• Young Kwang Chae, Andrew A Davis, Sarita Agte, Alan Pan, Nicholas I Simon, Wade T Iams, Marcelo R Cruz, Keerthi Tamragouri, Kyunghoon Rhee, Nisha Mohindra, Victoria Villaflor, Wungki Park, Gilberto Lopes, and Francis J Giles.
• Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA young.chae@northwestern.edu andrew-davis@northwestern.edu.
• Oncologist. 2019 Jun 1; 24 (6): 820-828.

BackgroundTissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC).Materials And MethodsA total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length.ResultsHigher ctDNA TMB was significantly correlated with smoking history (p < .05, chi-squared test). Among patients treated with immune checkpoint inhibitors (n = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3-24.6; p < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3-27.1; p < .01, respectively). In a small independent validation cohort (n = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade.ConclusionThe findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes.Implications For PracticeBiomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.© AlphaMed Press 2019.

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