Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer

The oncologist

article

Young Kwang Chae¹  Nisha Mohindra¹  Victoria Villaflor¹  Wungki Park⁴  Gilberto Lopes⁴  Francis J. Giles¹  Andrew A. Davis²  Sarita Agte³  Alan Pan²  Nicholas I. Simon²  Wade T. Iams²  Marcelo R. Cruz¹  Keerthi Tamragouri²  Kyunghoon Rhee² 

[1] Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University Feinberg School of Medicine;Department of Medicine, Northwestern University Feinberg School of Medicine;Robert H. Lurie Comprehensive Cancer Center of Northwestern University;Division of Hematology and Medical Oncology, Department of Medicine, Miller School of Medicine, University of Miami

关键词: Circulating tumor DNA (ctDNA);    Tumor mutational burden (TMB);    NSCLC;    PD-1;    PD-L1;   

DOI  :  10.1634/theoncologist.2018-0433

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background Tissue 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 Methods A 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. Results Higher 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. Conclusion The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes. Implications for Practice Biomarkers 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.

【 授权许可】

CC BY|CC BY-NC