Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2019

The gut microbiome as an intervention target for neratinib-induced diarrhea (#160)

Kate Secombe 1 , Joanne Bowen 1 , Imogen Ball 1 , Joseph Shirren 1 , Anthony Wignall 2 , Alshad Lalani 3 , Irmina Diala 3
  1. Adelaide Medical School, University of Adelaide, Adelaide, South Australia
  2. Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
  3. Puma Biotechnology, San Francisco, California, USA

Introduction

HER2 and EGFR targeting tyrosine kinase inhibitors (TKI) used in breast cancer treatment cause diarrhoea as a drug class effect. Diarrhoea is the most frequently observed adverse event of the oral, irreversible pan-HER TKI, neratinib and has previously been shown to have an inflammatory basis. The gut microbiome is important in inflammatory gut changes and may play a role in neratinib-induced diarrhoea. This study aimed to determine if neratinib changes gut microbial composition, and whether targeting these changes with probiotics prevents diarrhoea.  

Methods

Caecal contents from Wistar rats treated for 28 days with 50 mg/kg neratinib (n=6) or vehicle (n=6) were taken to analyse bacterial composition by 16S pyrosequencing. A second study was conducted to examine probiotic efficacy for prevention of neratinib induced diarrhoea. Rats (n=48) received 50 mg/kg neratinib, and concomitant 4x108 cfu VSL#3 (probiotic cocktail of Lactobacilli, Bifidobacteria and Streptococcus spp.) or vehicle for 28 days.

Results

Compared to vehicle control, neratinib-treated rats had a significantly lower Firmicutes:Bacteriodetes ratio (P=0.041) and levels of the genus Blautia post-treatment (P=0.001). The Firmicutes:Bacteroides ratio has been implicated in obesity and general health. The Blautia genus is important in nutrient assimilation. Microbial changes at the genus level were not correlated with diarrhoea severity. In the second study, rats treated with VSL#3 did not have significantly altered diarrhoea or intestinal damage scores compared to neratinib alone (P>0.05).

Conclusions

Neratinib treatment caused changes to the caecal microbiome. More research is needed to determine if these are acute or chronic changes. However, targeting microbial changes with a multi-species probiotic did not alter diarrhoea levels. Further research is required to determine if VSL#3 was able to modulate rat caecal microbial profiles. Future work will examine antibiotic ablation of gut microbiome to determine causality in the development of neratinib-induced diarrhoea.