Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Plain Language Summary
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.
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Data availability
Due to contractual obligations with the funding foundation and ethical restrictions defined in the informed consent, the datasets generated and analyzed in this study are not publicly available. Data may be made available from the corresponding author upon reasonable request and subject to approval by the funding organization and the institutional review board.
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Acknowledgements
The authors would like to thank the YongLin Healthcare Foundation for their sponsorship and Germark Biotechnology Co., Ltd for performing the bioinformatics analyses. This study was supported by the YongLin Healthcare Foundation under study protocol No. QCR18001 and supported by grants 109-2314-B-037-142-MY2, 111-2314-B-037-092-, 112-2314-B-037-007-, 114-2314-B-040-038- from the National Science and Technology Council and the grants KMUH110-0M38, KMUH110-0R39, KMUH110-0R40, KMUH111-1R33, KMTTH-111-R013, KMTTH-112-R006, and KMGH-113G002 from the Kaohsiung Medical University Hospital and Kaohsiung Medical University Gangshan Hospital.
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M.-F.H. and C.-L.L. performed the experiments; S.-H.M. performed the cfDNA and statistical analysis; F.-M.C., J.-Y.C., S.-L.S., J.-Y.K., S.-F.Y. carried out the patient recruitment and specimen collection; C.-P.C. designed, analyzed the data and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
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Hou, MF., Li, CL., Moi, SH. et al. Longitudinal multiomics analysis of endocrine therapy effects and gut microbiota in breast cancer recurrence. Commun Med (2026). https://doi.org/10.1038/s43856-026-01384-1
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DOI: https://doi.org/10.1038/s43856-026-01384-1
