TY - JOUR
T1 - Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer
AU - Chae, Young Kwang
AU - Davis, Andrew A.
AU - Agte, Sarita
AU - Pan, Alan
AU - Simon, Nicholas I.
AU - Iams, Wade T.
AU - Cruz, Marcelo R.
AU - Tamragouri, Keerthi
AU - Rhee, Kyunghoon
AU - Mohindra, Nisha
AU - Villaflor, Victoria
AU - Park, Wungki
AU - Lopes, Gilberto
AU - Giles, Francis J.
N1 - Publisher Copyright:
© AlphaMed Press 2019
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - Circulating tumor DNA (ctDNA)
KW - NSCLC
KW - PD-1
KW - PD-L1
KW - Tumor mutational burden (TMB)
UR - http://www.scopus.com/inward/record.url?scp=85062994004&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2018-0433
DO - 10.1634/theoncologist.2018-0433
M3 - Article
C2 - 30867242
AN - SCOPUS:85062994004
SN - 1083-7159
VL - 24
SP - 820
EP - 828
JO - Oncologist
JF - Oncologist
IS - 6
ER -