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

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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<sub>0</sub>), second (C<sub>1</sub>) and/or third (C<sub>2</sub>) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (<i>KRAS, BRAF, TP53</i>) or hypermethylation (<i>WIF1, NPY</i>). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.</p><p><b>Results:</b> 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 C<sub>0</sub> had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5–12.6; <i>P</i> < 0.0001). By analyzing the evolution of the ctDNA concentration between C<sub>0</sub> and C<sub>2</sub> or C<sub>1</sub> (C<sub>2or1</sub>), 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” (<i>n</i> = 58) versus “bad ctDNA responder” (<i>n = 15</i>) had a better objective response rate (<i>P</i> < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09–0.40; <i>P</i> < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11–0.57; <i>P</i> < 0.001).</p><p><b>Conclusions:</b> This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. <i>Clin Cancer Res; 23(18); 5416–25. ©2017 AACR</i>.</p></div>