Longitudinal multiomics analysis of endocrine therapy effects and gut microbiota in breast cancer recurrence

The gut microbiota influences breast cancer development through the estrobolome, a collection of bacterial genes involved in estrogen metabolism. While estrogen and the gut microbiota mutually affect each other, the long-term effects of oral endocrine therapy (ET) on the gut microbiota remain unclear. Furthermore, the relationship between gut microbiota profiles and breast cancer recurrence is not well understood. This study aims to investigate the long-term impact of oral ET on gut microbiota composition in disease-free and recurrent breast cancer patients. We enrolled 48 participants divided into four groups: tamoxifen only (Tam), letrozole only (Let), chemotherapy plus letrozole without recurrence (CLet), and chemotherapy plus letrozole with recurrence (Recu). Fecal samples were collected for 16S rRNA sequencing. Blood samples for cell-free DNA (cfDNA) analysis and tissue samples for EndoPredict (EPclin) scoring. Here we show that long-term ET administration does not significantly alter overall gut microbial composition. However, patients with recurrence display lower α-diversity and higher abundances of Sutterella and Ruminococcus compared with non-recurrent patients. cfDNA profiles do not differ significantly between groups. Notably, high EPclin scores predict chemotherapy benefit, but recurrence still occurs in some cases. In such patients, gut microbial markers effectively distinguish recurrence and are associated with poorer progression-free survival, particularly in those with larger tumors. This study provides the first human evidence with long-term ET administration to reveal that, besides genetic profiles, the gut microbiota is another critical factor that we should consider in the influence and prediction of breast cancer recurrence in the future. Breast cancer treatments often include long-term hormone therapy, but little is known about how these drugs affect the bacteria living in our gut. In this study, we followed women receiving different endocrine therapies and analyzed their gut microbiota before and after one year of treatment. We discovered that women whose cancer later returned had less diverse gut bacteria and higher amounts of certain species, including Sutterella and Ruminococcus. These bacterial patterns were linked to poorer treatment outcomes, especially in patients with larger tumors. Our findings suggest that gut bacteria may influence how breast cancer responds to therapy and could serve as an additional factor to help predict disease recurrence in the future. Hou, Li, Moi et al., find that long-term endocrine therapy does not alter overall gut microbiota composition in breast cancer patients, but recurrence is linked to reduced microbial diversity and specific bacterial signatures. These gut microbiota patterns predict poorer outcomes independent of established genetic risk scores, suggesting added value for recurrence risk stratification