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

• Published in: Clinical cancer research Vol. 23; no. 18; pp. 5416 - 5425
• Main Authors: Garlan, Fanny, Laurent-Puig, Pierre, Sefrioui, David, Siauve, Nathalie, Didelot, Audrey, Sarafan-Vasseur, Nasrin, Michel, Pierre, Perkins, Geraldine, Mulot, Claire, Blons, Hélène, Taieb, Julien, Di Fiore, Frederic, Taly, Valerie, Zaanan, Aziz
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.09.2017; American Association for Cancer Research
• Subjects: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biochemistry, Molecular Biology; Biomarkers, Tumor; Cancer; Chemotherapy; Circulating Tumor DNA; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - therapy; Computed tomography; Deoxyribonucleic acid; DNA; Effectiveness; Experimental design; Female; Humans; K-Ras protein; Life Sciences; Liquid Biopsy; Male; Metastases; Metastasis; Middle Aged; Multivariate analysis; Mutation; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Neuropeptide Y; Optimization; p53 Protein; Patients; Point mutation; Prognosis; Survival; Survival Analysis; Treatment Outcome; Workflow
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3155

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.