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

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, Francis J. Giles

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)820-828
Number of pages9
JournalOncologist
Volume24
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • Circulating tumor DNA (ctDNA)
  • NSCLC
  • PD-1
  • PD-L1
  • Tumor mutational burden (TMB)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer'. Together they form a unique fingerprint.

  • Cite this

    Chae, Y. K., Davis, A. A., Agte, S., Pan, A., Simon, N. I., Iams, W. T., Cruz, M. R., Tamragouri, K., Rhee, K., Mohindra, N., Villaflor, V., Park, W., Lopes, G., & Giles, F. J. (2019). Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer. Oncologist, 24(6), 820-828. https://doi.org/10.1634/theoncologist.2018-0433