Clinicopathological parameters for circulating tumor DNA shedding in surgically resected non-small cell lung cancer with EGFR or KRAS mutation

BACKGROUND: Circulating tumor DNA (ctDNA) is cell-free DNA that is released into peripheral blood by tumor cells. ctDNA harbors somatic mutations and mutant ctDNA obtained from blood can be used as a biomarker in advanced non-small cell lung cancer (NSCLC). In this study, we investigated the clinicopathological properties of tumors that shed ctDNA in surgically resected NSCLC patients. METHODS: Consecutive cases of NSCLC with matching surgically resected tissue specimens and peripheral or specimen blood samples were eligible for this study. EGFR and KRAS mutations in plasma ctDNA and formalin-fixed paraffin-embedded tissue were analyzed using peptide nucleic acid clamping-assisted method. The plasma and tissue results were compared according to clinicopathological features. RESULTS: Mutation analyses were available for 36 cases. EGFR and KRAS mutations were present in 41.7% (15/36) and 16.7% (6/36) of tissue samples, respectively. Among EGFR and KRAS-mutant tumors, plasma mutation detection sensitivity was 13.3% (2/15) for EGFR and 33.3% (2/6) for KRAS. The presence of ctDNA in plasma was significantly associated with higher pathological tumor stage (p = 0.028), nodal metastasis (p = 0.016), solid adenocarcinoma pattern (p = 0.003), tumor necrosis (p = 0.012), larger primary tumor diameter (p = 0.002) or volume (p = 0.002), and frequent mitosis (p = 0.018) in tissue specimens. All tumors larger than 4 cm in maximal diameter or 25 cm(3) in volume shed ctDNA in plasma. In subgroup analysis among EGFR mutated adenocarcinoma, ctDNA was significantly associated with nodal metastasis (p = 0.029), vascular invasion (p = 0.029), solid adenocarcinoma pattern (p = 0.010), and tumor necrosis (p = 0.010), high mitotic rate (p = 0.009), large pathological tumor size (p = 0.027), and large tumor volume on CT (p = 0.027). CONCLUSION: We suggest that primary or total tumor burden, solid adenocarcinoma morphology, tumor necrosis, and frequent mitosis could predict ctDNA shedding in pulmonary adenocarcinoma.