Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition
Abstract
The clinical application of PD1/PD-L1 targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma. We sought to explore the subset of microsatellite stable (MSS) CRC patients with high TMB, and identify the specific genomic signatures associated with this phenotype. Furthermore, we explore the ability to quantify TMB as a potential predictive biomarker of PD1/PD-L1 therapy in CRC. Formalin-fixed, paraffin embedded tissue sections from 6,004 cases of CRC were sequenced with a CLIA-approved CGP assay. MSI and TMB statuses were computationally determined using validated methods. The cutoff for TMB-high was defined according to the lower bound value that satisfied the 90% probability interval based on the TMB distribution across all MSI-High patients. MSS tumors were observed in 5,702 of 6,004 (95.0%) ...Continue Reading
Citations
Tumor-derived mutations in postoperative plasma of colorectal cancer with microsatellite instability
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