Abstract
BackgroundIt is well known that the gastrointestinal (GI) microbiota can influence the metabolism, pharmacokinetics, and toxicity of cancer therapies. Conversely, the effect of cancer treatments on the composition of the GI microbiota is poorly understood. We hypothesized that oral androgen receptor axis-targeted therapies (ATT), including bicalutamide, enzalutamide, and abiraterone acetate, may be associated with compositional differences in the GI microbiota.MethodsWe profiled the fecal microbiota in a cross-sectional study of 30 patients that included healthy male volunteers and men with different clinical states of prostate cancer (i.e., localized, biochemically recurrent, and metastatic disease) using 16S rDNA amplicon sequencing. Functional inference of identified taxa was performed using PICRUSt.ResultsWe report a significant difference in alpha diversity in GI microbiota among men with versus without a prostate cancer diagnosis. Further analysis identified significant compositional differences in the GI microbiota of men taking ATT, including a greater abundance of species previously linked to response to anti-PD-1 immunotherapy such as Akkermansia muciniphila and Ruminococcaceae spp. In functional analyses, we found an enriched representation of bacterial gene pathways involved in steroid biosynthesis and steroid hormone biosynthesis in the fecal microbiota of men taking oral ATT.ConclusionsThere are measurable differences in the GI microbiota of men receiving oral ATT. We speculate that oral hormonal therapies for prostate cancer may alter the GI microbiota, influence clinical responses to ATT, and/or potentially modulate the antitumor effects of future therapies including immunotherapy. Given our findings, larger, longitudinal studies are warranted.
Highlights
The gastrointestinal (GI) microbiota are known to influence the metabolism, pharmacokinetics, and toxicity of many drugs and xenobiotics [1], yet there are few mechanistic studies exploring this effect in relation to cancer therapies
A study in a melanoma model showed that the therapeutic benefit of anti-PD-L1 immunotherapy could be bolstered by feeding animals a strain of Bifidobacterium—a species commonly used in probiotic supplements—prior to initiating therapy [8]
For the purposes of our medication analyses, the designation “NoMeds” indicated men who were not undergoing androgen derivation therapy (ADT), “GNRH” were men only being treated with a gonadotropin-releasing hormone (GNRH) agonist/antagonist, and “oral ATT” were men being treated with oral androgen receptor axis-targeted therapies
Summary
The gastrointestinal (GI) microbiota are known to influence the metabolism, pharmacokinetics, and toxicity of many drugs and xenobiotics [1], yet there are few mechanistic studies exploring this effect in relation to cancer therapies. Fecal microbial transplant from human donors that were responders to anti-PD-1 immunotherapy into germ-free mouse allograft tumor models conferred antitumor efficacy of anti-PD-1 immunotherapy versus fecal samples transplanted from non-responders [9,10,11]. These studies indicate that members of the intestinal microbiome may be essential for cancer drug efficacy and that modulating intestinal microbiome composition may enhance therapeutic response. We hypothesized that oral androgen receptor axis-targeted therapies (ATT), including bicalutamide, enzalutamide, and abiraterone acetate, may be associated with compositional differences in the GI microbiota
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