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
• DOI: 10.1158/1078-0432.ccr-16-3155

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.
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
), second (C
) and/or third (C
) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (
) or hypermethylation (
). 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.
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
had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6;
< 0.0001). By analyzing the evolution of the ctDNA concentration between C
and C
or C
(C
), 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" (
= 58) versus "bad ctDNA responder" (
) had a better objective response rate (
< 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40;
< 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57;
< 0.001).
This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC.
.