Early Postoperative Remodeling of the Exhaled Volatilome Following Curative Surgery for Colorectal Cancer

Background: Exhaled volatile organic compounds (VOCs) may provide a non-invasive readout of biological changes in colorectal cancer (CRC). We characterized early postoperative changes in the exhaled volatilome after curative CRC surgery and explored a multivariable VOC signature associated with clinical state. Methods: In this prospective paired pilot study, breath samples were obtained from 38 patients before surgery (Before) and on postoperative day 10 (After) and from 44 healthy controls (Control). Proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) identified 61 informative volatile organic compound (VOC) features. Elastic Net-based stability selection with 1000 patient-grouped resampling iterations yielded a 16-feature panel. Pairwise univariate comparisons were performed with Benjamini–Hochberg false discovery rate (FDR) correction. Results: Five selected VOC features differed significantly between paired preoperative and postoperative samples. Two features (mass-to-charge ratio [m/z] 77.0576 and 103.074) no longer differed significantly from healthy controls postoperatively, whereas three (m/z 63.0157, 95.0534, and 101.05) remained significantly different. The highest discriminative performance was observed for After vs. Control (median ROC AUC = 0.811 [95% PR, 0.691–0.912]), followed by Before vs. Control (0.762 [0.629–0.869]) and Before vs. After (0.716 [0.567–0.823]). Conclusions: Measurable changes in the exhaled volatilome were observed on postoperative day 10 following curative colorectal cancer surgery, with heterogeneous patterns across individual VOC features and persistent differences from healthy controls. These findings should be interpreted as early postoperative volatilome remodeling rather than as evidence of tumor-specific metabolic normalization because the observed changes may reflect the combined influence of surgical trauma, postoperative recovery, and other biological and perioperative processes. The identified 16-feature multivariable VOC signature should therefore be regarded as exploratory and requires independent external validation. Further studies incorporating larger multicenter cohorts, serial sampling beyond the early postoperative period, appropriate non-oncological surgical control groups, and orthogonal chemical identification are required to determine the potential clinical relevance of longitudinal VOC patterns.