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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 numerous mass 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, and which 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 be more fully appreciated and taken forward.
A major concern we have is that Phillips et al refer to MAGIIC 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 a mass spectrum, and hence it cannot be referred to as biomarker. This single m/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 single m/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 the m/z value, but a review of the electron impact mass spectra of these eight compounds suggest it could be m/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 ion', to have the same or very similar retention times. And hence a better identification of the compound(s) should have been possible. That this has not been done, raises serious concerns about the quality of the calibration (or lack of) undertaken, which would result in unreliable identification of the volatiles and lead to too much speculation in the paper.
We suggest that without any chemical structure elucidation, an identification of any biomarker(s) is inappropriate. It needs to be ascertained what volatile or volatiles are contributing to the 'mass ion' before any suggestion of a biomarker is given. Until then it is too speculative to claim that the biomarker is a product of oxidative stress.
It is claimed that the MAGIIC biomarker, possibly composed of up to eight VOCs, is generated exclusively from the lung cancer nodules by oxidative stress. However, it cannot be ruled out that these VOCs are not generated by oxidative stress in cancer cells from other organs (breast, liver, pancreas, gastrointestinal, testicular, skin, head and neck etc) or by oxidative stress in distressed/inflamed cells/tissues due to other concomitant diseases like COPD, pneumonia, arthritis etc, or surgical procedures such as organ transplant etc. This needs to be further investigated before any volatile can be assigned as a unique biomarker for lung cancer.
With regards to 'suspicious pulmonary modules', it is not specified in the paper just what a suspicious nodule is. However, to be of use MAGIIC should be able to differentiate between benign and malignant lesions for those indeterminate solitary pulmonary nodules revealed at CT screening for lung cancer. There is no evidence to suggest that this is the case with the use of 'MAGIIC'.
In summary, the recent interesting paper by Phillips et al highlights the importance of a clinical breath test for lung cancer, and has provided an interesting finding that needs to be checked. However, we have raised several misgivings on the work presented; namely whether the so-called mass ion 'biomarker' (MAGIIC) can predict cancer in an indeterminate nodule population and whether the origins of the VOCs present in exhaled breath of lung cancer patients caused by oxidative stress can conclusively be proven with high specificity. We submit that there is a need to delineate the chemical structure of the volatiles in the exhaled breath of lung cancer patients, otherwise the work presented is too speculative. More information is required to identify the volatile resulting in the 'mass ion', which then needs to be validated by an independent study. If these issues cannot be addressed, then the proposed screening diagnostic test of using MAGIIC does not meet the basic criteria of being able to discriminate between lung cancer from any other affliction in the human body.