Utility of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients with Non-small Cell Lung Cancer.

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The utility of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).How does the utility of circulating tumor DNA (ctDNA) compare to that of solid tumor biopsy in non-small cell lung cancer (NSCLC) patients?We retrospectively evaluated 370 adult NSCLC patients treated at the City of Hope between November 2015 and August 2019 to assess the utility of ctDNA in mutation identification, survival, concordance with matched tissue samples in thirty-two genes, and tumor evolution.A total of 1688 somatic mutations were detected in 473 ctDNA samples from 370 NSCLC patients. Of the 473 samples, 177 had at least one actionable mutation with currently available FDA-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rates [FDR] < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR = 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR] 0.56, 95% CI: 0.37-0.85, p = 0.006). Overall survival was shorter in BRAF (HR 2.35, 95% CI: 1.24-4.6, p = 0.009, PIK3CA (HR 2.77, 95% CI: 1.56-4.9, P< 0.001 and KRAS-positive patients (HR 2.32, 95% CI: 1.30-4.1, P= 0.004). Gene-level concordance was 93.8% while the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsies. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.Although ctDNA exhibited similar utility to tissue biopsies, more mutations in targetable genes were missed in tissue biopsies. Therefore, the evaluation of ctDNA in conjunction with tissue biopsies may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.

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Authors: Moom R Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Hatim Husain, Karen L Reckamp, Marianna Koczywas, Erminia Massarelli, Andrea H Bild, Ravi Salgia


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