Dana-Farber Researchers Find Blood Test Could Guide Future Treatment in Ewing Sarcoma

Prospective national study validates circulating tumor DNA as a predictor of relapse risk and identifies low-, intermediate-, and high-risk patient groups

A blood test may help doctors identify which patients with Ewing sarcoma are at greater risk of relapse, according to a study led by investigators at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the Children’s Oncology Group. The findings lay the groundwork for more personalized treatment strategies in this rare cancer.

The study is the first to prospectively show that a blood test measuring circulating tumor DNA, or ctDNA, before treatment can help predict how patients with Ewing sarcoma will do. When combined with other clinical and genetic information, the test can sort patients into low-, intermediate-, and high-risk groups that could help guide future clinical trials. 

The findings were published in the Journal of Clinical Oncology.

“We need better ways to tell, at diagnosis, which patients may do very well with current therapy or even less therapy, and which patients need new approaches,” said co-senior author, Brian Crompton, MD, research co-director of the Solid Tumor Center at Dana-Farber/Boston Children’s. “This study gives us a stronger, more biologically informed way to understand risk.”

Ewing sarcoma is a rare bone and soft tissue cancer that mainly affects children, adolescents, and young adults. Patients with localized disease often do well, but treatment is intense and leaves survivors with lasting side effects. Patients whose cancer has already spread at diagnosis face much worse odds of cure. Even so, most patients still receive broadly similar chemotherapy regimens.

The new study was designed to address that gap.

Researchers analyzed blood samples from nearly 400 patients in two national studies: LEOPARD, which enrolled patients with localized Ewing sarcoma, and AEWS1221, a Children’s Oncology Group phase 3 trial for patients with newly diagnosed metastatic disease. The main analysis included 140 patients with localized disease and 255 with metastatic disease. The goal was to determine whether circulating tumor DNA, or ctDNA — fragments of tumor DNA found in the blood — could help predict which patients were most likely to relapse.

They found that patients with higher ctDNA levels at diagnosis had worse outcomes. When combined with tumor size, disease spread, and tumor genetics, ctDNA helped define distinct low-, intermediate-, and high-risk groups.

Among patients with localized disease, researchers identified a small group of patients with low-risk disease with low ctDNA, small tumors, and favorable genomics; none relapsed or died during the study period.

“That was an important finding,” said first author, David Shulman, MD, Director of AYA Sarcoma Program Dana-Farber, and Assistant Professor of Pediatrics, Harvard Medical School. “It suggests there may be a group of patients who could eventually benefit from less intensive treatment in a clinical trial setting.”

Among patients with metastatic disease, outcomes were especially poor when ctDNA remained detectable after the first cycle of chemotherapy or when TP53 mutations were found in the ctDNA. Patients with persistent ctDNA after one cycle had a 2-year event-free survival of 5.3%, compared with 63% for those whose ctDNA became undetectable. Researchers also identified an intermediate-risk metastatic group — patients with lung-only metastases, low ctDNA, and favorable genomics — with a 2-year event-free survival of 83% and overall survival of 100%.

“These findings show that not all Ewing sarcomas behave the same way,” said co-senior author, Steven DuBois, MD, MS, director of experimental therapeutics at Dana-Farber/Boston Children's. “This work creates a roadmap for smarter clinical trials in Ewing sarcoma, with the potential to reduce treatment for some patients and to intensify or rethink therapy for others.” 

Funding for this study was provided by the NCI Biomarker, Imaging, and Quality of Life Studies Funding Program (BIQSFP; S.G.D. and BDC), the Pediatric Cancer Research Foundation (B.D.C.), the Rally Foundation Research Grant (B.D.C.), the Collaborative Pediatric Cancer Research Awards Program (B.D.C.), the Nathaniel Cavallo Fund (B.D.C.), Team Fernando’s Fight (B.D.C.), Alex’s Lemonade Stand Centers of Excellence Grant (D.S.S., S.G.D.), The Khimani Fund (S.G.D.), Wicked Good Cause (S.G.D.), the ASCO/Conquer Cancer Young Investigator Award and Career Development Award (D.S.S.), Friends of Dana-Farber (D.SS.), the Boston Children’s Hospital Translational Research Program—CTREC Award (D.S.S.), the Harvard Catalyst KL2 Award (D.S.S.), NIH/NCI K08 5K08CA290061-02 (D.S.S.), the COG NCTN Operations Center Grant (U10CA180886), the COG NCTN Statistics & Data Center Grant (U10CA180899), the COG Biospecimen Bank Grant (U24CA196173), and The QuadW Foundation.