Cell-Free DNA, Tumor Molecular Concordance, and Clinical Correlates of Patients with Cancer Treated in a Large...

Blood collection, plasma processing, and cell-free DNA (cfDNA) purification were optimized to capture circulating tumor DNA without blood cell background DNA among 874 patients with cancer. cfDNA comprised predominantly mononucleosomal fragments [n = 874; mean (x¯) ± SD = 166 ± 5 bp] that generated comparably sized sequencing reads (x¯ ± SD = 162 ± 25 bp). Despite a vast range of cfDNA concentrations (0.50 to 1132.9 ng/mL) across 21 tumor types, matched tumor and blood specimens (n = 430 patients) revealed high concordance for coding (median = 97%) and clinical oncogenic mutations (median = 88% concordance). Therapeutically actionable mutations were identified in 233 patients by both assays, whereas 126 patients had oncogenic mutations without an established pharmacotherapeutic agent. An additional 48 patients (11%) had actionable mutations detected only in cfDNA assays, whereas 23 patients (5%) had mutations in tumor only. Concordance was high in both prevalent (lung, breast, and colon) and rare tumors (appendiceal, sarcoma). Cell-free DNA levels from diagnostic blood specimens were a strong indicator of patient survival duration independent of age, sex, tumor type, and stage, demonstrative of a potentially important role as a prognostic biomarker. Mutations in established oncogenes and tumor suppressors were readily detectable across all tumor types in circulating tumor DNA, indicating a diagnostic role for cfDNA from blood extending beyond the identification of companion therapeutics to patient screening and monitoring.