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Clin Cancer Res. 2016 Jun 15;22(12):2960-8. doi: 10.1158/1078-0432.CCR-15-2470. Epub 2016 Jan 12.

Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial.

Author information

1
Laboratoire de Recherche Translationnelle et Centre de RessourcesBiologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France. cecile.jovelet@gustaveroussy.fr.
2
Laboratoire de Recherche Translationnelle et Centre de RessourcesBiologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France. Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Villejuif, France.
3
Département de Biostatistiques et Epidémiologie, Gustave Roussy, Villejuif, France. INSERM U1018, Gustave Roussy, Villejuif, France. Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, Orsay, France.
4
Laboratoire de Recherche Translationnelle et Centre de RessourcesBiologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
5
Département de Biostatistiques et Epidémiologie, Gustave Roussy, Villejuif, France.
6
INSERM U981, Gustave Roussy, Villejuif, France.
7
Plateforme de Génomique Fonctionnelle, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
8
Plateforme de bioinformatique, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
9
Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Villejuif, France.
10
Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France.
11
Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France.
12
Département de Radiologie, Gustave Roussy, Villejuif, France.
13
Département de Biologie et Pathologie Médicales, Gustave Roussy, Villejuif, France.
14
Laboratoire de Recherche Translationnelle et Centre de RessourcesBiologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France. Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, Orsay, France. Département de Biologie et Pathologie Médicales, Gustave Roussy, Villejuif, France.
15
Direction de la Recherche Clinique, Gustave Roussy, Villejuif, France.
16
Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, Orsay, France. Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France.
17
Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, Orsay, France. INSERM U981, Gustave Roussy, Villejuif, France. Département d'Oncologie Médicale, Gustave Roussy, Villejuif, France.
18
Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, Villejuif, France. Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, Orsay, France. INSERM U981, Gustave Roussy, Villejuif, France.
19
Laboratoire de Recherche Translationnelle et Centre de RessourcesBiologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Département de Biologie et Pathologie Médicales, Gustave Roussy, Villejuif, France. Faculté de Pharmacie, Université Paris Sud, Châtenay-Malabry, France.

Abstract

PURPOSE:

Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).

EXPERIMENTAL DESIGN:

Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.

RESULTS:

Among the 283 patients with tDNA-cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%-61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.

CONCLUSIONS:

Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960-8. ©2016 AACR.

PMID:
26758560
DOI:
10.1158/1078-0432.CCR-15-2470
[Indexed for MEDLINE]
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