| Sumario: | Background & Significance: Advances in early detection and treatment have substantially improved survival in breast cancer survivors (BCS). However, across the cancer treatment trajectory and into longterm survivorship, 40% to 90% of women report a clinically meaningful burden of psychoneurological symptoms (PNS). Breast cancer survivors frequently experience PNS, such as pain, fatigue, anxiety, depression, and sleep disturbances, that persist beyond treatment and impair quality of life. Although the relationship between inflammatory perturbations and PNS is understood, the composition of biochemical mediators has not yet been clearly identified, nor has the involvement of other metabolites and metabolic pathways been elucidated. Purpose: The purpose of this study was to examine the longitudinal association between metabolite levels and PNS severity over one year. Methods: In this secondary analysis of a longitudinal, prospective study, PNS were assessed using the Brief Pain Inventory, General Sleep Disturbance Scale, Brief Fatigue Inventory, and Hospital Anxiety and Depression Scale. Untargeted metabolomics analysis was performed on blood serum samples using ultra high-performance liquid chromatography coupled with mass spectrometry. Data were collected at baseline, mid-point of chemotherapy, and at 6 and 12 months after initiating chemotherapy. Generalized estimating equations models were applied, adjusting for demographic covariates. Metabolite set enrichment analysis was conducted using MetaboAnalyst 6.0 to identify impacted metabolic super-pathways. Findings and Interpretations: Among the 74 participants (mean age = 51.3 years), most were postmenopausal (56.8%) and obese (BMI = 29.9±7.5 kg/m²), were diagnosed with stage II cancer (62.2%), and received radiation therapy (78.4%). We identified 140 metabolites significantly associated with PNS out of the 2,395 metabolites tested, with 38 named metabolites. Anxiety was associated with 2-aceto-2-hydroxy-butanoate (b=-2.40, p=5.79x10-6) and 1-pyrrolidinecarboxaldehyde (b=-0.753, p=8.61x10-6), while sleep disturbance associated with 4,6-O-ethylidene-D-glucose (b=9.83, p=4.82x10-6) and 5-hydroxytryptophol (b=7.82, p=5.55x10-4). Fatigue showed the most associations, including 3-hydroxystachydrine (b=1.02, p=3.79x10- 8) and N-acetylglycine (b=0.927, p=5.89x10-5), and pain were associated with inulin (b=-3.19, p=5.39x10- 5). Taurine/hypotaurine and cysteine metabolism were the most impacted pathways in the enrichment analysis. Discussion: These findings highlight distinct metabolite profiles underlying PNS and suggest that sulfur amino acid- and oxidative stress-related pathways may contribute to symptom variability. Future work should prioritize longitudinal and mechanistic studies to validate these metabolic signatures across survivorship trajectories and explore whether targeted metabolic or lifestyle interventions may alleviate symptom burden.
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