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Cancer Therapy: Clinical

Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer

Alain R. Thierry, Brice Pastor, Zhi-Qin Jiang, Anastasia Katsiampoura, Christine Parseghian, Jonathan M. Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou and Scott Kopetz
Alain R. Thierry
Institut de Recherche en Cancerologie de Montpellier, IRCM U1194 Inserm
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  • For correspondence: alain.thierry@inserm.fr
Brice Pastor
Institut de Recherche en Cancerologie de Montpellier, IRCM U1194 Inserm
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Zhi-Qin Jiang
Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center
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Anastasia Katsiampoura
The University of Texas MD Anderson Cancer Center
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Christine Parseghian
GI Medical Oncology, UT MD Anderson Cancer Center
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Jonathan M. Loree
The University of Texas MD Anderson Cancer Center
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Michael J. Overman
Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center
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Cynthia Sanchez
IRCM
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Safia El Messaoudi
IRCM, INSERM U1194
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Marc Ychou
Laboratoire Biologie Specialisee, CRLC Val d'Aurelle Paul Lamarque
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Scott Kopetz
Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center
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DOI: 10.1158/1078-0432.CCR-17-0232
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Abstract

Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. <p>Experimental design: We evaluated under blinded conditions the ability of cell free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results: Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.</p> <p>Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.

  • Received January 25, 2017.
  • Revision received March 28, 2017.
  • Accepted April 6, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst April 11, 2017
doi: 10.1158/1078-0432.CCR-17-0232

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Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Alain R. Thierry, Brice Pastor, Zhi-Qin Jiang, Anastasia Katsiampoura, Christine Parseghian, Jonathan M. Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou and Scott Kopetz
Clin Cancer Res April 11 2017 DOI: 10.1158/1078-0432.CCR-17-0232

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Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Alain R. Thierry, Brice Pastor, Zhi-Qin Jiang, Anastasia Katsiampoura, Christine Parseghian, Jonathan M. Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou and Scott Kopetz
Clin Cancer Res April 11 2017 DOI: 10.1158/1078-0432.CCR-17-0232
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Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

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