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

Abstract

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 the 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: A total of 15 patients treated with metronomic capecitabine were compared to 16 patients under a conventional dose. The unweighted-unifrac index of the metronomic group was statistically significantly lower than that of the routine group (P = 0.025). Besides that, the Bray-Curtis distance-based redundancy analysis illustrated that the microbial genera between the two groups can be separated partly. Nine Kyoto Encyclopedia of Genes and Genomes (KEGG) modules were enriched in the metronomic group, while no KEGG modules were significantly enriched in the routine group. Moreover, univariate and multivariate analyses suggested that the median progression-free survival (PFS) was significantly shorter in patients with the gut microbial composition of Slackia (9.2 vs. 32.7 months, P = 0.004), while the patients with Blautia obeum had a significantly prolonged PFS than those without (32.7 vs. 12.9 months, P = 0.013). Conclusions: The proof-of-principle study suggested that the gut microbiota of patients receiving metronomic chemotherapy was different in terms of diversity, composition, and function from those under conventional chemotherapy, and the presence of specific bacterial species may act as microbial markers associated with drug resistance monitoring and prognostic evaluation.

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment

“…Importantly, the gut humanized avatar AT3 bearers that were subjected to FMT containing species from the Eubacterium genus ( E. rectale, E. eligens, E. ventriosum) or C. aerofaciens exhibited a reduced tumor growth rate compared with eubiotic control mice. A pioneering study [ 32 ] focusing on the possible involvement of microbiota changes in the beneficial effects of metronomic (versus standard dosing of) capecitabine in 15 metastatic HER2 negative BC described differences in commensalism between the two CT regimens and the association of Slackia and Blautia obeum with poor and favorable clinical outcome, respectively. Therefore, it will be important to validate the capacity of specific chemotherapeutic agents to eliminate unfavorable bacteria or to expand favorable commensals in future clinical studies.…”

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth

“…To date, there have been no human studies linking microbiota disruptions causatively to BrCa progression. However, several human studies have described a loss of gut microbial diversity in patients with BrCa compared to normal control subjects ( Goedert et al., 2015 ; Guan et al., 2020 ; Wu et al., 2020 ; Zhu et al., 2018 ). Thus, our observations intimate that, in these studies, the microbiota may be influencing BrCa progression rather than changing as a consequence of it.…”

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

“…( Figure 5C ) Also, modulations in bacterial deoxynucleotide storage amplify 5-FU-induced autophagy and cell death in host cells. A Chinese prospective study of the fecal composition of 31 females treated for HER2 negative breast cancer used 16S rRNA sequencing to analyze the variations of the gut microbiota during a maintenance chemotherapy comparing metronomic versus conventional dose of capecitabine ( 232 ). While alpha diversity was not different between the two treatment modalities, beta diversity varied significantly between the two groups, with a relative depletion of Cyanobacteria , Chloroplast, Blautia , and Streptophyta in stools of the metronomic capecitabine -treated females.…”

“…These metabolic traits are reminiscent of polyamine synthesis closely linked with the activation of the autophagic machinery mandatory for the immunogenicity of cancer cell death ( 233 ) ( Figure 5B ). Although concerning for breast cancer females, and underpowered, this pioneering study suggests that distinct chemotherapeutic regimen influence the composition of the gut microbiota that in turn, could impact clinical outcome ( 232 ).…”