Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care

Safia El Messaoudi, Florent Mouliere, Stanislas Du Manoir, Caroline Bascoul-Mollevi, Brigitte Gillet, Michelle Nouaille, Catherine Fiess, Evelyne Crapez, Frederic Bibeau, Charles Theillet, Thibault Mazard, Denis Pezet, Muriel Mathonnet, Marc Ychou, Alain R. Thierry*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC). Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate). Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P = 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P = 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P = 0.0089 and P = 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/BRAF-mutant cohort of patients (P = 0.0052) and appeared as a strong independent prognostic factor (P = 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P = 0.67). Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment.

Original languageEnglish
Pages (from-to)3067-3077
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number12
DOIs
Publication statusPublished - 15 Jun 2016

Cite this

El Messaoudi, S., Mouliere, F., Du Manoir, S., Bascoul-Mollevi, C., Gillet, B., Nouaille, M., ... Thierry, A. R. (2016). Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clinical Cancer Research, 22(12), 3067-3077. https://doi.org/10.1158/1078-0432.CCR-15-0297