Serial Circulating Tumor DNA in Predicting and Monitoring the Effect of Neoadjuvant Chemoradiotherapy in Patients with Rectal Cancer: A Prospective Multicenter Study

Abstract

Purpose: We investigated the value of circulating tumor DNA (ctDNA) in predicting tumor response to neoadjuvant chemoradiotherapy (nCRT), monitoring tumor burden, and prognosing survival in patients with locally advanced rectal cancer (LARC). Experimental Design: This prospective multicenter trial recruited 106 LARC patients for treatment of nCRT followed by surgery. Serial ctDNA were analyzed by NGS at four time points: at baseline, during nCRT, pre-surgery and post-surgery. Results: In total, 1098 mutations were identified in tumor tissues of the 104 patients being analyzed (median, 7 mutations per patient). ctDNA was detected in 75%, 15.6%, 10.5%, and 6.7% of cases at the four time points, respectively. None of the 29 patients with pathological complete response (ypCR) had preoperative ctDNA detected. Preoperative ctDNA positive rate was significantly lower in the well responded patients with pathological tumor regression grade of ypCAP 0-1 than ypCAP 2-3 group (P < 0.001), lower in ypCR than non-ypCR group (P = 0.02), and lower in ypT 0-2 than ypT 3-4 group (P = 0.002). With a median follow-up of 18.8 months, thirteen patients (12.5%) experienced distant metastasis. ctDNA positivity at all four time points was associated with a shorter metastasis-free survival (MFS) (P < 0.05). Multivariate analyses showed that the median VAF of mutations in baseline ctDNA was a strong independent predictor of MFS (HR=1.27, P < 0.001). Conclusions: We show that ctDNA is a real-time monitoring indicator that can accurately reflect the tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of MFS.