Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.
“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.
Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.
The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.
Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.
“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”
In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.
The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.
Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.
Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.
The phylogenetic composition of common bacterial taxa was similar for both cohorts.
In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.
The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.
An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.
Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.