BackgroundPatients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD.Research QuestionCan eNose technology be used for prospective detection of early lung cancer in patients with COPD?Study Design and MethodsBreathCloud is a real-world multicenter, prospective, follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis.ResultsExhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. PCs 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve (AUCs) of 0.89 (CI, 0.83-0.95) and 0.86 (CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and AUC of 0.90 (CI, 0.84-0.95).InterpretationExhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD. Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD. Can eNose technology be used for prospective detection of early lung cancer in patients with COPD? BreathCloud is a real-world multicenter, prospective, follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis. Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. PCs 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve (AUCs) of 0.89 (CI, 0.83-0.95) and 0.86 (CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and AUC of 0.90 (CI, 0.84-0.95). Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD. Take-home PointsStudy Question: Can electronic nose (eNose) technology be used for prospective detection of early lung cancer in patients with COPD?Results: The eNose was able to discriminate patients with COPD who subsequently received a lung cancer diagnosis from those who did not receive such a diagnosis with 87% accuracy, an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95), 86% sensitivity, and 89% specificity.Interpretation: These results show that eNose assessment may detect early stages of lung cancer in patients with COPD and therefore may be of value in screening this risk group. Study Question: Can electronic nose (eNose) technology be used for prospective detection of early lung cancer in patients with COPD? Results: The eNose was able to discriminate patients with COPD who subsequently received a lung cancer diagnosis from those who did not receive such a diagnosis with 87% accuracy, an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95), 86% sensitivity, and 89% specificity. Interpretation: These results show that eNose assessment may detect early stages of lung cancer in patients with COPD and therefore may be of value in screening this risk group. Patients with COPD are at higher risk of lung cancer developing, with studies showing a relative risk of twofold to fourfold compared with the general population.1de Torres J.P. Marín J.M. Casanova C. et al.Lung cancer in patients with chronic obstructive pulmonary disease—incidence and predicting factors.Am J Respir Crit Care Med. 2011; 184: 913-919Crossref PubMed Scopus (225) Google Scholar Although several biomarkers are candidates for lung cancer discovery, such as autoantibodies, complement fragments, microRNA, circulating DNA, DNA methylation, RNA and protein profiling, and metabolomics,2Seijo L.M. Peled N. Ajona D. et al.Biomarkers in lung cancer screening: achievements, promises, and challenges.J Thorac Oncol. 2019; 14: 343-357Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar no validated biomarkers have been discovered yet that can identify patients with COPD who are at a higher risk of lung cancer developing. During the past decade, screening studies using low-dose CT (LDCT) imaging have shown significant reductions (up to 39% in women) in lung cancer mortality rates among high-risk individuals, who were defined based on tobacco use history (status, pack-years, quit time) and age (50-75 years).3Aberle D.R. Adams A.M. Berg C.D. et al.Reduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (7282) Google Scholar, 4Ru Zhao Y. Xie X. de Koning H.J. Mali W.P. Vliegenthart R. Oudkerk M. NELSON lung cancer screening study.Cancer Imaging. 2011; 11 (spec no A(1a)): S79-S84Crossref PubMed Scopus (145) Google Scholar, 5de Koning H.J. van der Aalst C.M. de Jong P.A. et al.Reduced lung-cancer mortality with volume CT screening in a randomized trial.N Engl J Med. 2020; 382: 503-513Crossref PubMed Scopus (1347) Google Scholar Interestingly, a recently published study showed that patients with COPD are at higher risk of lung cancer regardless of tobacco use history.6Park H.Y. Kang D. Shin S.H. et al.Chronic obstructive pulmonary disease and lung cancer incidence in never smokers: a cohort study.Thorax. 2020; 75: 506-509Crossref PubMed Scopus (44) Google Scholar Because the of screening be by the risk of to COPD and the inclusion of these patients in lung cancer screening L.M. risk for after lung of a pulmonary an analysis of Med. 2011; PubMed Scopus Google et risk of mortality and for lung cancer Thorac Full Text Full Text PDF PubMed Scopus Google Scholar by imaging and follow-up to patients with C. et in low-dose computed screening for lung Med. PubMed Scopus Google Scholar an for an and that can be at the of a that can the of high-risk for follow-up screening is to in clinical Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for the early detection of lung L.M. Peled N. Ajona D. et al.Biomarkers in lung cancer screening: achievements, promises, and challenges.J Thorac Oncol. 2019; 14: 343-357Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar eNose technology is an that advanced for analysis of the of in exhaled M. et and early diagnosis of lung Thorac Oncol. Full Text Full Text PDF PubMed Scopus Google The electronic nose technology in clinical a 2019; PubMed Google Scholar The of in exhaled breath the in the both in the and in and Google Scholar analysis of these for in lung M. et and early diagnosis of lung Thorac Oncol. 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