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Observational Study
. 2025 Mar 6;15(1):7874.
doi: 10.1038/s41598-025-91734-1.

The gut microbiota during tamoxifen therapy in patients with breast cancer

Lars E Hillege  1   2 , David J M Barnett  3   4 , Janine Ziemons  5   6 , Romy Aarnoutse  5   6 , Judith de Vos-Geelen  5   7 , Robin van Geel  8   9 , Maaike de Boer  5   7 , Yvonne E A van Riet  10 , Jeroen Vincent  11 , John Penders  3   4 , Marjolein L Smidt  5   6
Affiliations
Observational Study

The gut microbiota during tamoxifen therapy in patients with breast cancer

Lars E Hillege et al. Sci Rep. .

Abstract

Tamoxifen is essential in treating estrogen receptor-positive (ER+) breast cancer, primarily through its active metabolite, endoxifen. Emerging research suggests potential interactions between tamoxifen and gut microbiota. This study investigates the effects of tamoxifen on gut microbiota composition in postmenopausal ER+ and human epidermal growth factor receptor 2 negative (HER2-) breast cancer patients and explores correlations between gut microbiota and endoxifen plasma levels. This prospective observational study included postmenopausal ER+/HER2- breast cancer patients. Fecal and blood samples were collected before and during 6-12 weeks of tamoxifen therapy. Gut microbiota composition was analyzed using 16S rRNA amplicon sequencing of the hypervariable V4 gene region, and plasma endoxifen levels were measured using liquid chromatography-mass spectrometry. Changes in microbial diversity and composition were assessed, with correlations to endoxifen levels. A total of 62 patients were included. Tamoxifen significantly increased microbial richness (p = 0.019), although overall community structure remained consistent between pre- and during-treatment samples. Notable changes were observed in specific microbial taxa, with significant increases in genera such as Blautia (padjusted = 0.003) and Streptococcus (padjusted = 0.010), and decreases in Prevotella_9 (padjusted = 0.006). No significant correlations between gut microbiota and endoxifen levels were identified after multiple comparisons. Tamoxifen therapy increases gut microbial diversity in postmenopausal ER+/HER2- breast cancer patients, though overall microbial community structure remains stable. The absence of significant correlations with endoxifen levels suggests that while tamoxifen affects the gut microbiota, its role in endoxifen metabolism requires further study. More comprehensive research is needed to understand the relationship between tamoxifen, gut microbiota, and therapeutic outcomes.

Keywords: Antineoplastic agents; Breast neoplasms; Postmenopausal.

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Conflict of interest statement

Declarations. Competing interests: LEH, JZ, and MLS have received research funding from Danone Global Research & Innovation Center, outside the submitted work. Additionally, MLS, RA, and JVG have received funding from Servier, and MLS from Illumina, all outside the submitted work. JVG has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, all outside the submitted work. JP has received research funding from Friesland Campina outside the submitted work. All other authors have no competing interests. All other authors have no competing interests. Ethics approval and consent to participate: The study was approved by the Medical Ethics Committee of azM/UM and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.

Figures

Fig. 1
Fig. 1
(A, B) Violin plots illustrating the distribution of alpha-diversity measurements at two different time points (T0 and T1), highlighting whether alpha-diversity increases (green line) or decreases (purple line) between paired samples. Each plot shows the density of values with individual data points overlaid as black dots. (A) Shannon index. (B) ASV richness. (C, D) Violin plots illustrating the distribution of the shifts in alpha-diversity measurements (C Δ Shannon; D Δ ASV-richness) between T0 and T1 for paired samples. The dashed line in the plot indicates zero (no change), serving as a reference point to easily identify increases or decreases in alpha-diversity.
Fig. 2
Fig. 2
Ordination plots derived from unconstrained principal components analysis (PCA) based on centered-log-ratio transformed abundances, showing the composition of the microbial community at ASV (A) and genus (B) levels for T0 and T1. P-values from the PERMANOVA analysis are indicated on the plots. (C) Violin plot illustrating the distribution of within-subject dissimilarity between T0 and T1 for paired samples (Aitchison distances calculated at ASV-level). The width of the plot at different levels indicates the frequency of observations. The dashed line represents the median within-subject dissimilarity.
Fig. 3
Fig. 3
Differential abundant taxa between T0 and T1. Log10-transformed relative abundances of the 24 taxa that were statistically different in abundance between the timepoints before (T0) and during tamoxifen therapy (T1). The thick line represents the mean value, whereas thin lines represent shifts in abundance over time in individual patients.
Fig. 4
Fig. 4
Heatmap of Spearman correlation coefficients for the correlations between the relative abundance of bacterial taxa on genus level and alpha-diversity measurements at T1 and plasma levels of endoxifen at T1, BMI, and antibiotic use between T0 and T1 (AB_T0_T1). An asterisk indicated p < 0.05 and a circle indicates FDR-corrected p < 0.05.
See this image and copyright information in PMC

References

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