Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma.
OBJECTIVE
The application of the tumor-specific genomic fusion sequence as noninvasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated.


METHODS
EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic EWSR1-FLI1 copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. EWSR1 fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared with tumor volumes calculated from MRI or CT imaging studies.


RESULTS
Kinetics of EWSR1 fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell-free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development.


CONCLUSIONS
Genomic fusion sequences represent promising noninvasive biomarkers for improved therapy monitoring in EwS. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response. Clin Cancer Res; 22(17); 4356-65. ©2016 AACR.
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany. Manuela.Krumbholz@uk-erlangen.de.
Manuela
M
Krumbholz
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
Julia
J
Hellberg
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
Benedikt
B
Steif
Department of Radiology, University Hospital Erlangen, Erlangen, Germany.
Tobias
T
Bäuerle
Department of Radiology, University Hospital Erlangen, Erlangen, Germany.
Clarissa
C
Gillmann
Department of Nuclear Medicine, University Hospital Erlangen, Erlangen, Germany.
Torsten
T
Fritscher
Department of Pathology, University Hospital Erlangen, Erlangen, Germany.
Abbas
A
Agaimy
Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Germany.
Benjamin
B
Frey
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
Joerg
J
Juengert
Department of Pathology, University Hospital Muenster, Muenster, Germany.
Eva
E
Wardelmann
Department of Pathology, University Hospital Muenster, Muenster, Germany.
Wolfgang
W
Hartmann
Cooperative Ewing Sarcoma Study Group, Department of Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.
Heribert
H
Juergens
Cooperative Ewing Sarcoma Study Group, Department of Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.
Uta
U
Dirksen
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
Markus
M
Metzler
D000293:Adolescent; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000073890:Liquid Biopsy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000097:blood* / Q000235:genetics*; D049268:Positron-Emission Tomography; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D012680:Sensitivity and Specificity; D014178:Translocation, Genetic; D047368:Tumor Burden; D055815:Young Adult
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C576197:EWSR1-FLI1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS