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

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 pathologic response, necessitating early-prediction tools. We investigated dynamic circulating tumor DNA (ctDNA) analysis for early response monitoring in patients with LARC 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 and recurred positive) and low-risk (early clearance and persistent negative) groups. Poor response was defined as pathologic 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 pathologic response (pTRG 0-1). The poor response rate was 59.4% in the high-risk group versus 12.4% in the low-risk group (P < 0.001). High-risk dynamic ctDNA status was a strong independent predictor of poor response (OR = 11.69; 95% confidence interval, 5-27.25; P < 0.001). Both delayed/no clearance (OR = 12.64; P < 0.001) and recurred positivity (OR = 8.91; P < 0.001) 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 patients with LARC 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.