Abstract
Background/Objectives: Breast cancer is the most common malignancy among women, and early detection is critical for improving outcomes. The Breast Imaging Reporting and Data System (BI-RADS) standardizes reporting, but the BI-RADS 4 category presents a major challenge, with malignancy risk ranging from 2% to 95%. Consequently, most women in this category undergo biopsies that ultimately prove unnecessary. This study evaluated whether exhaled breath analysis could distinguish malignant from benign findings in BI-RADS 4 patients. Methods: Participants referred to the McGill University Health Centre Breast Center with BI-RADS 3-5 findings provided multiple breath specimens. Breathprints were captured using an electronic nose (eNose) powered breathalyzer, and diagnoses were confirmed by imaging and pathology. An autoencoder-based model fused the breath data with BI-RADS scores to predict malignancy. Model performance was assessed using repeated cross-validation with ensemble voting, prioritizing sensitivity to minimize false negatives. Results: The breath specimens of eighty-five participants, including sixty-eight patients with biopsy-confirmed benign lesions and seventeen patients with biopsy-confirmed breast cancer within the BI-RADS 4 cohort were analyzed. The model achieved a mean sensitivity of 88%, specificity of 75%, and a negative predictive value (NPV) of 97%. Results were consistent across BI-RADS 4 subcategories, with particularly strong sensitivity in higher-risk groups. Conclusions: This proof-of-concept study shows that exhaled breath analysis can reliably differentiate malignant from benign findings in BI-RADS 4 patients. With its high negative predictive value, this approach may serve as a non-invasive rule-out tool to reduce unnecessary biopsies, lessen patient burden, and improve diagnostic decision-making. Larger, multi-center studies are warranted.