Can ctDNA Testing Help Personalize Osteosarcoma Treatment?

Advances in genetic sequencing and unprecedented collaboration among research institutions are helping scientists better predict prognosis, track treatment response, and move closer to personalized therapies for osteosarcoma.

For decades, researchers have sought to understand the many complexities of osteosarcoma: how it starts, why it behaves so differently from patient to patient, and what causes some tumors to resist treatment. The answers may be written in our DNA, yet for years, two barriers stood in the way: technological limits and a historically fragmented research landscape.

Brian Crompton, MD

Today, both are shifting. Advances in DNA sequencing technology now allow scientists to detect and analyze tiny fragments of tumor DNA circulating in the bloodstream. At the same time, a new era of collaboration among institutions is breaking down silos that once slowed discovery. Together, these developments are making personalized, data-driven osteosarcoma care possible for the first time.

We sat down with Brian Crompton, MD, a member of The Osteosarcoma Institute Strategic Advisory Board, to learn more about circulating tumor DNA (ctDNA) research and a new collaborative effort called BrightSeq aimed at applying new genetic insights to pediatric oncology.

What Is Circulating Tumor DNA?

As tumor cells grow and divide, they release small fragments of genetic material into the bloodstream. These fragments, or ctDNA, can be detected through a simple blood draw, offering a cost-effective way to learn about a patient’s tumor and disease burden without the need for an invasive surgical procedure.

ctDNA was first detected in patients with adult cancers in the 1970s, but only recently has the technology advanced enough to make this kind of testing practical and reliable. Dr. Crompton and other research teams were among the first to detect ctDNA in pediatric patients with Ewing sarcoma, a cancer that has a distinctive genetic signature.

“We were able to find evidence of circulating tumor DNA first in patients with Ewing sarcoma because they have a very unique molecular hallmark,” Dr. Crompton explains. “It can only come from Ewing sarcoma.”

Circulating Tumor DNA in Pediatric Tumors

Since that discovery, Dr. Crompton’s team and others, have confirmed that ctDNA can be found in most pediatric solid tumors, including osteosarcoma. Just as important, the amount of ctDNA appears to have meaning. Higher levels of ctDNA are often associated with worse prognosis.

“We were able to show that higher amounts of ctDNA relative to the normal cell-free DNA is a sign of more aggressive disease,” Dr. Crompton says. “We do not know exactly why, but more aggressive cancers seem to shed more ctDNA.”

When patients begin cancer treatment, ctDNA levels usually drop. If they do not, that can be an early warning sign. “We are now studying how quickly ctDNA clears from the bloodstream to understand how well a tumor is responding,” he says. “We have done that successfully in Ewing sarcoma, and the results are promising in osteosarcoma and neuroblastoma.”

ctDNA Testing Can Give a Clearer Picture of Risk

Until recently, one of the biggest challenges in osteosarcoma research has been understanding which patients face higher risks. At diagnosis, physicians typically rely on imaging to determine whether the disease has spread. That single factor often determines whether a patient is considered average risk or high risk.

Dr. Crompton hopes ctDNA testing will provide more precise information.

“There are a lot of projects to find better prognostic biomarkers, but one of them is clearly going to be ctDNA.” —Brian Crompton, MD

“If you come to the clinic, the only way we currently know whether you have an average chance of cure or high-risk disease is whether you have metastatic spread,” he says. “There are a lot of projects to find better prognostic biomarkers, but one of them is clearly going to be ctDNA.”

This approach to determining osteosarcoma prognosis, often called a liquid biopsy, involves drawing a small amount of blood and analyzing it for ctDNA. Because it can be repeated easily, ctDNA testing allows doctors to monitor how a tumor changes during and after treatment, giving them a clearer sense of risk at every stage.

The BrightSeq Collaboration

Dr. Crompton’s work with ctDNA helped lay the foundation for BrightSeq, a collaboration that launched in 2025 by Dana-Farber Cancer Institute, Boston Children’s Hospital, and Broad Clinical Labs. The name stands for Boston Research in Innovative Genomics for Hematologic and Tumor Sequencing.

In this transformative partnership, each institution contributes essential expertise: Boston Children’s provides world-class molecular pathology and CLIA-certified testing; Dana-Farber brings clinical and translational oncology experience; and the Broad Institute supplies the high-throughput sequencing and informatics infrastructure.

“What makes BrightSeq special is how these strengths come together in one seamless system,” Dr. Crompton says. In a field where cross-institutional collaboration can be rare and logistically difficult, BrightSeq has become a model already drawing attention from other cancer centers.

“All three institutions said, ‘Let’s each do the part we’re good at,’ and it worked,” he says. “It’s such a strong model, and I think it’s going to make it possible to efficiently return molecular tests in a way we’ve never done before for pediatric oncology.”

Opportunities for Future Osteosarcoma Research

The ability to study ctDNA opens new doors for osteosarcoma research. Dr. Crompton and his team hope to use these tools to track how tumors evolve, identify why they sometimes become resistant to chemotherapy, and explore new ways to stop relapse before it happens.

“If you find common mechanisms of resistance, then in theory you could target them and prevent relapse,” Dr. Crompton says. “And if you prevent relapse, you can cure more patients. That is one area of the lab that I am really excited about.”

In the future, ctDNA could help researchers understand why some patients respond better to treatment than others and perhaps even lead to earlier detection of the disease. For osteosarcoma patients and families, this means the potential for faster answers and more tailored treatment decisions.