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Breath analysis identified malignant pulmonary nodules
Breath analysis distinguished benign pulmonary nodules from malignant nodules in a high-risk cohort based on lung cancer-related volatile organic compound profiles, according to study results.
In addition, the breath analysis differentiated adenocarcinoma from squamous cell carcinoma, and it also distinguished between early vs. advanced disease.
“Low-dose computed tomography (LDCT) screening programs for lung cancer are expected to be launched in many countries in the near future,” Nir Peled, MD, PhD, of the Thoracic Cancer Research and Detection Center at Sheba Medical Center, affiliated with Tel Aviv University in Israel, and colleagues wrote. “A dramatic increase in the detection of pulmonary nodules should be anticipated, and accordingly, a dramatic increase in invasive procedures, in the related morbidity, and the health care costs.”
A complementary biomarker assay technique that distinguishes benign from malignant nodules in a noninvasive, cost-effective manner is needed to minimize the false-positive rate in future LDCT screening programs, Peled and colleagues wrote.
In previous studies, exhaled volatile organic compounds — emitted from the membrane of the cancer cells and/or from the surrounding microenvironment to the bloodstream — have been reported as possible lung cancer biomarkers. In addition, earlier studies demonstrated that the breath volatile organic compound profiles of patients with lung cancer differ from those of healthy people.
To compare the profiles of benign vs. malignant pulmonary nodules, the researchers used gas chromatography with mass spectrometry and information from chemical nanoarrays to assess the profiles of 72 patients. This specific technique permitted the classification and quantification of a variety of separate breath volatile organic compounds, whereas the cross-reactive chemical nanoarray provided an accessible and inexpensive diagnostic tool.
All patients underwent clinical investigation, including wedge resection, bronchoscopy and/or lobectomy. Patients without a definitive histologic diagnosis were followed by serial CT imaging.
In the study, alveolar exhaled breath was collected in chemically inert Mylar bags after a 3-minute procedure of lung washout, designed to avoid ambient contaminants and nasal entrainment of gas from entering the sampling bags. Each participant provided breath of at least one Mylar bag of 750 mL.
Researchers using the gas chromatography/mass spectrometry analysis identified a significantly higher concentration of 1-octene in the breath of patients with lung cancer, according to study results. In addition, the nanoarray differentiated significantly between benign vs. malignant pulmonary nodules (P<.0001; accuracy 88 ± 3%), between adenocarcinoma and squamous cell carcinomas (P<.0001; 88 ± 3%) and between early-stage and advanced disease (P<.0001; 88 ± 2%).
“This study offers an inexpensive and portable tool to further improve the noninvasive-biomarker-based investigation of patients who are not candidates for invasive procedures or in cases where the tissue is hard to sample,” Peled and colleagues wrote. “More specifically, breath analysis with nanoarray could serve as a primary and/or a secondary screener for pulmonary nodules-positive patients after LDCT, and might avoid delay in performing an invasive investigation when cancer is suspected, rather than proceeding with follow-up imaging.”
The researchers identified 53 pulmonary nodules as malignant and 19 as benign with similar smoking histories and comorbidities. Nodule size (mean ± SD) was 2.7 ± 1.7 cm in malignant nodules vs. 1.6 ± 1.3 cm (P=.004) in benign nodules. Within the malignant group, 47 were non–small cell lung cancer and six were small cell lung cancer. Thirty patients exhibited early-stage disease and 23 had advanced disease.
“The reported breath test in this study could have significant impact on reducing unnecessary investigation and reducing the risk of procedure-related morbidity and costs,” Peled and colleagues wrote. “In addition, it could facilitate faster therapeutic intervention, replacing time-consuming clinical follow-up that would eventually lead to the same intervention. Further studies using a larger cohort of patients are under way and will be published elsewhere.”
Perspective
Back to TopInvestigators continue to search for noninvasive modalities for the detection of lung cancer. If successful, such methods could be used as both a tool for diagnosis and surveillance in lung cancer. With the recent discovery that early detection using low-dose CT scans improves patient survival, it has become increasingly important that clinicians be able to identify high-risk patients who require additional, often invasive, diagnostics. Thus, strategies that can complement CT scanning are of particular clinical value.
In this manuscript, Peled and colleagues present breath analysis as a potential noninvasive modality for distinguishing malignant from benign pulmonary nodules. The examination of volatile organic compounds for diagnosis in lung cancer is not necessarily a new concept; however, it has yet to become standard in clinical practice. Here, the authors examined breath from 72 patients using two separate modalities: gas chromatography/mass spectrometry (GC/MS) and a chemical nanoarray. One volatile organic compound identified by GC/MS appeared to distinguish malignant from benign pulmonary nodules. The nanoarray distinguished malignant from benign, adenocarcinoma from squamous cell subtype and early vs. advanced stage lung cancer.
The findings of the study provide additional support for breath analyses as a viable method for lung cancer detection. However, as the authors correctly point out, execution and interpretation of these assays are both costly and time consuming, thus limiting their immediate broad application. In addition, patient numbers for such studies remain low, requiring validation in much larger cohorts. Lastly, it will be essential that breath analyses continue to be validated, particularly among patients with smaller lung nodules (eg, 0.8 cm-2 cm) in whom surveillance imaging and invasive testing are both costly and carry morbidity. Nevertheless, breath biomarkers in lung cancer represent an exciting area of investigation, which if successful could impact how clinicians approach both diagnosis and surveillance in lung cancer.
Perspective
Back to Top
Lung nodules are an extraordinarily common problem in current practice because, in some areas of the country, more than half of people receiving a CT scan will have some abnormality classified as a nodule. Most of these findings are, in fact, benign/harmless scars and require no treatment at all, but they can be difficult to distinguish from malignant nodules, particularly when they are small.
This study adds an exciting new angle to a rapidly changing field of early detection of lung cancer. Tests that are noninvasive and capable of accurately distinguishing benign from malignant nodules would be a powerful and widely used tool for doctors seeing patients with lung nodules. The need for accuracy cannot be overstated though. It is critical for patients and doctors to understand how a test ‘performs,’ meaning that some tests will be negative when the disease is present, and sometimes a positive test occurs in individuals without the disease for which they are being tested.
Perspective
Back to TopThe management of pulmonary nodules represents a clinical challenge, and one that historically has involved careful monitoring. While this has proven to be reasonable for clinicians, it often evokes anxiety/unease among patients who must wait to return for repeated evaluations of nodules, which most often are benign.
The paper by Peled et al suggests that it may be possible to use expired breath samples to classify some of these lung nodules as malignant or benign. However, this finding is not yet ready for immediate application in the clinic. The diagnosis of lung cancer still requires a tissue sample, and that biopsy is often used to test for the presence of specific genetic mutations to guide the choice of chemotherapy agents. Also, the size of the pulmonary nodules in the study by Peled tended to be large and worrisome for malignancy — in fact, 53 of 72 of these large lung nodules were cancers.
We typically see pulmonary nodules when they are much smaller, generally less than 1 cm, and it remains to be determined whether or not breath samples will be able to shed light on how to manage these smaller lung nodules. Until those studies are completed, we will continue to track changes in these smaller lung nodules with close monitoring via chest CT examinations.