A prospective study of total plasma cell-free DNA as a predictive biomarker for response to systemic therapy in patients with advanced non-small-cell lung cancers.
BACKGROUND
While previous studies have reported on the prognostic value of total plasma cell-free deoxyribonucleic acid (cfDNA) in lung cancers, few have prospectively evaluated its predictive value for systemic therapy response.


METHODS
We conducted a prospective study to evaluate the association between changes in total cfDNA and radiologic response to systemic therapy in patients with stage IIIB/IV non-small-cell lung cancers (NSCLCs). Paired blood collections for cfDNA and computed tomography (CT) assessments by RECIST v1.0 were performed at baseline and 6-12 weeks after therapy initiation. Total cfDNA levels were measured in plasma using quantitative real-time polymerase chain reaction. Associations between changes in cfDNA and radiologic response, progression-free survival (PFS), and overall survival (OS) were measured using Kruskal-Wallis and Kaplan-Meier estimates.


RESULTS
A total of 103 patients completed paired cfDNA and CT response assessments. Systemic therapy administered included cytotoxic chemotherapy in 57% (59/103), molecularly targeted therapy in 17% (17/103), and combination therapy in 26% (27/103). Median change in cfDNA from baseline to response assessment did not significantly differ by radiologic response categories of progression of disease, stable disease and partial response (P = 0.10). However, using radiologic response as continuous variable, there was a weak positive correlation between change in radiologic response and change in cfDNA (Spearman's correlation coefficient 0.21, P = 0.03). Baseline cfDNA levels were not associated with PFS [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 0.93-1.20, P = 0.41] or OS (HR = 1.04, 95% CI 0.93-1.17, P = 0.51), neither were changes in cfDNA.


CONCLUSIONS
In this large prospective study, changes in total cfDNA over time did not significantly predict radiologic response from systemic therapy in patients with advanced NSCLC. Pretreatment levels of total cfDNA were not prognostic of survival. Total cfDNA level is not a highly specific predictive biomarker and future investigations in cfDNA should focus on tumor-specific genomic alterations using expanded capabilities of next-generation sequencing.
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA Sydney Medical School, University of Sydney, Sydney, Australia.
B T
BT
Li
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA.
A
A
Drilon
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA.
M L
ML
Johnson
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York.
M
M
Hsu
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York.
C S
CS
Sima
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA.
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C
McGinn
Department of Biochemistry, Keck School of Medicine, University of Southern California, Los Angeles.
H
H
Sugita
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA krism@mskcc.org.
M G
MG
Kris
Thoracic Oncology Program, Massachusetts General Hospital Cancer Center, Boston, USA.
C G
CG
Azzoli
D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality; D004273:DNA, Neoplasm / Q000097:blood*; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality; D011446:Prospective Studies; D011859:Radiography; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
biomarker; chemotherapy; non-small-cell lung cancer; plasma cell-free DNA