Recurrence Prediction by Multi-Omics in the Patient with Colorectal Peritoneal Metastases After Cytoreductive Surgery: A Prospective Biomarker Study

Abstract

Background: Colorectal cancer with peritoneal metastases (CRCPM) exhibits high recurrence post-cytoreductive surgery (CRS). This study evaluated tumor tissue biomarkers and combined circulating tumor DNA (ctDNA) and methylation analysis via ultra-deep next-generation sequencing (NGS) for recurrence prediction. Methods: CRCPM patients undergoing surgery were enrolled (n=21). Blood samples was collected at preoperative and postoperative, and tumor and adjacent tissues were collected. NGS assessed ctDNA and methylation in blood samples, while tumor mutations and methylation were analyzed in tumor. Recurrence was determined via imaging. Outcomes included progression-free survival (PFS) and overall survival (OS). Results: Of 17 patients with paired pre-/postoperative ctDNA testing, preoperative ctDNA levels were higher in those with extraperitoneal metastases versus peritoneal-only disease (0.1064 vs 0.0037). Postoperative ctDNA positivity correlated with 100% peritoneal recurrence. ctDNA-positive subgroups showed shorter PFS (HR=2.5; 95% CI:1.6–6.6). Patients persistently ctDNA-negative pre-/postoperatively had improved PFS versus those with positivity (HR=5.07; 95% CI:0.53–48.38). ctDNA methylation positivity was observed in all extraperitoneal metastasis cases and 70% of peritoneal-only cases. Baseline methylation positivity predicted worse OS overall and in peritoneal-only subgroups. Postoperative dual negativity for ctDNA and methylation correlated with better OS. Tumor mutations in EPHB1 (P = 0.012), ARFRP1 (P = 0.048), and ATR (P = 0.048) were significantly associated with PFS. Conclusion: Dynamic ctDNA and methylation monitoring, and tumor mutation profiling, may serve as sensitive biomarkers for early recurrence detection in CRCPM underwent CRS. These tools could enhance recurrence prediction and guide clinical management.