Use of plasma metabolomic profile to predict breast cancer survival: Risk stratification based on tumor nutrient dependencies.

Abstract

e12545 Background: Breast cancer is the most common cancer in women. Metabolic reprogramming is a hallmark of the disease. The propensity of cancer cells to exploit exogenous nutrient sources (auxotrophy) may offer insights into breast cancer aggressiveness. We applied plasma targeted mass spectrometry (MS/MS) to quantify metabolites in Stage I-III breast cancer patients to assess the impact of metabolic reprogramming on survival. Methods: Plasma samples from 154 early-stage and 57 advanced-stage breast cancer patients were examined by quantitative MS/MS. Concentrations of amino acids (AA), biogenic amines, lipids, and carbohydrates were correlated with 5-year survival. Statistical significance applied univariate and multivariate analyses with false discovery rate (FDR) corrections. Results: Metabolic signatures link AA and energy metabolite concentrations with breast cancer survival. Reduced plasma arginine (Arg) (p=0.02, AUC=0.712) was associated with shorter survival, reflecting impaired nitric oxide (NO) synthesis and dysregulated polyamine metabolism, components of tumor micro-environmental remodeling. Dimethyl arginine (DMA) and symmetric DMA (SDMA) were elevated, as were DMA/Arg (p=0.001, FDR=0.02) and SDMA/Arg (p=0.002, FDR=0.02) ratios, reflecting reduced Arg availability and NO synthase (NOS) inhibition under hypoxic stress. Lactate (Lac) (p=4.94e-4) and fumarate (Fum) (p=0.005, FDR=0.06) accumulation and the Arg/Lac (p=0.03, FDR=0.19) ratio reflect glycolytic flux and Krebs cycle perturbation, known as the "Warburg phenotype," correlating with tumor aggressiveness. Elevated methionine sulfoxide (Met-SO) (p=0.04, FDR=0.19), a measure of oxidative damage, is linked to altered one-carbon metabolism and epigenetic regulation. In luminal subtypes, tryptophan catabolism and a high kynurenine/tryptophan (Kyn/Trp) ratio (p=0.001, FDR=0.002), indicative of immune dysregulation, predicted shorter 5-year survival. A composite equation [(Leucine/SDMA)/(Aspartate/Threonine)] (p=8.14e-9, FDR=1.77e-8) stratified 5-year survival more effectively than clinical stage. Conclusions: Results confirm the metabolic plasticity of breast cancer, revealing auxotrophic dependency on AAs and energy substrates. Arginine depletion and the accumulation of its methylated derivatives (DMA, SDMA) suggest dual metabolic suppression—NOS inhibition and polyamine disruption—supporting hypoxia tolerance and immune evasion. The interplay between glycolytic reprogramming (Lac & Fum), oxidative stress (Met-SO), and mitochondrial dysfunction provides a biochemical framework for tumor aggressiveness. These metabolomic signatures offer prognostic insights across clinical stages and highlight therapeutic targets in AA metabolism, mitochondrial bioenergetics, and epigenetic reprogramming.