Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study)

Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first-or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C-0), second (C-1) and/or third (C-2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyseswere adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line. Results: Eighty-two patients with mCRC treated in first(82.9%) or second-(17.1%) line chemotherapy were included. Patients with a high (> 10 ng/mL) versus low (<= 0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C-0 and C-2 or C-1 (C-2or1), we classified the patients in two groups (named good or bad ctDNA responders). In multivariate analysis, patients belonging to the group called good ctDNA responder (n = 58) versus bad ctDNA responder (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001). Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. (C) 2017 AACR.