The composition of the intestinal microbiota influences the development of inflammatory disorders.,However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition.,Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis.,Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development.,We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis.,Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis.,Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.,A subset of cancer patients treated with immune checkpoint blockade develops colitis.,Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.
The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors.,We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.,Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed.,Mutational analysis was performed using the OncoCarta Panel.,Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.,In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt).,There was no difference in response to chemotherapy based on mutation status (35-37%).,The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis.,Survival from stage IV melanoma diagnosis was not significantly different based on mutation status.,The DDFI was significantly shorter in patients with BRAFV600K/R versus BRAFV600E melanoma in univariate and multivariate analyses.,BRAF and NRAS mutation status does not influence survival in metastatic melanoma.