Abstract A61: Evaluation of ctDNA in children with relapsed or refractory neuroblastoma treated with 131I-MIBG
Authors: Shulman David S. , Klega Kelly , Marachelian Araz , Matthay Katherine K. , Park Julie R. , Granger M. Meaghan , DuBois Steven G. , Crompton Brian D. 
Published: June 2020

Abstract
Objectives: Circulating tumor DNA (ctDNA) has been shown to be detectible in children with neuroblastoma, yet little is known about the dynamics of how ctDNA levels change during treatment. 131I-MIBG is a targeted radiopharmaceutical selectively taken up by 90% of neuroblastomas. We evaluated changes in ctDNA levels and identified somatic events from ctDNA in a cohort of patients treated with 131I-MIBG.
Methods: NANT 11-01 is a randomized phase 2 study for patients with relapsed or refractory neuroblastoma designed to evaluate the benefit of radiosensitizing agents in combination with 131I-MIBG (MIBG vs. MIBG + vincristine/irinotecan vs. MIBG + vorinostat). Patients had samples collected beginning prior to therapy (c1d1), 72 hours after 131I-MIBG (c1h72), cycle 1 day 15 (c1d15) and for patients who met criteria for a second cycle, cycle 2 day 1 (c2d1). Ultra-low-pass whole-genome sequencing (ULP-WGS) was used to quantify ctDNA in each plasma sample by identifying somatic segmental copy number changes. The correlation between baseline %ctDNA and disease burden using Curie score from the patient’s pretreatment MIBG scan was assessed with linear regression. ctDNA levels and copy number changes were analyzed descriptively.
Results: 112 samples from 49 patients were evaluated. The number of patients with detectable ctDNA changed throughout therapy as follows: c1d1 40.4% (19/47); c1h72 42.5% (17/40); c1d15 18% (2/11); and c2d1 0% (0/14) detectable. Among patients with detectable ctDNA, median ctDNA levels at these timepoints were as follows: 17% (range 3.9-91%) at c1d1; 22% (range 2.9-86%) at c1hr72; and 18% (range 3.5-33%) at c1d15. There was a nonsignificant positive correlation between baseline ctDNA levels and baseline Curie score (n=47; R2 = 0.07; p=0.081). MYCN amplification was detected in ctDNA in 4 out of 5 patients with detectable ctDNA known to have MYCN amplified tumors, but never in patients without known MYCN amplification.
Conclusions: ctDNA is detectable using ULP-WGS at multiple time points for patients with neuroblastoma treated with 131I-MIBG. ctDNA levels declined during therapy and were rarely detectable at cycle 1 day 15 or by the start of cycle 2. MYCN amplification was identified in the plasma from the majority of patients with MYCN amplified disease if ctDNA levels were detectable. After enrollment is completed for this study, we plan to determine whether baseline ctDNA and changes in ctDNA levels are associated with treatment response.
Citation Format: David S. Shulman, Kelly Klega, Araz Marachelian, Katherine K. Matthay, Julie R. Park, M. Meaghan Granger, Steven G. DuBois, Brian D. Crompton. Evaluation of ctDNA in children with relapsed or refractory neuroblastoma treated with 131I-MIBG [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A61.