Dynamic ctDNA Monitoring Guides Early Treatment Intensification in Locally Advanced Rectal Cancer Undergoing Neoadjuvant Chemotherapy

Abstract Purpose: Neoadjuvant chemotherapy (NCT) has been accepted as the standard management for locally advanced rectal cancer (LARC) without high-risk factors. However, many patients experience poor pathological response, necessitating early prediction tools. We investigated dynamic circulating tumor DNA (ctDNA) analysis for early response monitoring in LARC patients undergoing NCT. Experimental Design: In this biomarker substudy of the multicenter randomized COPEC trial, 153 patients with low-/intermediate-risk LARC were enrolled. Plasma samples (n=526) were collected at baseline and after each cycle of NCT. ctDNA was analyzed via tumor-informed sequencing. Patients were classified by dynamic status into high-risk (delayed/no clearance, recurred positive) and low-risk (early clearance, persistent negative) groups. Poor response was defined as pathological tumor regression grade (pTRG) 3 or distant metastasis. The association between ctDNA status and responses was analyzed. Results: No patient with high-risk ctDNA dynamics achieved a major pathological response (pTRG 0-1). The poor response rate was 59.4% in the high-risk group versus 12.4% in the low-risk group (p0.001). High-risk dynamic ctDNA status was a strong independent predictor of poor response (odds ratio OR=11.69, 95% CI 5.00–27.25, p0.001). Both delayed/no clearance (OR=12.64, p0.001) and recurred positivity (OR=8.91, p0.001) were significant risk factors. A single preoperative ctDNA-positive result also predicted poor response (OR=11.27, p 0.001). Conclusions: Dynamic ctDNA monitoring identifies LARC patients at high risk for NCT failure as early as two cycles into treatment, which can form the basis for an adaptive trial design and eventual personalization of therapy selection.