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

Xiuwen Guan,Binghe Xu,Shaochuan Li,Zongbi Yi,Fang Liang,Binliang Liu,Lixi Li,Xiaoying Sun,Chunxiao Li,Fei Ma

doi:10.3389/fonc.2020.00902

Abstract

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 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.

Highlights

Capecitabine, an oral prodrug of fluorouracil, has been proven effective in metastatic breast cancer and is widely used as firstline chemotherapy in patients resistant to anthracycline, taxane, or both [1,2,3,4]
Main eligibility included [1] confirmed histologic/cytologic diagnosis of HER2-negative metastatic breast cancer, [2] receiving firstline chemotherapy with docetaxel plus capecitabine for six cycles and randomized to receive the maintenance chemotherapy with capecitabine of either conventional dosage regimens or metronomic dosage regimens, [3] current maintenance chemotherapy with single-agent capecitabine for more than 1 month, [4] with measurable lesions defined by the revised Response Evaluation Criteria in Solid Tumors guidelines version 1.1 (RECIST 1.1), [5] Eastern Cooperative Oncology Group performance status
A total of 31 patients hospitalized in China National Cancer Center, including metastatic breast cancer patients treated with a metronomic dose of capecitabine and patients treated with conventional dose, were enrolled

Summary

Introduction

Capecitabine, an oral prodrug of fluorouracil, has been proven effective in metastatic breast cancer and is widely used as firstline chemotherapy in patients resistant to anthracycline, taxane, or both [1,2,3,4]. In HER2-negative breast cancer patients who have residual invasive disease on pathological testing after a standard neoadjuvant chemotherapy containing anthracycline and taxane, the addition of adjuvant capecitabine therapy is proven to prolong disease-free survival and overall survival [5]. Treatment is intended to prevent tumor progression for a relatively extended period of time; low-dose metronomic administration of chemotherapy may be an ideal choice for maintenance treatment. Capecitabine is one of the ideal agents in a metronomic schedule for its antiangiogenic activity resulting from the metronomic dosage [9]

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Discussion

Conclusion