R de Vries1, M Muller2, V van der Noort3, W S M E Theelen4, R D Schouten4, K Hummelink5, S H Muller6, M Wolf-Lansdorf4, J W F Dagelet7, K Monkhorst8, A H Maitland-van der Zee7, P Baas4, P J Sterk7, M M van den Heuvel9. 1. Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands; Breathomix B.V., Reeuwijk, The Netherlands. Electronic address: rianne.devries@amc.nl. 2. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: m.muller@nki.nl. 3. Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 5. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 6. Department of Clinical Physics and Instrumentation, Netherlands Cancer Institute, Amsterdam, The Netherlands. 7. Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands. 8. Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 9. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Respiratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Abstract
BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients. METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96). CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.
BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLCpatients. METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLCpatients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 143 NSCLCpatients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96). CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.
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