. 2018 Aug;119(5):615-621.

doi: 10.1038/s41416-018-0212-9. Epub 2018 Aug 21.

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group

David S Shulman¹, Kelly Klega¹, Alma Imamovic-Tuco¹, Andrea Clapp², Anwesha Nag², Aaron R Thorner², Eliezer Van Allen^{3

4}, Gavin Ha⁴, Stephen L Lessnick⁵, Richard Gorlick⁶, Katherine A Janeway¹, Patrick J Leavey⁷, Leo Mascarenhas⁸, Wendy B London¹, Kieuhoa T Vo⁹, Kimberly Stegmaier¹, David Hall¹⁰, Mark D Krailo^{10

11}, Donald A Barkauskas^{10

11}, Steven G DuBois¹, Brian D Crompton^{12

13

14}

Affiliations

¹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
² Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Broad Institute, Cambridge, MA, USA.
⁵ Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital Research Institute and the Division of Pediatric Heme/Onc/BMT at The Ohio State University, Columbus, OH, USA.
⁶ Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
⁸ Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
¹⁰ Children's Oncology Group, Monrovia, CA, USA.
¹¹ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA. briand_crompton@dfci.harvard.edu.
¹³ Broad Institute, Cambridge, MA, USA. briand_crompton@dfci.harvard.edu.
¹⁴ Department of Pediatric Oncology, 450 Brookline Avenue, Boston, MA, USA. briand_crompton@dfci.harvard.edu.

PMID: 30131550
PMCID: PMC6162271
DOI: 10.1038/s41416-018-0212-9

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group

David S Shulman et al. Br J Cancer. 2018 Aug.

. 2018 Aug;119(5):615-621.

doi: 10.1038/s41416-018-0212-9. Epub 2018 Aug 21.

Authors

Affiliations

¹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
² Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Broad Institute, Cambridge, MA, USA.
⁵ Center for Childhood Cancer and Blood Diseases at Nationwide Children's Hospital Research Institute and the Division of Pediatric Heme/Onc/BMT at The Ohio State University, Columbus, OH, USA.
⁶ Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
⁸ Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
¹⁰ Children's Oncology Group, Monrovia, CA, USA.
¹¹ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA. briand_crompton@dfci.harvard.edu.
¹³ Broad Institute, Cambridge, MA, USA. briand_crompton@dfci.harvard.edu.
¹⁴ Department of Pediatric Oncology, 450 Brookline Avenue, Boston, MA, USA. briand_crompton@dfci.harvard.edu.

PMID: 30131550
PMCID: PMC6162271
DOI: 10.1038/s41416-018-0212-9

Erratum in

Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.
Shulman DS, Klega K, Imamovic-Tuco A, Clapp A, Nag A, Thorner AR, Van Allen E, Ha G, Lessnick SL, Gorlick R, Janeway KA, Leavey PJ, Mascarenhas L, London WB, Vo KT, Stegmaier K, Hall D, Krailo MD, Barkauskas DA, DuBois SG, Crompton BD. Shulman DS, et al. Br J Cancer. 2019 Apr;120(8):869. doi: 10.1038/s41416-019-0424-7. Br J Cancer. 2019. PMID: 30880335 Free PMC article.

Abstract

Background: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.

Methods: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.

Results: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.

Conclusions: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.

PubMed Disclaimer

Conflict of interest statement

Dr. Lessnick holds patents related to the diagnosis of Ewing sarcoma. Dr. Ha has a pending patent relevant to genomic technologies. The other authors declare no competing interests.

Figures

**Fig. 1**
a EFS by ctDNA detection in patients with newly diagnosed localised Ewing sarcoma. b Overall survival by ctDNA detection in patients with newly diagnosed localised Ewing sarcoma

**Fig. 2**
a EFS by ctDNA detection in patients with newly diagnosed localised osteosarcoma. b Overall survival by ctDNA detection in patients with newly diagnosed localised osteosarcoma

**Fig. 3**
a EFS by 8q gain among patients with newly diagnosed localised osteosarcoma and detectable ctDNA. b Overall survival by 8q gain among patients with newly diagnosed localised osteosarcoma and detectable ctDNA

See this image and copyright information in PMC

References

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Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group

Affiliations

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group

Authors

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Conflict of interest statement

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