Clinical utility of longitudinal circulating tumor DNA analysis in metastatic colorectal cancer patients receiving palliative chemotherapy.

[BACKGROUND] This study aims to evaluate the use of circulating tumor DNA (ctDNA) for identifying mutation profiles and monitoring dynamic changes in patients with metastatic colorectal cancer (mCRC) undergoing palliative chemotherapy.

[METHODS] This prospective observational study enrolled patients with mCRC treated at Asan Medical Center, Korea, between July 2018 and April 2020. ctDNA analysis was performed on plasma samples collected at baseline, first progression (PD), and second PD. Baseline ctDNA profiles were compared with matched tumor NGS data, and longitudinal changes in ctDNA were tracked over time. Clinical outcomes were correlated with ctDNA concentration and variant allele frequency (VAF).

[RESULTS] A total of 33 patients were included. ctDNA was detected in 93.9% of patients at baseline. The most frequent mutations were in APC and TP53 (81.8%), followed by KRAS (39.4%) and PIK3CA (30.3%). The median baseline ctDNA VAF was 17.7%, with significantly higher levels observed in patients with liver metastases. The overall concordance rate between plasma and tissue samples was 86.9%, with high accuracy in determining RAS/RAF mutation status. During treatment, acquired mutations emerged; notably, anti-EGFR therapy was associated with new RAS mutations (predominantly Q61 variants), while anti-VEGF therapy induced a broader range of genetic alterations. Elevated baseline ctDNA levels and higher maximum VAF at first PD were significantly correlated with shorter overall survival.

[CONCLUSIONS] ctDNA analysis offers a non-invasive approach for comprehensive genomic profiling in mCRC. Its ability to monitor genetic alterations and predict clinical outcomes underscores its potential utility in guiding personalized treatment strategies and monitoring resistance in clinical practice.