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Expert CritiqueFROM THE ASCO Reading Room
Multiple research studies are underway. As proof of principle for monitoring, exhaled breath samples analyzed by chromatographic and mass spectrometric studies do identify multiple specific volatile organic compounds (VOCs), of which a few (Styrene in particular) were indicative of tumor response to chemotherapy or targeted therapy. There was 85% concordance with traditional imaging modalities (employing RECIST).
For screening purposes, the same exhaled breath analyses do indicate a specific VOC pattern per sample, showing some success in identifying the presence of a malignant process as well as with lesser success, the histology of lung cancer. Especially intriguing is the development of devices such as the so-called "electronic nose," made up of a quartz array of gas sensors, which can enable testing in a clinical environment. It is difficult to imagine clinical implementation any time soon at this point. Surely, a sign of things to come, but for now it remains an interesting concept still to be clinically validated.
The Response Evaluation Criteria in Solid Tumors (RECIST) is the current gold standard for monitoring treatment efficacy in lung cancer and other "solid tumors," but the question has been raised about whether the tool is simply too time-consuming. Proponents of a breath-based method for tracking the diagnosis and course of treatment in lung cancer say they think that is the case.
"The time intervals between consecutive computerized tomography [CT] scans [with RECIST] might be too long to allow early identification of treatment failure," Inbar Nardi-Agmon, MD, of Sheba Medical Center in Tel Aviv, and colleagues, wrote in the Journal of Thoracic Oncology. "Breath analysis ... as a monitoring tool ... can provide the oncologist with a quick bedside method of identifying a lack of response to an anticancer treatment."
The researchers put their theory to the test by analyzing 143 breath-exhaled breath samples from 39 patients with advanced lung cancer, using gas chromatography-mass spectrometry (GC-MS) to identify the composition and seek specific volatile organic compounds (VOCs). A nanomaterial-based sensor array was then used to analyze the breath samples. This array contained 40 cross-reactive, chemically diverse chemi-resistors that responded to VOCs in the patients' breath.
The patients also underwent periodic CT scans to evaluate their response to treatment, and RECIST served as the standard to monitor treatment efficacy. The study was a follow-up of preliminary results presented at the 2014 American Society of Clinical Oncology meeting.
Most of the patients in the new study (85%) had non-small cell lung cancer with different histological diagnoses, and all had a primary tumor in their lungs at the time of enrollment.
Approximately 82% of the patients received first-line chemotherapy, with the remainder undergoing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase tyrosine kinase tyrosine-inhibitor (TKI) therapy. Breath samples were taken, on average, a little over every 6 weeks.
Three VOC biomarkers were identified by the researchers as indicative of treatment response:
- Dodecan, 4-methyl;
"Styrene appears to be the most interesting VOC in our study, being the only one that showed significant changes in concentration in both comparisons (baseline sample versus disease control samples and disease control versus progressive disease samples)," Nardi-Agmon et al noted.
There was 85% success in monitoring disease control (stable disease/partial response). For the cases wrongly identified, the researchers noted that some in that group may have been categorized incorrectly at initial assessment or the time interval between sampling may have been too long.
"This study indicates that exhaled breath analysis may serve as a simple, user-friendly method of monitoring response to systemic therapy in lung cancer," they wrote. "The particular importance is the potential to recognize failure very early in the course of therapy, before it becomes manifest by routine imaging schedules. This may help the physician to make better, more up-to-date, rational decisions regarding the cancer treatment selected for each patient."
However, they also acknowledged that they had a small sample size. In addition, no specific VOC markers for lung cancer have been defined.
But not having these markers may not be such a problem, according to Italian researchers.
Rosamaria Capuano, of the University of Rome Tor Vergata, and colleagues noted in a 2015 study that "the disease alters the concentration of a manifold of compounds, modifying the overall chemical composition of the breath."
The group collected the breath and air inside both lungs, using a modified bronchoscopic probe, of 30 patients -- 20 who had been diagnosed with lung cancer and the remainder with lung ailments. The team examined the samples with GC-MS and a device called an "electronic nose," which is an ensemble of 8 quartz microbalance gas sensors.
The control group of non-cancer individuals were found to be affected by various pathologies that required an endoscopic lung exam. The lung cancers were mixed between adenocarcinomas and squamous cancer cells.
A total of 17 compounds were identified as related to lung cancer by comparison with existing mass spectral libraries. "These compounds are plausible components of breath, and some of them have been found as characteristic VOCs in lung cancer," the authors noted.
They found that the lung cancer identification properties of the electronic nose did not depend on the lung from which a sample is collected, but that GC-MS analysis showed that a small difference between the two lungs can exist.
"These data indicate that a certain difference between the lungs exists, and thus a minor portion of VOCs is directly exhaled from the cells in the breath."
They observed that this quantity is too tiny to give rise to a complete discrimination by GC-MS and to be captured by the sensors of the electronic nose.
The electronic nose results showed a 93% correct classification rate via a partial least squares discriminant analysis of the data (PLS-DA) related to mixed-expired breath in the lung cancer group and 96% in the noncancer group.
The researchers reported that the application of PLS-DA only to the cancer data did not obtain more than 56% correct classification between adenocarcinomas and squamous cancer cells. According to the authors, the difference in VOCs between adenocarcinomas and squamous cancer cells is smaller than the resolution of the electronic nose's sensors.
Analysis of air captured in the lungs and exhaled breath found a substantial preservation of VOCs, but that the dilution pattern is not the same for all compounds. "This leads to a distortion of the pattern that could be important for electronic nose sensors, whose signal depends on the VOCs pattern," the authors stated.
Air sampling preservation technology was listed as a possible limitation of the study, but the best available techniques to mitigate temperature and humidity differentials were used by the researchers.
The authors said their work confirms the power of breath analysis in signaling lung cancer, but it also "suggests that cancer-related VOCs may likely be non-specific for a given kind of cancer, but they may be rather indicative of cancer diseases occurring in some non-identified body compartment."
Standardized Breath Collection
Of course, results from two studies, no matter how positive, will not topple RECIST any time soon. In order for breath analysis to be ready for prime-time, "larger studies should be implemented in true screening settings, paying particular attention to standardization in breath collection, consideration of covariates, and validation in independent population samples," advised Agne Krilaviciute, of the German Cancer Research Center in Heidelberg, and colleagues.
In a review article, Krilaviciute et al analyzed results from 73 studies of exhaled breath analysis for cancer detection using standard analysis techniques and the electronic nose. Among those studies, two-thirds were performed in lung cancer. The team pointed out that good discrimination required a combination of multiple biomarkers, and that the area under the receiver operating characteristic curve or accuracy reached levels of 0.9 or higher in multiple studies. But "huge variability" was also found among the studies.
Still, the researchers declared breath analysis to be "a young field of research with great potential in cancer screening, and that with further advancements in the area, breath test may have the potential to become a useful supplement and improve existing screening tools for a variety of cancers."