Abstract
<div>Abstract<p>Introduction: <i>ATM</i> is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC), however limited characterization has been pursued. Methods: Clinicopathologic, genomic, and treatment data were collected for 5172 patients with NSCLC tumors which underwent genomic profiling. ATM immunohistochemistry (IHC) was performed on 182 NSCLCs with <i>ATM</i> mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. <i>ATM</i><sup>MUT </sup>NSCLC was significantly associated with female sex (P=0.02), ever smoking status (P<0.001), non-squamous histology (P=0.004) and higher tumor mutational burden (DFCI: P<0.0001; MSK: P<0.0001) compared to <i>ATM</i><sup>WT</sup> cases. Among 3687 NSCLCs with comprehensive genomic profiling, co-occurring <i>KRAS</i>, <i>STK11</i>, and <i>ARID2</i> oncogenic mutations were significantly enriched among <i>ATM</i><sup>MUT</sup> NSCLCs (Q<0.05), while <i>TP53</i> and <i>EGFR</i> mutations were enriched in <i>ATM</i><sup>WT</sup> NSCLCs. Among 182<i> ATM</i><sup>MUT</sup> samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs 28.6%, P<0.0001) compared to tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N=1522) and chemo-immunotherapy (N=951) were similar between <i>ATM</i><sup>MUT </sup>and <i>ATM</i><sup>WT</sup> NSCLCs. Patients with concurrent <i>ATM/TP53</i> mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusion: Deleterious <i>ATM </i>mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific <i>ATM</i> mutations in NSCLC.</p></div>
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