A prospective observational trial in patients with advanced non-small cell lung cancer (NSCLC) has found that an electronic nose device that detects chemicals in the breath can identify with 85% accuracy those patients who will or will not respond to the latest immunotherapies. Results from the trial, which is published in Annals of Oncology, showed that the eNOSE demonstrated better predictive accuracy than invasive and time-consuming immunohistochemistry (IHC) testing for the PD-L1 biomarker, which is the current gold standard for predicting NSCLC response to anti-PD-1 immunotherapies such as nivolumab or pembrolizumab.

“We found that before the start of treatment with immunotherapy, the eNose analysis of exhaled breath from the patients with non-small cell lung cancer could distinguish between responders and nonresponders with an accuracy of 85%,” said study co-first author Mirte Muller, PhD, from the department of thoracic oncology at the Netherlands Cancer Institute. “eNose technology is cheap compared to other available medical technologies and diagnostic tests and biomarkers. The eNose qualifies as a noninvasive and rapid point-of-care test that provides feedback within seconds in the doctor’s office. Our results form a solid base for taking the next step to validate these findings in a large prospective multi-center study.” The study is described in a paper titled, “Prediction of response to anti-PD-1 therapy in patients with non-small cell lung cancer by electronic nose analysis of exhaled breath.”

Immune checkpoint inhibitors (ICIs) have “dramatically improved” the treatment of advanced NSCLC, the authors wrote, but are only effective in a subset of patients, “which was about 20% when we started the study,” commented Michel van den Heuvel, professor of thoracic oncology at the Radboud University Medical Centre (Nijmegen,The Netherlands), who led the research. “Currently, there is no test available that can accurately predict who will benefit from this treatment, apart from PD-L1 testing by immunohistochemistry. This is today’s biomarker of choice, despite its analytic and predictive limitations, when making clinical decisions about whether or not to treat a patient with immunotherapy.”

One potential alternative to IHC testing is molecular profiling of exhaled air, the authors suggested. The air we breathe out from our lungs contains thousands of volatile organic compounds (VOCs). These VOCs can vary depending on metabolic processes that occur in different parts of the body, such as the lungs. The eNose is a small device comprising sensors that can detect these VOCs in exhaled air. The researchers reasoned that the mix of VOCs in the breath of patients with advanced NSCLC might indicate whether or not the patient would respond to anti-PD1 therapy.

“We hypothesized that exhaled breath analysis using eNose technology might be a noninvasive and rapid alternative to the current standard and would enable doctors to avoid treating patients with an immunotherapy to which they would not respond,” explained co-first study author Rianne de Vries, a PhD student in the department of respiratory medicine at Amsterdam University Medical Centres. de Vries is chief operating officer of Netherlands-based Breathomix, which is developing the eNose device.

This is the eNose device. [Amsterdam University Medical Centers]
“When using the eNose, the patient takes a deep breath, holds it for five seconds, and then slowly exhales into the device,” de Vries explained. “The eNose sensors respond to the complete mixture of VOCs in the exhaled breath; each sensor has its highest sensitivity to a different group of molecules. The sensor readings are sent directly to and stored at an online server for real-time processing of the data and for ambient air correction because the air that you exhale is influenced by the air that you inhale. The measurement takes less than a minute, and the results are compared to an online database where machine-learning algorithms immediately identify whether or not the patient is likely to respond to anti-PD1 therapy.”

For their eNose trial the Netherlands Cancer Institute researchers recruited 143 patients with advanced NSCLC, between March 2016 and February 2018. The eNose device was used to take the breath profiles of the patients two weeks before they started treatment with nivolumab or pembrolizumab. After three months standard criteria (Response Evaluation Criteria of Solid Tumours, RECIST) were applied to assess whether or not each patient was responding to the treatment. Results from the first 92 patients (the training set), who started treatment between March 2016 and February 2017, were validated by the results from the same tests on the remaining 51 patients *te validation set, who started treatment after April 2017.

The overall findings indicated that eNose demonstrated 85% accuracy in predicting response to the immunotherapies. “Our findings show that breath analysis by eNose can potentially avoid application of ineffective treatment to patients that are identified by eNose as being nonresponders to immunotherapy, which in our study was 24% of the patients,” Muller added. “This means that in 24% of NSCLC patients this treatment could be avoided, without denying anyone effective treatment.” The results also found that “in comparison with the currently used biomarker the eNose outperforms PD-L1 in all areas,” the investigators stated.

Although immunotherapy tends to have fewer side effects than chemotherapy—fatigue is the most common—it can trigger more serious side effects in about 10% of patients. These include inflammation of organs such as the lungs, liver, and bowel, when the body’s immune system starts to attack its own cells. Identifying who will not respond to immunotherapy means that patients could be spared potential side effects.

van den Heuvel concluded, “We are convinced that this study merely scratches the surface. It represents the first introduction of modern precision medicine, namely that molecular fingerprints can be easily obtained and quickly analyzed on the spot. This truly offers new possibilities for the individual patient and the doctor. The power of this eNose system is that it has been properly validated, both technically and clinically, which is essential. We believe that analysis of exhaled breath is going to become an important diagnostic tool and will guide future treatment in oncology as well as in many other diseases.”

The reported study is the first, to the authors’ knowledge, that has used an eNose to identify responsiveness to anti-PD-1 therapy. “Our study extends the work of Shlomi et al., who were able to discriminate between patients with lung cancer that harbor the EGFR mutation from those with wild-type EGFR using eNose technology,” they wrote. “ … we have recently shown that exhaled breath analysis allows clinical and inflammatory phenotyping of chronic airway diseases at the point-of-care and may therefore facilitate personalized anti-inflammatory strategies … Given the clinically applicable technology, the present data may qualify  breath assessment as a real-time tool for stratification of patients with NSCLC.”

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