Plasma multi-omics reveals molecular remodeling and prognostic biomarkers in advanced breast cancer treated with trastuzumab deruxtecan

Abstract

Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, has demonstrated clinical activity in HER2-positive and HER2-low advanced breast cancer. However, treatment outcomes remain heterogeneous, and circulating molecular correlates of treatment and prognosis are incompletely defined. Twenty-nine patients receiving T-DXd were included in the clinical cohort, of whom 16 provided paired pre- and post-two-cycle plasma for multi-omics profiling. Proteomics used 4D-DIA LC-MS/MS; metabolomics used UHPLC-high-resolution MS in positive/negative modes. Treatment-associated features were identified by paired statistics, fold change, and multivariate criteria, followed by enrichment, correlation, joint pathway mapping, and exploratory PFS-oriented Cox/LASSO-Cox analyses. Proteomics identified 4,444 proteins; 508 were differentially expressed (136 up, 372 down), enriched in translation/ribosome, complement/coagulation, acute-phase, cytoskeletal/adhesion, and lipid transport pathways. Metabolomics detected 3,596 features; 70 were differential (43 up, 27 down), enriched in amino acid, tryptophan, nucleotide/energy, and lipid metabolism. Cross-omics analysis revealed structured correlations and joint purine metabolism mapping. Exploratory baseline analyses selected six protein and four metabolite prognostic biomarkers for PFS visualization. Paired plasma multi-omics revealed T-DXd-associated proteomic and metabolic remodeling. The molecular patterns and PFS-associated biomarkers are hypothesis-generating and require validation in larger independent cohorts.