eP649 - Clinical Impact of Circulating Tumor DNA Methylation Status of Tumor Suppressor Genes in Precision Medicine for Stage IV Colorectal Cancer

Purpose/Background: Hypermethylation of tumor suppressor genes can lead to cancer development and progression through gene silencing. A number of methylated genes have been identified and investigated to examine the correlations between epigenetic signatures and the colorectal diagnosis, staging, tendency to metastasize, prognosis, and response to treatment. Liquid biopsies, defined as the sampling and analysis of non-solid biological tissue (primarily blood), are considered useful for monitoring diseases such as cancer with the added benefit of being largely noninvasive.The current study investigated the significance of circulating tumor DNA (ctDNA) methylation in colorectal cancer (CRC).Methods/Interventions: Ninety-five patients who underwent resection of stage IV adenocarcinoma of the colon and rectum were enrolled in this study. Patients were ineligible if they had multiple synchronous or metachronous cancers or underwent preoperative treatment. Patient background, clinicopathological factors, and gene promoter methylation status were analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was performed using bisulfite-modified DNA for methylation of the CHFR, SOX11, and CDO1 promoters. The relative methylation value (RMV) was used to evaluate the final quantification of DNA methylation.Results/Outcomes: Forty-nine patients underwent curative resection for Stage IV disease (Cur group), 32 underwent incurable resection (Incur group), 9 underwent curative resection for primary tumor and metastatic organs following neoadjuvant systemic chemotherapy (NAC-Cur group), and 5 underwent incurable resection even after neoadjuvant systemic chemotherapy (NAC-Incur group). In the Cur group, the CHFR-RMV high patients had a significantly worse recurrence-free survival (RFS) than the CHFR-RMV low patients (p=0.001). Conversely, the RFS did not significantly differ between the SOX11- and CDO1-RMV high and low groups (p=0.25 and 0.12, respectively). Multivariate analyses of these two variables revealed that the maximum diameter of the primary tumor and CHFR-RMV were independent significant prognostic factors (hazard ratio=2.19 [1.01-4.72]; p=0.046 and hazard ratio=2.63 [1.29-5.36]; p=0.008, respectively). Similarly, in the NAC-Cur group, the SOX11-RMV high group had a significantly worse RFS than the SOX11-RMV low group (p=0.004). However, a multivariate analysis with these three variables did not converge, presumably because of the small number of patients in the NAC-Cur group. In contrast, in the Incur group, there were no significant differences in the cancer-specific survival between the CHFR-, SOX11-, and CDO1-RMV high and low groups (p=0.50, 0.18, and 0.08, respectively).Conclusion/

Discussion: Our current study demonstrated the usefulness of the ctDNA methylation status in predicting the possibility of curative resection for Stage IV disease as well as the long-term outcomes after curative resection for distant metastases.