Co-mutations in DNA damage response pathways serve as potential biomarkers for immune checkpoint blockade

Biomarkers such as programmed death receptor 1 ligand (PD-L1) expression, tumor mutational burden (TMB), and high microsatellite instability are potentially applicable to predict the efficacy of immune checkpoint blockade (ICB). However, several challenges such as defining the cut-off value, test platform uniformity, and low frequencies limit their broad clinical application. Here we identify co-mutations in the DNA damage response (DDR) pathways of homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER) (defined as co-mut+) that are associated with increased TMB and neoantigen load and increased levels of immune gene expression signatures. In four public clinical cohorts, co-mut+ patients presented a higher objective response rate and a longer progression-free survival or overall survival than co-mut- patients. Overall, identification of DDR co-mutations in HRR-MMR or HRR-BER as predictors of response to ICB provides a potentially convenient approach for future clinical practice.

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