Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy.

Simple Summary: This study investigates the fecal and tumor microbiome as potential biomarkers of tumor response to neoadjuvant immunotherapy in combination with chemoradiation. We performed 16S rRNA amplicon sequencing on fecal and tumor samples, as well as fecal metabolomics, on biosamples collected from patients with resectable esophageal or gastroesophageal junction carcinoma before and during treatment. The fecal microbiome of patients whose tumors achieved a pathologic complete response revealed enrichment in sphingolipid and primary bile acids, with corresponding elevated abundance of several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. While these results provide initial insight, further study is necessary to validate these data and determine how microbes alter the immune response with neoadjuvant immunotherapy. Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II–III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray–Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI. [ABSTRACT FROM AUTHOR]