A Networks-Based Approach Identifies DDR Genes Not Associated With TMB Yet Predictive of Immune Checkpoint Response

Immune checkpoint blockade (ICB) therapies have had remarkable success for treatment of solid tumors. However, as only a subset of patients exhibit responses, there is a continued need for biomarker development. Numerous reports have shown a link between tumor mutational burden (TMB) and ICB response, while others have identified a link between ICB response and mutation in DNA Damage Repair (DDR) genes. However, it remains unclear to what extent mutations in DDR genes hold predictive value above and beyond their association with TMB. Herein we present a novel, networks-based test and Network Based-Expected TMB Score (N-BETS) with higher specificity for discriminating DDR genes and pathways that are associated with elevated TMB. Moreover, we find that mutations in certain DDR genes that are not associated with elevated TMB are nevertheless predictive of ICB benefit in two separate studies, demonstrating that their inactivation contributes to ICB response in a TMB independent manner.