Genetic Risk for Colorectal Cancer Is Associated With Earlier Onset and Higher Incidence of Immune Checkpoint Inhibitor Colitis

Introduction: Immune-checkpoint inhibitors (ICIs) have improved survival and have become standard treatment for multiple cancer types. Immune-related adverse events (irAEs) including colitis can be severe and life-threatening. Genetic predisposition to irAEs and specifically colitis are poorly understood. Methods: We included patients treated with ICIs across all cancer subtypes. irAEs were defined according to CTCAE v5.0. Patients with colitis were known to have biopsy-proven involvement. Data on use of biologics (vedolizumab or infliximab) for treatment of colitis were collected. We imputed common germline features from panel sequenced tumors. We investigated the influence of germline features on irAEs using multivariate and multistage survival analysis. We further analyzed the association between known polygenic risk scores (PRS) and the development of ICI colitis. Results: 1478 patients who received ICIs were included. The most common cancer subtypes were non-small cell lung cancer (N=617, 41.7%), melanoma (N=199, 13.5%), and renal cell carcinoma (N=141, 9.5%). Of the 675 (45.7%) patients who developed any grade irAEs, 320 (47.4%) were ≥ grade 3. The most common irAEs were colitis (N=152, 22.5%), pneumonitis (N=93, 13.8%), and hepatitis (N=83, 12.3%). Of patients who developed ICI colitis, 99 (65.1%) were ≥ grade 3, and 34 (22.4%) required treatment with biologics. Among >100 risk scores, we discovered a very significant association between colorectal cancer PRS and ICI colitis (HR=1.15, P=9.2x10-4). This result remained significant even after excluding patients with colorectal cancer. When examining PRS by quintile, individuals with the highest quintile colorectal cancer PRS had higher rates and earlier onset of ICI-colitis (Figure 1). We found no association between ulcerative colitis PRS and ICI colitis. Conclusion: Our study is the first to report on a novel association between genetic risk for colorectal cancer and risk of developing ICI colitis. Our results, if validated, have significant implications on early identification and long-term management of patients with ICI colitis.Figure 1.: Association between Colorectal Cancer Risk Polygenic Risk Score and ICI Colitis