Serum Metabolomic Profiles Associated with Psychoneurological Symptoms in Women with Early-Stage Breast Cancer Over One Year

Abstract

Background: Breast cancer survivors frequently experience psychoneurological symptoms (PNS), such as pain, fatigue, anxiety, depression, and sleep disturbances, that persist beyond treatment and impair quality of life. Inflammatory and metabolic dysregulation, including alterations in the tryptophan/kynurenine pathway, have been implicated, yet longitudinal data and racial differences remain understudied. This study examined the longitudinal association between metabolite levels and PNS severity over time and explored their interactions with race. Methods: We performed untargeted serum metabolomic profiling and applied generalized estimating equations (GEE), adjusting for demographic covariates. Interaction terms were included to evaluate race-specific metabolite associations. Metabolite set enrichment analysis was conducted to identify impacted metabolic super-pathways using MetaboAnalyst 6.0. Results: Among 74 participants, 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 (β=-2.40, p=5.79×10-6) and 1-pyrrolidinecarboxaldehyde (β=-0.753, p=8.61×10-6), while sleep disturbance associated with 4,6-O-ethylidene-D-glucose (β=9.83, p=4.82×10-6) and 5-hydroxytryptophol (β=7.82, p=5.55×10-4). Fatigue showed the most associations, including 3-hydroxystachydrine (β=1.02, p=3.79×10-8) and N-acetylglycine (β=0.927, p=5.89×10-5), and pain were associated with inulin (β=-3.19, p=5.39×10-5). Race-metabolite interactions revealed unique patterns for Black women, particularly for sleep disturbances, pain and fatigue. Taurine/hypotaurine and cysteine metabolism were the most impacted pathways in the enrichment analysis. Conclusions: These findings highlight distinct metabolite profiles underlying PNS and suggest that sulfur amino acid- and oxidative stress-related pathways may contribute to symptom variability. Specific metabolites may reflect underlying metabolic pathway differences across racial groups. These results provide a foundation for future mechanistic studies and metabolically targeted interventions in cancer survivorship.