Gut Microbiota Profiling in Patients With HER2-Negative Metastatic Breast Cancer Receiving Metronomic Chemotherapy of Capecitabine Compared to Those Under Conventional Dosage

Purpose: Low-dose metronomic chemotherapy can achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose. Characterizing the gut microbiota of cancer patients under different dosage regimens may describe a new role of gut microbiota associated with drug efficacy. Therefore, we evaluated the composition and function of gut microbiome associated with metronomic capecitabine compared to conventional dosage. Methods: The fecal samples of HER2-negative metastatic breast cancer patients treated with capecitabine as maintenance chemotherapy were collected and analyzed by 16S ribosome RNA gene sequencing. Results: 15 patients treated with metronomic capecitabine were compared to 16 patients under conventional dose. The unweighted-unifrac index of metronomic group were statistically significantly lower than routine group. Besides, Bray-Curtis distance based redundancy analysis (dbRDA) illustrated that the microbial genera between two groups can be separated partly. Nine Kyoto Encyclopedia of Genes and Genomes (KEGG) modules were enriched in metronomic group, while no KEGG modules was significantly enriched in routine group. Moreover, univariate and multivariate analysis suggested the median progression-free survival (PFS) was significantly shorter in the patients with the gut microbial composition of Slackia (9.2 vs 32.7 months, P=0.004), while the patients with the Blautia obeum had significantly prolonged PFS than those without (32.7 vs 12.9 months, P=0.013). Conclusions: The proof-of-principle study suggested that gut microbiota of the patients receiving metronomic chemotherapy was different in the diversity, composition and function from those under the conventional chemotherapy, and the presence of specific bacterial species may act as microbial markers associated with drug resistance monitoring and prognostic evaluation.