Potential effect of the gut microbiome on tumour response to anti-cancer treatment in patients diagnosed with pancreatic ductal adenocarcinoma.

Abstract

757 Background: Chemotherapy is the standard of care for pancreatic ductal adenocarcinoma (PDAC), however, recent research has identified bacteria in the human gut microbiome that may influence patient response to chemotherapy. These bacteria are also present in faeces, and are thought to be representative of the bacteria in the pancreatic ductal system. Preliminary studies have suggested that patients with more advanced PDAC demonstrate lower levels of Firmicutes, and higher levels of Proteobacteria. Additionally, research has shown bacteria in the Firmicutes phylum possess several anti-cancer properties, which may improve patient treatment response, meanwhile, Gammaproteobacteria (Proteobacteria phylum), have been shown to attenuate gemcitabine efficacy and worsen treatment response. Methods: This prospective study involved 14 participants with locally advanced PDAC. Participants received combinations of Gemcitabine, Nab-Paclitaxel, and durvalumab (immunotherapy). Participant tumours were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Gut microbial profiling was completed on stool samples taken pre-treatment using PacBio HiFi full-length 16S rRNA sequencing. Results: 16S rRNA sequencing identified that of the 4 patients that died due to disease progression, 3 patients had a low Firmicutes abundance, and a high Proteobacteria abundance. The rother patient demonstrated low levels of Actinobacteriota and Bacteroidota, and a low bacterial diversity. One participant showed a significant increase in CA19-9 (1066.7%), and exhibited a low abundance of Actinobacteriota and Bacteroidota, a high abundance of Proteobacteria, and a low diversity. 5 participants demonstrated a significant treatment response (according to CA19-9 and RECIST analysis), with 4 patients showing a high Firmicutes abundance, high levels of Actinobacteriota or Bacteroidota, and low levels of Proteobacteria. The remaining patient demonstrated a low abundance of Firmicutes and Proteobacteria, yet, displayed the highest abundance of Actinobacteriota and Bacteroidota. Conclusions: This exploratory study suggests an association between microbial composition and treatment response, with Firmicutes potentially being associated with an improved treatment response, and Proteobacteria with a worsened response. We believe this study to be one of the first to explore correlation of microbiome with clinical treatment response in PDAC.