al.

    Chemotherapy control by breath profile with application of SPME-GC/MS method

    J. Sep. Sci.

    (2012)
  • L. Gao et al.

    Metabolic profiling of plasma from benign and malignant pulmonary nodules patients using mass spectrometry-based metabolomics

    Metabolites

    (2013)
  • A.K. Omeri et al.

    Comparison of high-resolution computed tomography findings between pseudomonas aeruginosa pneumonia and cytomegalovirus pneumonia

    Eur. Radiol.

    (2014)
  • S.A. Kovalchik et al.

    Targeting of low-dose ct screening according to the risk of lung-cancer death

    New Engl. J. Med.

    (2013)
  • R.P. Morton et al.

    Low-dose head computed tomography in children: a single institutional experience in pediatric radiation risk reduction

    J. Neurosurg. Pediatr.

    (2013)
  • C.-C. Chang et al.

    Tumour and lymph node uptakes on dual-phased 2-deoxy-2-[18f]fluoro-d-glucose positron emission tomography/computed tomography correlate with prognostic parameters in breast cancer

    J. Int. Med. Res.

    (2014)
  • Cited by (90)

    View all citing articles on Scopus

    Jiemin Zhou obtained her MD in Clinical Medicine from Nanjing Medical University in 2011, and completed her residency at People's Hospital of Jiangsu Province, Nanjing, China, in 2012. Currently, Dr. Zhou is an MSc student in the Faculty of Pharmaceutical Sciences at the University of British Columbia, Vancouver, BC, Canada.

    Zi-Ao Huang obtained his BSc and MSc (under the supervision of Prof. Haiping Xia) in Chemistry from Xiamen University in 2013 and 2016, respectively. He is currently a PhD student in the Department of Chemistry of the University of British Columbia.

    Ujendra Kumar: received his Ph.D. in Zoology from University of Jodhpur, India. He is presently a Professor in the Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada. His research interests focus on structure, function and regulation of somatostatin receptors in neurodegenerative diseases and cancer biology.

    David Da Yong Chen received his BSc from Xiamen University, China, and Ph.D. in Chemistry from University of Alberta. After a short stint as a Postdoctoral Fellow in Chemistry and the Department of Medical Microbiology and Infectious Diseases, University of Alberta, he joined the faculty in the Chemistry Department at the University of British Columbia in July 1994. Dr. Chen is currently a full professor of Chemistry, faculty of Science, as well as an Associate Member of the UBC Department of Anesthesiology, Pharmacology & Therapeutics in the Faculty of Medicine, UBC. He is the recipient of the 2002 Royal Society of Chemistry (RSC) Award in Analytical Separation Methods, and the Charles McDowell Award for Excellence in Research in 2003, a gold medal given to the most outstanding young scientist at UBC. For his contribution in analytical chemistry, Dr. Chen was awarded the W. A. E. McBryde Medal and the Maxxam Award by the Canadian Society for Chemistry in 2008 and 2015, respectively.

    1

    These two authors contributed equally to this paper.

    View full text