Serum Metabolites as Predictors of Symptom Burden in Patients with Breast Cancer Undergoing Chemotherapy

Technical Summary: Serum Metabolites as Predictors of Symptom Burden in Patients with Breast Cancer Undergoing Chemotherapy

Problem Statement
Patients with breast cancer undergoing chemotherapy frequently experience a high burden of gastrointestinal (GI) and neuropsychological symptoms, such as nausea, fatigue, and cognitive impairment, which significantly degrade quality of life and may persist into survivorship. While demographic and clinical risk factors (e.g., age, chemotherapy regimen) are known, they fail to fully explain inter-individual variability in symptom severity. Current understanding of the biological mechanisms driving these co-occurring symptoms remains incomplete, particularly regarding metabolic perturbations. Previous pilot work suggested links between lipid/amino acid metabolism and specific symptoms like fatigue and chemotherapy-induced nausea (CIN), but comprehensive longitudinal data across the entire chemotherapy course is lacking. This study addresses the gap in understanding how serum metabolite levels change from pre-chemotherapy through treatment completion and how these changes correlate with symptom occurrence and severity.

Methodology
This descriptive, longitudinal cohort pilot study (n=10) was conducted between July 2024 and March 2025 at Mayo Clinic and the University of Iowa.

• Participants: Adult women (≥21 years) with newly diagnosed stage I–III breast cancer, chemotherapy-naïve, and scheduled to begin treatment. Exclusion criteria included metastatic disease, recent radiation, cognitive impairment, or GI comorbidities.
• Data Collection: Participants completed assessments at four timepoints:
  • T1: 5–7 days before chemotherapy.
  • T2: After the 1st or 2nd cycle.
  • T3: After the 3rd cycle.
  • T4: One month post-completion.
• Measures:
  • Symptoms: Evaluated using the Memorial Symptom Assessment Scale (MSAS) for 12 GI and 11 neuropsychological symptoms (occurrence, severity, distress).
  • Diet: Assessed via the NHANES Dietary Screener Questionnaire (DSQ) for intake of fiber, whole grains, calcium, sugar, etc.
  • Metabolomics: Serum samples were processed via gas chromatography-mass spectrometry (GC-MS). Data were normalized and log-transformed.
• Statistical Analysis: Non-parametric Wilcoxon signed-rank tests identified significant median log fold changes in metabolites from T1 to subsequent timepoints. Wilcoxon rank-sum tests compared metabolite levels between patients with and without specific symptoms. Given the exploratory nature, unadjusted p-values <0.05 were highlighted.

Key Results

• Symptom Burden: Five patients experienced >3 GI symptoms at T2 and T3. At all timepoints, ≥6 patients reported moderate-to-severe neuropsychological symptoms. GI symptom severity increased significantly from T1 to T2 and did not fully return to baseline by T4.
• Dietary Intake: Across all timepoints, mean daily intake of fiber, whole grains, and calcium was below USDA recommendations, while added sugar intake exceeded recommendations.
• Metabolite Perturbations (T1 vs. T2/T3):
  • Fatty Acids: Significant decreases were observed in long-chain fatty acids (laurate, myristate, oleate, linolenate, linoleate) at T2 and T3. Palmitate decreased at T2; heptanoate and pentadecanoate decreased at T3.
  • Carbohydrates: Glycerol decreased at T2 and T3. Glucose-6-phosphate and 6-phosphogluconate increased at T2, while inositol decreased at T2.
  • Amino Acid Derivatives: β-hydroxy-beta-methyl-butyric acid (HMB) decreased at T2 and T3. α-ketoisocaproate, α-ketoisovalerate, and DOPA decreased at T2; mandelate decreased at T3.
  • Ketone Bodies & Organic Acids: β-hydroxybutyrate decreased at T2 and T3. Pyruvate and 2-hydroxybutyrate decreased at T2, while 3-hydroxypropionate increased at T2.
  • Pyrimidine Derivatives: Cytosine and orotate increased at T2.
  • Recovery: By T4 (one month post-treatment), metabolite levels generally returned to baseline (T1) levels, with no significant differences observed.
• Metabolite-Symptom Associations:
  • Dry Mouth: Associated with perturbations in 3-hydroxypropionate (T2) and heptanoate (T2).
  • Difficulty Concentrating: Associated with mandelate levels at T3.
  • Fatigue: Associated with glucose-6-phosphate (T1), 3-hydroxypropionate (T3), and 6-phosphogluconate (T2).
  • Co-occurring Fatigue and Concentration Issues: Associated with pyruvate (T1) and 3-hydroxypropionate (T3).

Significance and Claims
The authors posit that chemotherapy-induced changes in metabolites involved in cellular energy metabolism (specifically the tricarboxylic acid cycle, fatty acid β-oxidation, and pentose phosphate pathway) may explain the patient experience of symptoms. The observed decreases in long-chain fatty acids and amino acid derivatives suggest potential inadequacies in dietary intake or metabolic shifts toward energy conservation and oxidative stress management.

The study claims that:

1. Metabolic Biomarkers: Specific serum metabolite changes correlate with the occurrence and severity of GI and neuropsychological symptoms, suggesting a biological basis for symptom clusters.
2. Dietary Influence: The concurrent decrease in essential fatty acids and amino acids, alongside poor dietary intake reported by patients, indicates that metabolic perturbations may reflect nutritional deficits exacerbated by chemotherapy.
3. Mechanistic Insight: The findings support the hypothesis that hepatotoxicity-related mechanisms and shifts in energy substrate availability (e.g., reduced ATP synthesis potential) drive symptomatology.

Limitations and Future Directions
The authors explicitly acknowledge the study's limitations, primarily the small sample size (n=10) and the lack of multiple-testing corrections, rendering the findings exploratory. Variability in chemotherapy and antiemetic regimens may also confound results. The paper concludes that larger sample size studies are required to build robust metabolic prediction models for symptom burden and to validate these associations for targeted interventions.