Dr Randall on the Clinical Utility of Tumor-Informed ctDNA Deep Sequencing for Osteosarcoma Surveillance

"The peak for positive ctDNA occurred 2.7 months earlier than the peak for relapse/progression verified by imaging... this is effectively earlier than radiographic detection for a disease where early intervention may matter."

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 clinical utility of tumor-informed deep sequencing of circulating tumor DNA (ctDNA) for monitoring patients with osteosarcoma, according to results from a longitudinal study.

To address the inherent difficulties of molecular residual disease (MRD) surveillance in this setting, investigators evaluated a personalized ctDNA panel approach to predict tumor relapse in a longitudinal, prospective study.

The study enrolled patients diagnosed with osteosarcoma between August 2019 and June 2023, with primary tumor samples undergoing whole exome sequencing to facilitate the creation of individualized MRD panels. Researchers successfully generated these customized panels for 85.5% of the participants (n = 83), underscoring the feasibility of this precision medicine approach for the vast majority of the osteosarcoma population. Among the 59 patients who had both successful panel customization and available blood samples, 13 demonstrated positive ctDNA detection following surgery.

The findings highlighted a strong correlation between ctDNA status and clinical outcomes, Randall reported. Patients with negative post-operative ctDNA at various intervals—including 1 to 6 months post-surgery, after the completion of adjuvant chemotherapy, and more than 6 months post-surgery—experienced significantly improved event-free survival (EFS) vs those with detectable ctDNA (P < .05). Furthermore, findings from both univariate and multivariate Cox regression analyses confirmed that ctDNA results were a statistically significant predictor of EFS, Randall noted. Specifically, positive ctDNA results were associated with HRs of 7.43 (95% CI, 2.67-20.62) and 7.74 (95% CI, 1.55-38.75), respectively, indicating its value as a robust marker for poor prognosis.

Randall emphasized that liquid biopsy provided a critical advantage by identifying relapse/progression events an average of 92.6 days earlier than conventional imaging. Notably, the peak for positive ctDNA detection occurred 2.7 months before radiographic verification. These results represent a potentially vital advancement in surveillance, offering a significant lead-time advantage in a disease where early intervention is paramount for improving patient survival, he concluded.