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International Framework Establishes Path Toward Risk-Adapted Osteosarcoma Treatment

International Framework Establishes Path Toward Risk-Adapted Osteosarcoma Treatment 1024 575 Lauren Dembeck
test tube of blood held in gloved hands

A new international framework prioritizes molecular classifiers that could enable risk-adapted, biologically informed treatment for children, adolescents, and young adults with osteosarcoma.

 

Despite substantial advances in understanding osteosarcoma biology, treatment has remained largely unchanged for more than four decades. An international working group has now developed a framework for translating emerging molecular classifiers into clinical trials and, ultimately, more individualized treatment for children, adolescents, and young adults with the disease.

The framework, published in npj Precision Oncology, addresses a persistent limitation in osteosarcoma care: patients receive the same intensive combination of chemotherapy and surgery despite marked biological and clinical differences among their tumors. An estimated 10% to 20% of patients may survive with surgery alone, while 30% to 40% of patients with localized disease and approximately 80% with metastatic disease die despite intensive therapy.

“The treatment I give patients who come to my clinic today is essentially the same treatment I would have offered in 1982,” says Ryan D. Roberts, MD, PhD, a pediatric oncologist and principal investigator in the Center for Childhood Cancer Research at Nationwide Children’s and senior author of the paper. “It is highly toxic, and it still does not cure a substantial proportion of patients. At the same time, some patients likely receive much more treatment than they need.”

Dr. Roberts and lead author Amanda Marinoff, MD, pediatric hematologist-oncologist at University of California San Francisco Benioff Children’s Hospital, assembled experts from the United States, Canada, and Europe to systematically evaluate candidate molecular classifiers, or biological characteristics that may help distinguish patients according to prognosis. The group considered classifiers across five domains: genomics, transcriptomics, epigenetics, cell-surface proteins, and circulating analytes. Each was assigned to one of four evidence levels based on reproducibility, generalizability, independent prognostic value and clinical feasibility.

Pretreatment circulating tumor DNA (ctDNA), consisting of tumor-derived DNA fragments detectable in the blood, emerged as the most clinically mature classifier. Studies have shown that ctDNA burden at diagnosis is associated with outcomes independent of metastatic status, and measurements after the first cycle of chemotherapy may provide an even stronger prognostic signal.

“Circulating tumor DNA gives us a much earlier indication of which patients are likely to do well and which are not,” says Dr. Roberts. “It may eventually also allow us to obtain additional molecular information without repeatedly biopsying the tumor.”

MYC status and three RNA-based classifiers also demonstrated reproducible prognostic associations and warrant prospective evaluation. Before any classifier can guide treatment, however, investigators must validate it in independent patient populations, compare multiple classifiers within uniformly profiled cohorts, and determine how molecular findings should be integrated with clinical factors such as metastatic status, tumor location, and resectability.

“Some clinical characteristics may add important nuance to a patient’s prognosis, while others may simply reflect the tumor’s underlying biology,” adds Dr. Roberts. “A tumor may be large because molecular features are driving rapid growth. By evaluating the clinical and molecular features together, we can determine which provide independent information and develop the most accurate risk model.”

Nationwide Children’s investigators are leading follow-up analyses with collaborators at Dana-Farber Cancer Institute and the Broad Institute. The long-term goal is to make ctDNA testing, RNA sequencing and DNA sequencing part of routine molecular characterization at diagnosis and use the results to inform risk-adapted clinical trials.

“I look forward to being able to tell one patient that less-intensive treatment should be sufficient and another that we should begin with a promising clinical trial rather than wait for standard therapy to fail,” says Dr. Roberts. “This framework is the first step toward making that possible.”

 

 

Reference

Marinoff AE, Nathrath M, Shulman DS, Whittle SB, Pavisic J, Spentzos D, Albert CM, Nash JO, Shlien A, Cortés-Ciriano I, Marchais A, López-Fuentes E, Curtis C, Sweet-Cordero EA, Gorlick R, DelRocco N, Chugh R, Tap WD, Flanagan AM, Gaspar N, Crompton BD, Reed DR, Janeway KA, Grohar PJ, Livingston JA, Roberts RD. An international framework for clinical translation of molecular classifiers in osteosarcoma. npj Precision Oncology. 2026 May 5;10(1):266. doi: 10.1038/s41698-026-01456-4. PMID: 42086782; PMCID: PMC13346500.

About the author

Lauren Dembeck, PhD, is a freelance science and medical writer based in New York City. She completed her BS in biology and BA in foreign languages at West Virginia University. Dr. Dembeck studied the genetic basis of natural variation in complex traits for her doctorate in genetics at North Carolina State University. She then conducted postdoctoral research on the formation and regulation of neuronal circuits at the Okinawa Institute of Science and Technology in Japan.

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