Profiling the gut and oral microbiota of hormone-receptor positive, HER2-negative metastatic breast cancer patients receiving pembrolizumab and eribulin

Abstract

Abstract Changes occurring in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. We previously showed that anti-programmed cell death protein 1, pembrolizumab, plus microtubule-targeting chemotherapy, eribulin, has encouraging antitumor activity in previously pre-treated hormone receptor (HR)-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients in the KELLY phase II study (NCT03222856). Faecal (58) and saliva (67) samples were prospectively collected at baseline, after three treatment cycles, and end of treatment from a subset of 28 patients included in this trial. Shotgun metagenomic and 16S ribosomal ribonucleic acid gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize faecal and oral microbiota profiles. Overall, treatment did not cause significant gut or oral microbiota perturbations, indicating limited drug-related microbial toxicity. Dominant gut microbiota genera included Bacteroidesand Faecalibacterium, with a common oral microbe, Prevotella, also present. Several typical oral microbes i.e., Prevotella and Streptococcus, were observed in both saliva and faecal samples, suggesting potential translocation along the oral-gut axis. Further analysis appeared to show that clinical benefit was driven, in part, by gut-associated Bacteroides fragilis and baseline oral-associated Streptococcus with an abundance ≥40%. We also observed that cell-free supernatant from Bacteroides fragilis NCTC 9343 stimulated lactate dehydrogenase release, in a dose-dependent manner from the MCF-7 (HR-positive/HER2-negative) breast cancer cell line. These data suggest that certain gut and oral microbiota members influence efficacy of new combinatory anti-breast cancer therapies, which may in part be mediated via microbial metabolites.