ID #736 Ultra-sensitive plasma ctDNA assay enables detection of brain tumour DNA in peripheral blood and is prognostic in childhood brain cancer
Marion Mateos, Neevika Manoharan, Dong Anh, Khuong Quang, Wenhan Chen, Rob Salomon, Charles Shale, Faustine Ong, Shampavi Sriharan, Santosh Valvi, Sanders Nicholas, Chelsea Mayoh, Mojgan Toumari, Wenyan Li, Sam El-Kamand, Marie Wong, Jordan Hansford, Frank Alvaro, Sajad Razavi Bazaz, Louise Cui, Vanessa Tyrrell, Edward Cuppen, Michelle Haber, Paul Ekert, Peter Priestley, David Ziegler, Loretta Lau, Mark CowleyAbstract
Background
Circulating tumour DNA (ctDNA) isolated from cerebrospinal fluid of children with medulloblastoma has been shown to be prognostic for recurrence[1]. However, obtaining CSF is invasive and often not feasible. It is generally accepted that ctDNA cannot be detected in plasma using conventional assays. Sensitive plasma-based ctDNA analysis could enable less invasive disease monitoring.
Aims
We aimed to develop a highly sensitive plasma-based ctDNA assay for brain cancer patients enrolled in the ZERO Childhood Cancer Program.
Methods
Our personalised ctDNA assay used paired tumour-normal whole genome sequencing data from each individual to design a panel of ∼400 patient-specific tumour biomarkers. We detected ctDNA in plasma down to a tumour fraction of 0.005%. We evaluated 63 patients treated for brain cancer who had plasma collected through the ZERO precision medicine program. Diagnoses included embryonal brain cancers (n = 22); high-grade glioma (n = 30); low-grade glioma (n = 5); ependymoma (n = 8); choroid plexus carcinoma (n = 2); and CIC-rearranged CNS sarcoma (n = 1). For embryonal brain cancer patients, we assessed the survival association between ctDNA positivity at i) 3 months from treatment commencement (“early response”) and ii) the end of treatment.
Results
Fifty patients (79%) had positive plasma ctDNA, with variable clearance. In embryonal brain cancer, end of treatment ctDNA positivity correlated with progression-free (p = 0.011) but not overall survival (p = 0.18, n = 18 evaluable). Early response ctDNA did not correlate with either progression-free or overall survival (p > 0.05). In high-grade glioma, plasma ctDNA was detected in 10/20 patients (50%) with confirmed progression (9/10 at < 0.4% tumour fraction), whereas 3 patients with pseudo-progression did not have detectable ctDNA.
Conclusion
We have developed an ultra-sensitive plasma ctDNA assay capable of detecting brain tumour DNA in peripheral blood. End of treatment plasma ctDNA positivity in embryonal brain tumours predicted subsequent recurrence, supporting its potential role in guiding post-therapy management. Validation in larger, uniformly treated cohorts is planned.
1. Liu, A. P. Y. et al. Serial assessment of measurable residual disease in medulloblastoma liquid biopsies. Cancer Cell. 2021; 39: 1519-1530