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. 2022 Jul 29;8(1):89.
doi: 10.1038/s41523-022-00455-5.

Changes in intestinal microbiota in postmenopausal oestrogen receptor-positive breast cancer patients treated with (neo)adjuvant chemotherapy

Romy Aarnoutse  1   2 , Janine Ziemons  3   4 , Lars E Hillege  3   4 , Judith de Vos-Geelen  3   5 , Maaike de Boer  3   5 , Saskia M P Bisschop  4 , Birgit E P J Vriens  6 , Jeroen Vincent  7 , Agnes J van de Wouw  8 , Giang N Le  9 , Koen Venema  10   11   12 , Sander S Rensen  4   10 , John Penders  9   10   12 , Marjolein L Smidt  3   4
Affiliations

Changes in intestinal microbiota in postmenopausal oestrogen receptor-positive breast cancer patients treated with (neo)adjuvant chemotherapy

Romy Aarnoutse et al. NPJ Breast Cancer. .

Abstract

This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.

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Conflict of interest statement

J.d.V.G. has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre and Servier. All outside the submitted work. J.d.V.G., M.L.S. and R.A. have received institutional research funding from Servier. All outside the submitted work. M.d.B. received research funding from Roche, Novartis, Pfizer, Eisai and AstraZeneca outside this submitted work. M.d.B. received a travel grant from Roche outside this submitted work. The other authors declare no competing financial interest. The Kootstra Talent Fellowship partly financially supported this study. K.V. acknowledges support in funding from the Dutch Province of Limburg. All authors declare no competing non-financial interests.

Figures

Fig. 1
Fig. 1. Flow chart.
The flow chart presents the number of patients included and the number of faecal samples collected by those patients during the study period. Multiple patients who did not collect a faecal sample at T2 were able to collect a faecal sample at T3. In total, 44 patients collected 153 faecal samples at four-time points. 28 participants provided all four samples. The total group is presented in the middle. On the left and right sides, the total group is subdivided into neoadjuvant and adjuvant groups.
Fig. 2
Fig. 2. Relative abundances of microbiota before, during and after chemotherapy.
A Relative abundances of different phyla before AC-D (n = 44), during AC (n = 43), during D (n = 29) and after AC-D treatment (n = 37). B Composition plot of individual samples (of participants who provided all four samples, n = 28) indicating changes in the relative abundance of most common genera over the course of AC-D treatment.
Fig. 3
Fig. 3. Microbiota diversity before, during and after chemotherapy.
A Changes in α-diversity measures of the 28 participants who provided all four samples before AC-D, during AC, during D and after AC-D treatment, measured in terms of observed species richness (p = 0.042; n = 28) and Shannon index (p = 0.206; n = 28) (Supplementary Table 5). B Pairwise comparison (Wilcoxon signed-rank sum test with Bonferroni correction) of all samples before AC-D (n = 44), during AC (n = 43), during D (n = 29) and after AC-D treatment (n = 37) revealed significant differences in observed species richness between T0-T3 (p = 0.003; n = 37) (Supplementary Table 6). The boxplot in Fig. 3B shows the medians, IQR’s, minimum, maximum and an outlier.
Fig. 4
Fig. 4. Ordination plots.
Ordination plots derived from unconstrained Principal Components Analysis (PCA) based on the Aitchison distance, showing the overall composition of the microbial community at phylum (A) and genus level (B) before AC-D (n = 44), during AC (n = 43), during D (n = 29) and after AC-D treatment (n = 37). Taxa that were present in less than five samples were excluded from this analysis. Data were transformed using centre-log-ratio transformation. Names are given for taxa, which contributed most to overall microbial variation.
Fig. 5
Fig. 5. Differential abundant taxa during the course of AC-D.
Log10 abundance of taxa with significant differential abundance before AC-D (n = 44), during AC (n = 43), during D (n = 29) and after AC-D treatment (n = 37). P values below boxplots indicate significant differential abundances analysed with a pairwise Wilcoxon signed-rank sum test (Supplementary Table 10). A Phylum level. B Genus level. The boxplots show the medians, IQRs, minimum, maximum and outliers.
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