Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non–Small Cell Lung Cancer

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Abstract
Recent developments in immune checkpoint inhibitors (ICIs) have improved the survival in a multitude of advanced malignant neoplasms, including non–small cell lung cancer (NSCLC).1-6 However, most patients receiving ICIs do not derive a benefit. An important aspect of immunotherapy is how to identify and develop predictive biomarkers of ICI response.7,8 The commonly used clinically applicable predictive biomarker has been programmed cell death 1 ligand 1 (PD-L1), also known as cluster of differentiation 274 or CD274 (OMIM 605402) determined with immunohistochemistry. The Keynote-024 study1 found that the presence of tumor PD-L1 expression more than 50% was associated with the efficacy of pembrolizumab in first-line therapy. However, the sensitivity and specificity of PD-L1 expression are modest,9 which has prompted the search for additional tools.10,11 Mutation of mismatch repair (MMR) genes is known contribute to damage to the DNA damage response (DDR) pathway, which is associated with an increase in the tumor mutation burden (TMB),12 including catalytic subunit of DNA polymerase epsilon (POLE) (OMIM 174762) gene; DNA polymerase δ 1, catalytic subunit (POLD1) (OMIM 174761); breast cancer susceptibility gene 1 (BRCA1) (OMIM 113705); and breast cancer susceptibility gene 2 (BRCA2) (OMIM 600185), which are associated with the efficacy of ICIs in treating lung cancer, but the frequency of occurrence among patients with lung cancer is low.13-15

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