Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

被引:126
作者
El Messaoudi, Safia [1 ,2 ,3 ,4 ]
Mouliere, Florent [1 ,2 ,3 ,4 ,11 ]
Du Manoir, Stanislas [1 ,2 ,3 ,4 ]
Bascoul-Mollevi, Caroline [1 ,2 ,3 ,4 ,5 ]
Gillet, Brigitte [6 ]
Nouaille, Michelle [7 ]
Fiess, Catherine [8 ]
Crapez, Evelyne [1 ,2 ,3 ,4 ]
Bibeau, Frederic [1 ,2 ,3 ,4 ,9 ]
Theillet, Charles [1 ,2 ,3 ,4 ]
Mazard, Thibault [1 ,2 ,3 ,4 ,10 ]
Pezet, Denis [6 ]
Mathonnet, Muriel [7 ]
Ychou, Marc [1 ,2 ,3 ,4 ,10 ]
Thierry, Alain R. [1 ,2 ,3 ,4 ]
机构
[1] Inst Rech Cancerol Montpellier, IRCM, Montpellier, France
[2] INSERM, U1194, Montpellier, France
[3] Univ Montpellier, F-34059 Montpellier, France
[4] Inst Reg Canc Montpellier, Montpellier, France
[5] Inst Reg Canc Montpellier, Unie Biometrie, Montpellier, France
[6] Univ Auvergne, UMR Unit Inserm, Serv Chirurg Digest,U1071, Ctr Hosp Univ Clermont Ferrand,Unite Oncol Digest, Clermont Ferrand, France
[7] Ctr Hosp Univ Limoges, Serv Chirurg Digest, Ctr Invest Clin, INSERM 0801, Limoges, France
[8] Inst Reg Canc Montpellier, Serv Rech Clin, Montpellier, France
[9] Inst Reg Canc Montpellier, Serv Anatomopathol, Montpellier, France
[10] Inst Reg Canc Montpellier, Serv Chirurg Digest, Montpellier, France
[11] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England
关键词
CELL-FREE DNA; KRAS-MUTATION STATUS; BREAST-CANCER; TUMOR DNA; GASTROINTESTINAL CANCER; BRAF MUTATIONS; LIQUID BIOPSY; LUNG-CANCER; SURVIVAL; INTEGRITY;
D O I
10.1158/1078-0432.CCR-15-0297
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2016 AACR.
引用
收藏
页码:3067 / 3077
页数:11
相关论文
共 41 条
[31]   Serial assessment of human tumor burdens in mice by the analysis of circulating DNA [J].
Rago, Carlo ;
Huso, David L. ;
Diehl, Frank ;
Karim, Baktiar ;
Liu, Guosheng ;
Papadopoulos, Nickolas ;
Samuels, Yardena ;
Velculescu, Victor E. ;
Vogelstein, Bert ;
Kinzler, Kenneth W. ;
Diaz, Luis A., Jr. .
CANCER RESEARCH, 2007, 67 (19) :9364-9370
[32]   High Levels of Cell-Free Circulating Nucleic Acids in Pancreatic Cancer are Associated With Vascular Encasement, Metastasis and Poor Survival [J].
Singh, Nidhi ;
Gupta, Surabhi ;
Pandey, R. M. ;
Chauhan, Shyam S. ;
Saraya, Anoop .
CANCER INVESTIGATION, 2015, 33 (03) :78-85
[33]   Circulating DNA is a Useful Prognostic Factor in Patients with Advanced Non-small Cell Lung Cancer [J].
Sirera, Rafael ;
Bremnes, Roy M. ;
Cabrera, Andrea ;
Jantus-Lewintre, Eloisa ;
Sanmartin, Elena ;
Blasco, Ana ;
del Pozo, Nieves ;
Rosell, Rafael ;
Guijarro, Ricardo ;
Galbis, Jose ;
Javier Sanchez, Jose ;
Camps, Carlos .
JOURNAL OF THORACIC ONCOLOGY, 2011, 6 (02) :286-290
[34]   Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer [J].
Spindler, Karen-Lise Garm ;
Appelt, Ane L. ;
Pallisgaard, Niels ;
Andersen, Rikke F. ;
Brandslund, Ivan ;
Jakobsen, Anders .
INTERNATIONAL JOURNAL OF CANCER, 2014, 135 (12) :2984-2991
[35]   Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan [J].
Spindler, Karen-Lise Garm ;
Pallisgaard, Niels ;
Vogelius, Ivan ;
Jakobsen, Anders .
CLINICAL CANCER RESEARCH, 2012, 18 (04) :1177-1185
[36]   Multimarker Circulating DNA Assay for Assessing Blood of Prostate Cancer Patients [J].
Sunami, Eiji ;
Shinozaki, Masaru ;
Higano, Celestia S. ;
Wollman, Robert ;
Dorff, Tanya B. ;
Tucker, Steven J. ;
Martinez, Steve R. ;
Singer, Frederick R. ;
Hoon, Dave S. B. .
CLINICAL CHEMISTRY, 2009, 55 (03) :559-567
[37]   Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA [J].
Thierry, Alain R. ;
Mouliere, Florent ;
El Messaoudi, Safia ;
Mollevi, Caroline ;
Lopez-Crapez, Evelyne ;
Rolet, Fanny ;
Gillet, Brigitte ;
Gongora, Celine ;
Dechelotte, Pierre ;
Robert, Bruno ;
Del Rio, Maguy ;
Lamy, Pierre-Jean ;
Bibeau, Frederic ;
Nouaille, Michelle ;
Loriot, Virginie ;
Jarrousse, Anne-Sophie ;
Molina, Franck ;
Mathonnet, Muriel ;
Pezet, Denis ;
Ychou, Marc .
NATURE MEDICINE, 2014, 20 (04) :430-+
[38]   Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts [J].
Thierry, Alain R. ;
Mouliere, Florent ;
Gongora, Celine ;
Ollier, Jeremy ;
Robert, Bruno ;
Ychou, Marc ;
Del Rio, Maguy ;
Molina, Franck .
NUCLEIC ACIDS RESEARCH, 2010, 38 (18) :6159-6175
[39]   Circulating free DNA concentration is an independent prognostic biomarker in lung cancer [J].
Tissot, Claire ;
Toffart, Anne-Claire ;
Villar, Stephanie ;
Souquet, Pierre-Jean ;
Merle, Patrick ;
Moro-Sibilot, Denis ;
Perol, Maurice ;
Zavadil, Jiri ;
Brambilla, Christian ;
Olivier, Magali ;
Couraud, Sebastien .
EUROPEAN RESPIRATORY JOURNAL, 2015, 46 (06) :1773-1780
[40]   Prediction of breast tumor progression by integrity of free circulating DNA in serum [J].
Umetani, Naoyuki ;
Giuliano, Armando E. ;
Hiramatsu, Suzanne H. ;
Amersi, Farin ;
Nakagawa, Taku ;
Martino, Silvana ;
Hoon, Dave S. B. .
JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (26) :4270-4276