Exploratory Plasma Metabolomic Analysis of Aerobic Exercise-Associated Responses During Anthracycline-Based Chemotherapy in Patients with Breast Cancer: A Randomized Controlled Trial

Background/Objectives: Anthracycline-based chemotherapy is associated with systemic toxicities in patients with breast cancer. Aerobic exercise may help mitigate treatment-related effects, but its associated metabolic responses during chemotherapy remain poorly understood. This study assessed biochemical and circulating metabolomic responses to aerobic exercise during anthracycline-based chemotherapy. Methods: This exploratory secondary analysis included 40 participants from a randomized controlled trial (trained n = 21; control, n = 19). Participants in the trained group completed a 12-week aerobic exercise intervention during chemotherapy. Biochemical markers and untargeted plasma LC–MS metabolomic profiles were assessed before and after intervention. Exploratory metabolic candidates were evaluated using linear mixed-effects models with Benjamini–Hochberg correction. Results: Significant Group × Time interactions were observed for 10 of 12 physiological and biochemical markers after BH-FDR correction in the primary analysis. However, baseline-adjusted ANCOVA sensitivity analyses showed that only IL-6 retained statistical significance after BH-FDR correction (adjusted between-group difference: −15.58 pg/mL, 95% CI: −20.72 to −10.45; FDR < 0.001). Despite limited global metabolomic separation, sequential screening identified 26 candidate features, seven of which showed significant Group × Time interactions after correction across candidates. Five had putative annotations, including lysophosphatidylcholine (LPC) 14:1, lysophosphatidylethanolamine (LPE) 17:1, cis-7-hexadecenoic acid, L-ascorbate, and vitamin E acetate. In a full-feature sensitivity analysis, only Com_3317_pos remained significant after BH-FDR correction across all 1150 metabolic features (FDR = 0.0228). Conclusions: Aerobic exercise during anthracycline-based chemotherapy was associated with changes in circulating biochemical markers, although these findings were less robust after baseline adjustment. Untargeted metabolomics identified exploratory exercise-associated metabolic features, particularly those putatively related to lipid metabolism, but most did not remain significant after full-feature multiple-testing correction. Further validation is warranted.