Liming Cao, Long Long, Min Li, Huaping Yang, Pengbo Deng, Xinru Mao, Jianxing Xiang, Bing Li, Tengfei Zhang, Chengping Hu

The development of next-generation sequencing (NGS) has revolutionized the understanding of oncogenesis of multiple types of cancer, including non-small cell lung cancer (NSCLC). However, there has been some debate over the utility of NGS for predicting patient prognosis and determining molecular targeted therapy. Therefore, we sought to demonstrate the numerous applications of NGS in the prognostic predictions and treatment of NSCLC patients. We performed NGS on either liquid or tissue tumor biopsies obtained from 53 NSCLC patients. The sequences were analyzed for oncogenic mutations, which were then correlated to clinical prognosis and smoking history. NGS of tumor biopsies detected both well-known driver mutations as well as rare or novel mutations. EGFR was the most frequently mutated gene, accounting for 32.4% (33/102) of the somatic mutations in this study. The EGFR mutations detected included rare variants such as EGFR exon 19 insertion (K745_E746insIPVAIK) and in cis H835L+L833V. Additionally, novel RET fusion mutations PCM1-RET and ADD3-RET were detected in two adenocarcinoma patients. To demonstrate the functional applications of NGS, we correlated mutations with patient characteristics, outcomes of matched targeted therapy, and outcomes based on allelic frequency of the EGFR-T790M mutation. Finally, we demonstrated that circulating tumor DNA can be used both to measure response to targeted therapy and as a predictor of clinical outcome, by presenting a case study of a single patient. We demonstrated that NGS can be used in multiple applications to effectively identify potential oncogenic driver mutations, guide mutation-targeted therapy decisions, and predict clinical outcomes in Chinese NSCLC patients.