Faecal microbiota composition is related to response to CDK4/6-inhibitors in metastatic breast cancer: A prospective cross-sectional exploratory study

BackgroundCDK4/6-inhibitors with endocrine therapy represent the standard of treatment of hormone receptor-positive(HR+)/HER2-negative metastatic breast cancer (MBC). Gut microbiota seems to predict treatment response in several tumor types, being directly implied in chemotherapy resistance and development of adverse effects. No evidence is available on gut microbiota impact on efficacy of HR+ breast cancer treatment.Patients and methodsWe assessed the potential association among fecal microbiota and therapeutic efficacy of CDK4/6-inhibitors on 14 MBC patients classified as responders (R) and non-responders (NR) according to progression-free survival. A stool sample was collected at baseline and V3–V4 16S targeted sequencing was employed to assess its bacterial composition. Statistical associations with R and NR were studied.ResultsNo significant differences were observed among R and NR in terms of α-/β-diversity at phylum and species level. Machine-learning (ML) algorithms evidenced four bacterial species as discriminant for R (Bifidobacterium longum, Ruminococcus callidus) and NR (Clostridium innocuum, Schaalia odontolytica), and an area under curve (AUC) of 0.946 after Random Forest modeling. Network analysis evidenced two major clusters of bacterial species, named Species Interacting Groups (SIG)1-2, with SIG1 harboring 75% of NR-related bacterial species, and SIG2 regrouping 76% of R-related species (p<0.001). Cross-correlations among several patients' circulating immune cells/biomarkers and bacterial species' relative abundances showed associations with potential prognostic implications.ConclusionsOur results provide initial insights on the gut microbiota involvement in sensitivity and/or resistance to CDK4/6-inhibitors+endocrine therapy in MBC. If confirmed in larger trials, several microbiota manipulation strategies might be hypothesized to improve response to CDK4/6-inhibitors.Data availability statementAll raw data (fastq.gz files) and clinical metadata, complying to FAIR principles (https://www.go-fair.org/fair-principles/), are available at NCBI SRA portal under PRJNA946762 Bioproject.