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

TLDR

Markers of chemotherapy efficacy in metastatic colorectal cancer are essential for optimizing treatment strategies. The study evaluated whether early changes in circulating tumor DNA could serve as a marker of therapeutic efficacy in metastatic colorectal cancer patients. In a prospective cohort of 82 mCRC patients receiving first‑ or second‑line chemotherapy, plasma ctDNA was quantified by picodroplet‑digital PCR at baseline and subsequent cycles, with CT scans assessed by RECIST v1.1 and multivariate analyses adjusting for age, gender, ECOG performance status, metastatic synchronicity, and treatment line; patients were classified as good or bad ctDNA responders based on ctDNA evolution between cycles. High baseline ctDNA (>10 ng/mL) predicted shorter overall survival (6.8 vs. 33.4 months, HR 5.64), while good ctDNA responders had higher objective response rates and longer progression‑free (8.5 vs.

Abstract

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 (C0), second (C1) and/or third (C2) 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 analyses were 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 C0 and C2 or C1 (C2or1), 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. Clin Cancer Res; 23(18); 5416-25. ©2017 AACR.