Table 4.
Biomarkers in Ewing Sarcoma (EwS). Summary of the most relevant blood-based EwS biomarkers, encompassing diagnosis, prognosis and prediction of response to therapy, along with relevant references and levels of evidence. BM, bone marrow; CTX, chemotherapy; ddPCR, droplet digital polymerase chain reaction; Dx, diagnosis; EFS, event-free survival; IL, interleukin; PET, positron emission tomography; PB, peripheral blood; Pts, patients; WGS, whole-genome sequencing.
| Biomarker Characteristics | Patient Characteristics | Study Details | |||||
|---|---|---|---|---|---|---|---|
| Type | Category | Biomaterial | Number | Disease Status | Detection Rate (% Positive) |
Conclusion | Reference |
| EwS-specific biomarkers | |||||||
| Circulating tumor cells | Diagnostic/ therapeutic |
PB, BM | 16 | PB, BM at diagnosis (1 pts, 6 pts) BM during therapy (2 pts) |
EwS cells in BM or PB can be identified by RT-PCR |
[406] | |
| Diagnostic/ therapeutic |
PB, BM | 28 | Primary and recurrent |
PB, BM in non-metastatic pts (25) PB, BM in metastatic/ relapsed pts (50) |
RT-PCR could serve as a EwS-specific marker of residual disease during CTX |
[407] | |
| Diagnostic/ prognostic |
Stem cell harvest; PB, BM |
11 | Stem cell harvest (100) | Number of cells may correlate with relapse after transplantation |
[408] | ||
| Circulating tumor RNA (ctRNA) |
Diagnostic/ prognostic |
PB | 28 | 68 | Detection preceded progression; specific transcript types may affect progression |
[409] | |
| Diagnostic/ prognostic |
PB, BM | 26 | BM at diagnosis (43) PB, BM during follow up (58) |
Occult tumor cells are strong predictors of recurrent disease in non-metastatic pts | [410] | ||
| Diagnostic/ therapeutic |
Tissue, PB | 10 | Tissue (83), PB (100) | EWSR1-FLI1 molecular diagnosis possible in PB even in absence of tissue; ctRNA correlated with 18F-FDG-PET parameters |
[411] | ||
| Circulating tumor cells + circulating tumor RNA |
Diagnostic/ therapeutic |
PB, BM, PBSC | 12 | Metastatic | PBSC (2.5) | RT-PCR signal declines in PB and BM during CTX | [412] |
| Diagnostic | PB | 1 | [413] | ||||
| Circulating tumor DNA (by EWSR1-FLI1 ctDNA PCR) |
Diagnostic/ therapeutic |
1 | ddPCR to detect ctDNA could serve as a EwS-specific marker of recurrence |
[397] | |||
| Diagnostic/ therapeutic |
PB | 20 | Localized and metastatic |
Kinetics of EWSR1-FLI1 ctDNA correlated with tumor volume | [414] | ||
| Diagnostic/ therapeutic |
PB | 20 | 100 | Combination of 18F-FDG-PET/CT and ctDNA quantification could serve as a EwS-specific marker for CTX response and relapse |
[415] | ||
| Circulating tumor cells + ctDNA PCR |
Diagnostic/ prognostic |
PB, BM | Flow cytometry (109) PCR (225) |
Flow cytometry (CD99(+), CD45(-)) (12.8) PCR (19.6) |
Detection of micrometastatic disease by flow cytometry or RT-PCR is not associated with outcome | [416] | |
| Circulating tumor DNA (by WGS) |
Diagnostic | Tissue, PB | 11 | WGS (100) | ctDNA by both NGS and ddPCR could serve as a EwS-specific marker | [417] | |
| Diagnostic/ therapeutic/ prognostic |
PB | 11 | ctDNA levels corresponded to CTX response | [418] | |||
| Diagnostic/ prognostic |
PB | 94 | ctDNA in localized pts (53) |
ctDNA detection associated with inferior outcomes |
[419] | ||
| Diagnostic | Tissue, PB | 2 | [420] | ||||
| Circulating cell-free mitochondrial DNA (ccf mtDNA) |
Diagnostic/ prognostic |
PB | 25 | ccf mtDNA levels associated with metastatic disease |
[421] | ||
| MicroRNA– miR-125b |
Diagnostic/ therapeutic |
PB | 63 | miR-125b elevated in pts compared to healthy controls; miR-125b downregulation correlated with poor response to CTX |
[422] | ||
| MicroRNA– miR34a |
Diagnostic/ therapeutic/ prognostic |
PB | 31 | Localized and metastatic |
High miR34a inversely correlated with tumor volume; miR34a elevated in localized compared to metastatic pts; miR34a increased in localized pts at diagnosis and after end of CTX |
[423] | |
| Extracellular vesicles (EV)– EwS-specific transcripts |
Diagnostic | Preclinical model | EVs could serve as a EwS-specific marker |
[424] | |||
| Extracellular vesicles (EV)– EwS soluble EV proteome |
Diagnostic/ prognostic |
PB | 10 | Localized and metastatic |
[425] | ||
| EwS-non-specific biomarkers (cytokines and other secreted peptides) | |||||||
| IGF-1 and IGF-BP3 | Prognostic | PB | 22 | Localized and metastatic |
High baseline IGF-1 and IGF-BP3 associated with improved EFS; IGF-BP3 and IGF-2 increased during CTX |
[426] | |
| IL-6 and IL-8 | Diagnostic/ therapeutic/ prognostic |
PB | 13 | Localized | [427] | ||
| Diagnostic/ prognostic |
Tissue, PB | 14 | IL-6 elevated in some pts with poor prognosis |
[428] | |||
| (Pro)cholecystokinin ((pro)CCK) | Diagnostic/ therapeutic/ prognostic |
Tissue, PB | 12 | Primary and recurrent |
ProCCK elevated in pts at primary Dx/ recurrence compared to pts during CTX; ProCCK correlated with tumor size |
[429] | |
| Pro-gastrin-releasing peptide (ProGRP) and neuron- specific enolase (NSE) |
Diagnostic | Tissue, PB | 9 | ProGRP could serve as a EwS-specific marker |
[430] | ||
| Diagnostic/ prognostic |
PB | 16 | ProGRP elevated in half of the pts; ProGRP reflected therapeutic response |
[431] | |||