Stool bacteriomic profiling in patients with metastatic renal cell carcinoma suggests an etiology of VEGF TKI-related diarrhea.

Abstract

421 Background: Vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF TKIs) remain a mainstay of therapy for patients with metastatic renal cell carcinoma (mRCC). Diarrhea represents a pervasive toxicity, with all grade diarrhea affecting roughly 50% of patients receiving VEGF TKIs. The underlying cause of diarrhea in these patients is poorly understood. Methods: Patients with mRCC receiving an FDA-approved VEGF TKI therapy for mRCC were consented. Stool was collected in a standardized fashion and total genomic DNA was isolated using the PowerSoil DNA isolation kit (Mo Bio, USA). A standard PCR protocol was used to amplify bacterial 16S rRNA genes from all samples. PCR primers were used to amplify the V4 and V5 regions of the 16S rRNA. Paired-end of sequencing 2X100bp was performed by Illumina HiSeq 2000, and sequences were clustered using the CD-HIT clustering algorithm. Taxonomy was then assigned using the RDP-II classifier. Non-clustered analyses were also performed, stratifying patients by the presence or absence of diarrhea at the time of stool collection. Results: Of 26 patients consented, 23 patients submitted stool specimens and 20 had sufficient data for the current analysis. Amongst these 20 patients, the median age was 63 and the majority of patients (60%) were intermediate risk by Heng criteria. Eight patients (40%) received VEGF TKI therapy in the first-line setting. Across all lines of therapy, the most commonly used VEGF TKI was sunitinib (44%). A total of 141 bacterial species were identified. With respect to differences in patients who did and did not have diarrhea, the Mann-Whitney U-test identified 7 species with a p value of <0.1. The largest difference was seen in two Bifidobacterium species, B. animalis and B. bifidum, with both bacteria more abundant in patients with no diarrhea. Conclusions: This is the first effort to use stool bacteriomic profiling to ascertain the etiology of VEGF TKI related diarrhea in patients with mRCC. Two Bifidobacterium spp identified in this analysis are commonly found in probiotics. Studies to use probiotics enriched with Bifidobacterium spp to prevent or ameliorate VEGF TKI-related diarrhea are currently in development.