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Comment on ‘volatile biomarker in breath predicts lung cancer and pulmonary nodules’

The high mortality rate associated with lung cancer is in part a result of the disease being detected in its late stage. This is simply because early stage diagnosis is challenging. There have been numerousmass spectrometric analysis studies of exhaled breath volatiles spanning decades of research involving lung cancer patients in a bid to discover breath biomarkers of the disease, andwhich hopefully are present from the early stages of the disease. Despite this intense work, no breath test for lung cancer has been forthcoming for clinical use. A major reason for this is that there has been little consensus between studies, with limited agreement as to which breath volatiles (or pattern of volatiles) can be used to discriminate people with lung cancer from those without. Although many breath volatiles have been proposed to result from lung cancer, not a single study, thus far, has specifically pinpointed the origins of the breath volatiles exclusively to lung cancer nodules and not oxidative stress in any other organ resulting from cancer or any other disease. This situation seems to have changed with a recently reported study by Phillips et al. In their study, they claim to have found a ‘mass ion’, which they refer to as a single volatile biomarker in the breath, that is apparently able to identify biopsy-proven lung cancer as well as suspicious pulmonary nodes [1]. They suggest that this ‘biomarker’ has the potential to be used as an ancillary to low-dose computerized tomography of the chest to predict whether a pulmonary nodule is malignant or not. They have named this biomarker ‘Mass Abnormalities in Gaseous Ions with Imaging Correlates’ (MAGIIC). Furthermore, they claim, from blinded studies, that they can predict lung cancer, which was confirmed by the independent tissue biopsies, and suspicious pulmonary nodules. Given the potential importance of the findings presented in their paper, we wish to raise some questions and issues we have on the key results and conclusions provided in the paper by Phillips et al Our aim for this comment is to open a forum for discussion in order to help clarify some important issues so that this work can bemore fully appreciated and taken forward. A major concern we have is that Phillips et al refer toMAGIIC as a single biomarker. However, we would question if this is appropriate terminology to use, because the MAGIIC is simply a mass to charge ratio (m/z) in amass spectrum, and hence it cannot be referred to as biomarker. This singlem/z is not assigned by the authors to any specific volatile, although it is believed to include C4 and C5 alkane derivatives, which are considered to be consistent with metabolic products of oxidative stress. Nevertheless, it is difficult to accept that a singlem/z can be used to provide sufficient specificity to diagnose lung cancer. Such an approach raises concerns of ‘voodoo’ correlations, i.e. where the ‘mass ion’ is statistically significant but is clinically meaningless—something the authors correctly highlight to be a central problem that has limited progress in breath research. To some extent, the authors recognize this by listing in their table 2 eight possible candidate volatile organic compounds (VOCs) that could be the cause of the ‘mass ion’ signal. The authors do not identify them/z value, but a review of the electron impactmass spectra of these eight compounds suggest it could bem/z 44. Independent of this, it is strange to use a m/z value from a GC-MS investigation as a ‘biomarker’. Why is the compound, which could be a biomarker, not correctly identified? Although the researchers admit that the chemical structure of MAGIIC was not determined with any certainty, it is claimed to be consistent with a volatile metabolite of alkane products of oxidative stress. It is highly surprising that the authors were unable to provide any clear identification given that GC was used and given that the ‘mass ion’was identified by not only m/z but also retention time (although neither are given in the paper). This raises doubt in the results presented, because it simply is not possible for all eight compounds, that are potential candidates for the ‘mass RECEIVED 24 July 2019