Molecular Residual Disease and Recurrence in Rectal Cancer Patients Undergoing Upfront Surgery: A Prospective Cohort Study.

Abstract

OBJECTIVE To evaluate the prognostic utility of postoperative circulating tumor DNA (ctDNA) for recurrence and treatment response in patients with rectal cancer undergoing upfront surgery. SUMMARY BACKGROUND DATA ctDNA-based molecular residual disease (MRD) testing shows promise in colorectal cancer, but its role in patients with rectal cancer not receiving neoadjuvant therapy is unclear. This study evaluates whether postoperative ctDNA predicts disease-free survival (DFS) and guides adjuvant chemotherapy (ACT) decisions. METHODS We analyzed ctDNA from patients with stage II-III rectal cancer (N=250) enrolled in the GALAXY study, multi-center registry in Japan. A clinically validated, personalized, tumor-informed 16-plex PCR-NGS assay (SignateraTM) was used to detect and quantify ctDNA. The primary outcome was DFS, defined as time from landmark to recurrence, death, or latest radiological assessment. RESULTS In the MRD window (2-10 wks post-surgery, before ACT), 14.2% (35/246) of patients were ctDNA-positive and had significantly shorter DFS (HR: 9.96, 95% CI: 5.76-17.2, P<0.0001). Among patients who were ctDNA-positive in the MRD window, a significant benefit from ACT was observed (HR: 0.28, 95% CI: 0.09-0.89, P=0.031), whereas no benefit was seen in ctDNA-negative patients (HR: 0.59, 95% CI: 0.26-1.35, P=0.211). When analyzing ctDNA dynamics from MRD window to 6-months post-surgery, recurrence risk was higher in patients who converted from ctDNA-negative to positive (HR: 8.22, 95% CI: 1.86-36.32, P=0.0055) and who remained ctDNA-positive (HR: 45.48, 95% CI: 14.31-144.57, P<0.0001) compared to serially ctDNA-negative patients. CONCLUSIONS Postoperative ctDNA status is a robust biomarker predicting recurrence risk and ACT benefit in patients with rectal cancer undergoing upfront surgery.