Dr Randall on the Use of Tumor-Informed ctDNA Deep Sequencing for Osteosarcoma Risk Stratification

"I think the most immediate application is risk stratification. Today, two patients may look identical on imaging... yet their underlying biologic risk may be very different."

R. Lor Randall, MD, FACS, the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center, discussed the transformative potential of tumor-informed sequencing of circulating tumor DNA (ctDNA) in managing osteosarcoma, emphasizing that while two patients may appear identical on imaging after standard surgery and chemotherapy, their underlying biologic risk can vary significantly.

To address the historical difficulties of molecular residual disease (MRD) monitoring in bone sarcomas, investigators conducted a longitudinal, prospective study to determine if personalized ctDNA panels could predict relapse earlier than conventional radiographic methods. Researchers successfully created individualized MRD panels for 85.5% of patients, demonstrating that this precision oncology approach is feasible for the vast majority of the osteosarcoma population. Results confirmed that patients with negative post-operative ctDNA at various intervals—including after the completion of chemotherapy—experienced significantly improved event-free survival (EFS) compared with those with detectable ctDNA (P < .05). Both univariate and multivariate analyses confirmed ctDNA results as a statistically significant predictor of EFS.

Randall highlighted that ctDNA’s ability to identify microscopic residual disease in patients who are radiographically disease-free is its most vital near-term function. This molecular insight allows for earlier detection of relapse, which in this study occurred an average of 92.6 days before it could be verified by imaging. Such a lead-time advantage provides a window of opportunity for more intensive surveillance, earlier imaging, or enrollment in clinical trials and future ctDNA-guided therapeutic strategies.

Despite these promising results, Randall cautioned that the study does not yet support changing treatment solely based on ctDNA status. He characterized the technology as a promising "emerging adjunct" rather than a replacement for conventional imaging. He concluded that while the data are compelling, prospective validation remains necessary before ctDNA-informed surveillance becomes the standard of practice in orthopedic oncology.