Metabolites Linked to Triple-Negative and Hormone-Positive Breast Cancer Risk
Scientists at the International Agency for Research on Cancer (IARC) and partner institutions have identified circulating metabolites associated with the risk of developing specific breast cancer subtypes, according to a study published on August 11, 2026, in BMC Medicine.
- Researchers analyzed pre-diagnostic plasma samples from the European Prospective Investigation into Cancer and Nutrition (EPIC) study using untargeted ultrahigh-performance liquid chromatography-mass spectrometry.
- Higher levels of tyrosine showed an association with a lower risk of triple-negative breast cancer (TNBC), while specific lipids and byproducts correlated with increased estrogen receptor-positive and progesterone receptor-positive tumor risk.
- Fifteen unknown metabolites appeared suggestively specific to TNBC risk and indicated potential involvement in inflammation pathways.
Untargeted Metabolomics Approach in the EPIC Cohort
The research team applied untargeted metabolomics to uncover biological pathways tied to triple-negative breast cancer risk, aiming to find mechanisms distinct from those driving hormone receptor-positive tumors. TNBC represents 10% to 15% of newly diagnosed breast cancer cases. It stands as one of the most aggressive forms of the disease, characterized by limited therapeutic options, high metastatic potential, and poorer prognosis. Its underlying etiology remains poorly understood relative to other breast cancer classifications.
Investigators utilized data from a nested case-control study embedded within the EPIC cohort. The analysis included 271 TNBC cases matched with 271 controls, alongside 271 estrogen receptor-positive and progesterone receptor-positive (ER+ and PR+) breast cancer cases matched with 271 controls. Using an untargeted ultrahigh-performance liquid chromatography-mass spectrometry method developed at IARC, the laboratory team measured more than 3,000 molecular features across these plasma samples.
Differential Metabolite Associations Across Subtypes
The findings revealed divergent metabolic profiles for different tumor types. Higher circulating levels of tyrosine demonstrated an inverse association with TNBC risk. Conversely, elevated levels of uric acid, octenoylcarnitine, hexadecenoylcarnitine, a bilirubin photodegradation product, and 2-hydroxy-3-methylbutyric acid associated with an increased risk of developing ER+ and PR+ tumors. Distinctly, higher levels of caffeine and 2-furoylglycine correlated with a lower risk of ER+ and PR+ tumors.
Beyond known compounds, the analysis isolated 15 unknown metabolites suggestively specific to TNBC risk. These uncharacterized features appear linked to the inflammation pathway, pointing to distinct immunological or inflammatory underpinnings in early TNBC pathogenesis.
Pathways for Future Research and Prevention
The study demonstrates that specific metabolic pathways help distinguish the risk profile of TNBC from that of ER+ or PR+ breast cancer. Investigators emphasize that replicating these findings across independent cohorts will be essential to validate the discoveries. Confirmation would sharpen our understanding of TNBC etiology and highlight potential lifestyle determinants or biological processes influencing tumor development.