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In oncology as well as for other conditions, circulating cell-free DNA analysis is considered as a breakthrough for diagnosis, prognosis, patient follow-up and theranostics.

GENESIS

Pioneering observations: In 2005, A.R. Thierry's team started to work on circulating DNA and provided breakthrough observations on the structure and origins of tumour-derived circulating DNA.

They were the first to demonstrate that tumour-derived circulating DNA was highly fragmented, as observed by atomic force microscopy and by qPCR size distribution studies. Their observations were considered as a major breakthrough since they were in contradiction with all previous data reports.

Based upon these breakthrough observations, A.R. Thierry’s group revisited Q-PCR based methods and designed the IntPlex® technology which is the first multiplex test for circulating DNA.

This work on liquid biopsy led to a patent linkage on the IntPlex® technology granted by the US in 2011 and another patent on the strong prognostic value of circulating DNA analysis by IntPlex® in 2014.

APPLICATIONS

Circulating DNA analysis will provide an answer to existing barriers to an accurate and dynamic tumour molecular analysis.

Our clinical validation studies showed how circulating DNA analysis by IntPlex® presents many advantages for tumour analysis across all phases of disease progression:


  • - Prediction of response
  • - Therapy monitoring
  • - Emergence of resistance
  • - Minimal residual disease
  • - Surveillance of recurrence
  • - Prognostics
  • - Screening
  • - Tumor micro-environment
  • - Multimarker and quantitative approach

Circulating DNA analysis by IntPlex® has been clinically validated on a cohort of over 700 metastatic colorectal cancer patients with the detection of KRAS/NRAS/BRAF point mutations for prognostic value and therapy selection. IntPlex® has been tested on more than 1000 samples from various tumor types, including EGFR mutations in lung cancer and PIK3CA mutations in breast cancer..

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DEVELOPMENT TIMELINE

    2015
  • - KRAS, NRAS, BRAF colorectal cancer theranostics, feasibility study
  • - BRAF, melanoma theranostics, feasibility study
  • - EGFR, lung cancer theranostics, feasibility study
    2016
  • - KRAS, NRAS, BRAF colorectal cancer theranostics, pilot kit
  • - EGFR, pilot kit
  • - PIK3CA, colorectal cancer and breast cancer theranostics, feasibility study
  • - Early detection of drug resistance (KRAS/NRAS/EGFR T790M)
    2017
  • - CE/IVD technical studies for EGFR, BRAF, KRAS/NRAS
  • - Monitoring of recurrence, colorectal cancer, breast cancer, lung cancer
  • - ESR1 breast cancer theranostics, feasibility study
    2018
  • - EGFR, BRAF, KRAS/NRAS CE/IVD kit
  • - PIK3CA, colorectal cancer and breast cancer, pilot kit
  • - ESR1, pilot kit
  • - Monitoring of patients with prostate cancer
  • - Treatment efficiency, pancreas cancer
  • - T-cell lymphoma, feasibility study

PUBLICATIONS

Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment. 2017
Ann Oncol 28:2149–2159
Thierry AR, El Messaoudi S, Mollevi C, Raoul JL, Guimbaud R, Pezet D, … Ychou M (2017a).

Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer. 2017
Clin Cancer Res 23:4578–4591
Thierry AR, Pastor B, Jiang Z-Q, Katsiampoura AD, Parseghian C, Loree JM, …Kopetz S

Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer. 2017
Clin Cancer Res 23:4146–4154
Parseghian CM, Parikh NU, Wu JY, Jiang Z-Q, Henderson L, Tian F, … Kopetz S

Circulating DNA as a strong multi-marker prognostic tool for metastatic colorectal cancer patient management care. 2016
Clin Cancer Res CCR-15-0297
El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, … Thierry AR

Origins, Structures, and Functions of Circulating DNA in Oncology, 2016
Cancer and Metastasis reviews, 35(3) pp 347–376
Thierry AR, El Messaoudi S, Gahan PB, Anker P and Stroun M

Circulating DNA as a strong multi-marker prognostic tool for metastatic colorectal cancer patient management care. 2016
Clinical Cancer Research, 15;22(12):3067-7
El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, … Thierry AR

A Targeted Q-PCR-Based Method for Point Mutation Testing by Analyzing Circulating DNA for Cancer Management Care. 2016
Methods Mol Biol. 2016;1392:1-16.
Thierry AR

Circulating DNA and cancer. 2015
AACR Education Book, 2015(1), 45.
Thierry AR

DNA studies using atomic force microscopy: capabilities for measurement of short DNA fragments. 2015
Frontiers in Molecular Biosciences, 2, 1
Pang D, Thierry AR & Dritschilo A

Detection of genetic alterations by Nucleic Acid analysis: Use of PCR and Mass Spectrometry Based Methods. 2015
In P. B. Gahan (Ed.), Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring (Vol. 5, pp. 89-111).
Mouliere F, Thierry AR & Larroque C

Circulating DNA and miRNA isolation. 2015
In P. B. Gahan (Ed.), Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring (Vol. 5, pp. 71-87).
Thierry AR, El Messaoudi S & Crapez E

Pre-analytical Requirements for Analyzing Nucleic Acids from Blood. 2015
In P. B. Gahan (Ed.), Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring (Vol. 5, pp. 45–69).
El Messaoudi S & Thierry AR

Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. 2014
Nature Medicine, 20(4), 430–435.
Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, … Ychou M

Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer. 2014
Molecular Oncology, 8(5), 927–941.
Mouliere F, El Messaoudi S, Pang D, Dritschilo A, & Thierry, AR

Circulating cell free DNA: Preanalytical considerations. 2013
Clinica Chimica Acta, 424:222-30
El Messaoudi S, Rolet F, Mouliere F, & Thierry AR

Circulating Cell-Free DNA from Colorectal Cancer Patients May Reveal High KRAS or BRAF Mutation Load. 2013
Translational oncology, 6(3), 319–328.
Mouliere F, El Messaoudi S, Gongora C, Guedj A.-S, Robert B, Del Rio M, … Thierry AR

The importance of examining the proportion of circulating DNA originating from tumor, microenvironment and normal cells in colorectal cancer patients. 2012
Expert Opinion on Biological Therapy, 12(S1), S209–S215.
Mouliere F, & Thierry, AR

High fragmentation characterizes tumour-derived circulating DNA. 2011
PloS one, 6(9), e23418.
Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, … Thierry AR

Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts. 2010
Nucleic Acids Research, 38(18), 6159–6175
Thierry AR, Mouliere F, Gongora C, Ollier J, Robert B, Ychou M, … Molina F

PATENTS

European patent PCT No. EP2011 / 065333
Authors: AR.Thierry and F. Molina
Analytical methods for cell free nucleic acids and application. September 2011

 

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