Circulating Biomarkers of Disease Burden in Patients With Relapsed or Refractory Neuroblastoma Treated With 131 I‐MIBG Therapy: A Report From the New Approaches to Neuroblastoma Therapy Consortium
Kevin Campbell, Kelly Klega, Araz Marachelian, Yueh‐Yun Chi, Erica Ma, Anahit Baregamyan, Julie R. Park, Meaghan Granger, Katherine K. Matthay, Shahab Asgharzadeh, Brian D. Crompton, Steven G. DuBoisABSTRACT
Background
Circulating tumor DNA (ctDNA) and neuroblastoma‐associated mRNA (NB‐mRNAs) transcripts are detectable in children with neuroblastoma. Less is known about how these biomarkers change during treatment and how they compare to each other. The purpose of this study was to quantify levels of ctDNA and NB‐mRNA before and after 131 I‐metaiodobenzylguanidine therapy ( 131 I‐MIBG).
Methods
We utilized peripheral blood and bone marrow samples from NANT11‐01 (NCT02035137), a multicenter, open label, randomized phase II clinical trial evaluating 131 I‐MIBG combinations for patients with relapsed or refractory neuroblastoma. Plasma samples were analyzed for percent ctDNA by ultra‐low passage whole genome sequencing (ULP‐WGS). Blood and bone marrow samples were analyzed for presence of five NB‐mRNAs by a TaqMan low density array (TLDA), called neuroblastoma‐5 (NB5). We evaluated associations between ctDNA and NB5 levels with measures of disease burden and response to therapy using Pearson's correlations and Wilcoxon rank‐sum tests.
Results
Samples from 87 patients were evaluated for ctDNA. The proportion of patients with detectable ctDNA decreased from baseline [44% (38/86)] to midcycle 1 [30% (7/23)], to the end of first course [14% (3/21)]. Baseline ctDNA levels correlated positively with total Curie score at baseline ( r = 0.27; p = 0.012) and baseline percent bone marrow involvement ( r = 0.39; p ≤ 0.001). The proportion of patients with positive NB5 in blood was 78% (29/37) at baseline versus 72% (13/18) at End of Course 1. Baseline blood NB5 levels correlated negatively with percent bone marrow involvement ( r = −0.56; p ≤ 0.001) and with sum of target lesions at baseline ( r = −0.4; p = 0.024). Baseline bone marrow NB5 levels correlated negatively with total Curie score at baseline ( r = −0.64; p ≤ 0.001) and percent bone marrow involvement ( r = −0.56; p ≤ 0.001). No marker was significantly associated with objective response. Baseline ctDNA levels were negatively correlated with both blood ( r = −0.79; p < 0.001) and bone marrow ( r = −0.5; p = 0.003) NB5.
Conclusions
ctDNA and NB‐mRNA are detectable at multiple time points in patients with relapsed or refractory neuroblastoma treated with 131 I‐MIBG. Both markers correlate with each other and with measures of disease burden, but not with objective response.