Circulating Tumor DNA Detection In Lung Cancer Patients Before And After Surgery

Background and Objective: Targeted therapy has been a standard treatment for non-small cell lung cancer patients. A broad molecular testing should be conducted to seek the actionable driver genes. Circulating tumor DNA (ctDNA) in peripheral blood is a“liquid biopsy” that contains representative tumor information including gene mutations.The peripheral blood samples are easily and repeatedly obtained compared to the tissue or biopsy. So ctDNA samples can be used to monitor response to treatment, disease progression and mutation of resistance, which may be especially valuable to lung cancer patients with tumors that can not be easily biopsied or removed. Targeted next-generation sequencing of circulating tumor DNA has begun to be applied to clinic. However,molecular profiling using tissue or biopsy samples is still the 'golden standard' at present.Whether rapid detection of plasma ctDNA and mutations with targeted sequencing has potential to be a useful clinical strategy to monitor patients' response to treatment,including surgery needs to be further validated in larger studies and matched with clinical outcome data. In this study, mutation concordance in matched tDNA and plasma ctDNA sample pairs of NSCLC and plasma ctDNA mutation frequencies before and after surgery were analyzed to verify whether targeted next-sequencing of plasma DNA is reliable to and whether ctDNA can be used as a biomarker.Methods: ? Tumor tissue and blood samples obtained before and after surgery were collected prospectively from 41 non-small lung cancer (NSCLC) patients. Somatic driver mutations in tumor DNA (tDNA) and pre- and post-op plasma ctDNA sample pairs were identified by targeted sequencing in a 50 cancer related genes panel including EGFR,KRAS, TP53, ERBB2, PIK3CA;? Pre-surgery plasma samples were analyzed for the presence of the following tumor biomarkers: cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), cytokeratin 19 fragment(CYFRA21-1), and neuron specifc enolase (NSE).Results: ? Overall, the concordance rate of mutations identified in tDNA and matched pre-op plasma ctDNA was 78.1%, a sensitivity of 69.2% and a specificity of 93.3%(, with a PPV of cancer of 94.7%. ? The frequency of 91.7% of ctDNA mutations decreased after surgery and these changes were observed as little as 2 days post-op. ? The presence of ctDNA had a higher positive predictive value than that of six tumor biomarkers in current clinical use.Conclusion: This study demonstrates the use of targeted sequencing to reliably identify ctDNA changes in response to treatment, indicating a potential utility of this approach in the clinical management of NSCLC.