Molecular Evolutionary Process of Advanced Gastric Cancer During Sequential Chemotherapy Detected by Circulating Tumor DNA

Abstract Background: Chemotherapy is the major strategy for advanced gastric cancer (AGC) patients, whereits efficacy has largely plateaued. Tumor evolutionary theory provides a promising strategy to optimize paradigm of cancer treatment, while current data of molecular changes during sequential chemotherapy is too insufficient to understandevolutionary process in tumors. Methods: Here, we performed NGS analysison 100 circulatingtumor DNA (ctDNA) samples collected from 27 AGC patients during treatment of sequentialchemotherapy. We observed dynamic changes of copy number instability (CNI) and gene-level copy number variations (CNVs) during the treatment.Results: Gene-levelCNV profiles were similar between baseline and end oftreatment. Subsequent regimens did not significantly change the CNV profiles driven by first-line regimens. Based on changes of copy number values of genes during treatment, resistance related genes of all four regimens were identified, respectively. These genes could be enriched into several common oncologic pathways, while exhibited a high inter-patient heterogeneity. Genes with different copy number values between baseline and end of treatment could be the targets of by molecular matched therapy. Conclusions: Our study provides important information to understand molecular evolutionary process of AGS patients during sequential chemotherapy first and can help to optimize future treatment strategies.