Sugar Coat Signals: Fucosylated Glycans Predict Survival in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is among the most aggressive and treatment-resistant breast cancer subtypes, lacking estrogen receptor, progesterone receptor, and HER2 expression. It disproportionately affects younger women, those with BRCA1 mutations, and women of African and Hispanic descent. With no targeted therapies available, there is an urgent need for better biomarkers to stratify patients and guide treatment decisions.

This study leveraged multiplexed spatial glycomics via matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to profile 348 N-glycans across 59 TNBC tumor samples from African American women. The platform used two sequential enzymatic approaches: Endo F3 to release core-fucosylated (CF) glycans specifically, followed by PNGase F to release remaining N-glycans. This enabled spatial discrimination of CF versus outer-arm fucosylated (OAF) N-glycans within intact tumor microenvironments, correlated with pathologist-annotated histology and over 75 clinical variables including tumor stage and survival status.

The spatial analysis revealed distinct localization patterns for CF and OAF glycan isomers within tumor microenvironments. Strikingly, OAF glycans showed strong and significant association with tumor stage, with expression rising from stage I through stage III before declining at stage IV — a pattern not seen with CF glycans. Of 68 N-glycans significantly associated with patient survival, 36 (52%) were OAF-modified. Among these, polylactosamine-containing OAF structures were particularly notable: high expression correlated with poor prognosis, and these structures were already detectable at early tumor stages, making them attractive candidates for early prognostic assessment.

These findings align with prior evidence linking polylactosamine glycans to metastasis in HER2+ and TNBC tumors and observations that OAF increases as breast epithelial cells adopt more aggressive phenotypes. The study adds important spatial resolution, showing where in the tumor these changes occur and connecting them directly to clinical outcomes in a well-characterized patient cohort.

The implications are multifaceted: OAF N-glycans appear to be dynamic, structure-specific markers of TNBC progression rather than static features. Their early detectability suggests utility in risk stratification at diagnosis, and their specificity to OAF rather than CF modifications points toward targeted glycan-based diagnostic or therapeutic strategies. Caveats include the single-institution cohort limited to African American women, which limits generalizability, and the retrospective cross-sectional design which precludes causal inference.