(1) Background: Colorectal cancer is one of the leading causes of cancer-related death, while early detection decreases incidence and mortality. Current screening programs involving fecal immunological testing and colonoscopy commonly bring about unnecessary colonoscopies, which adds burden to healthcare systems. The objective of this study was to provide an assessment of the diagnostic performance of an electronic nose serving as a complementary screening tool to improve current screening programs in clinical settings. (2) Methods: We conducted a case–control study that included patients from a medical center with colorectal cancer and non-colorectal cancer controls. We analyzed the composition of volatile organic compounds in their exhaled breath using the electronic nose. We then used machine learning algorithms to develop predictive models and provided the estimated accuracy and reliability of the breath testing. (3) Results: We enrolled 77 patients, with 40 cases and 37 controls. The area under the curve, Kappa coefficient, sensitivity, and specificity of the selected model were 0.87 (95% CI 0.76–0.95), 0.66 (95% CI 0.49–0.83), 0.81, and 0.85. For subjects at an early stage of disease, the sensitivity and specificity were 0.90 and 0.85. Excluding smokers, the sensitivity and specificity were 0.88 and 0.92. (4) Conclusions: This study highlights the promising potential of breath testing using an electronic nose for enabling early detection and reducing unnecessary treatments. However, more independent data for external validation are required to ensure applicability and generalizability.
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