Chromosomal instability of circulating tumor DNA reflect therapeutic responses in advanced gastric cancer

Gastric cancer is characterized by chromosomal instability. In this study, we investigated chromosomal instability quantified by copy number instability (CNI) score of circulating tumor DNA (ctDNA) during the drug treatment in advanced gastric cancer (AGC). A total of 55 pretherapeutic plasmas from 55 AGC patients and 75 plasmas during drug treatment of 26 AGC patients were collected. Plasma ctDNA was extracted and assessed by whole-genome sequencing (WGS) for somatic copy number alteration (SCNA), and according to which we calculated the CNI scores. We next assessed the correlations between chromosomal instability and therapeutic response. The cutoff value of chromosomal instability was defined as the mean + SD of the CNI scores (56.60) in cfDNA of plasmas from 100 healthy people. For 55 enrolled cases, chromosomal instability was observed in 27 (49%) prior to drug treatment, whose response rate (59%, 16/27) was higher than in 28 patients with stable chromosomes (32%, 9/28, P = 0.043). We also observed that CNI scores fluctuated during treatment in 26 patients. Specifically, the CNI scores in 93% (14/15) of patients sensitive to drug treatment reduced to the level of chromosomal stability and the CNI scores in 52% (13/25) of patients resistant to treatment elevated again. For ctDNA with developed resistance, the SCNA patterns were identical to those before treatment, whereas the CNI scores were lower than the pretherapeutic scores. We found that chromosomal instability based on ctDNA could predict and monitor therapeutic response in gastric cancer, although validation in a larger cohort will be necessary.