LB-002 Liquid biopsy identifies somatic KRAS mutations in paediatric cranio-spinal arterio-venous malformations: preliminary results Article Swipe

<h3>Introduction</h3> Vascular malformations frequently contain somatic mutations of vascular endothelium. Brain arterio-venous malformations (AVMs) have been shown via surgically resected tissues to contain somatic activating mutations in the KRAS gene, coding for a GTPase controlling the mitogen activating protein kinase (MEK/MAP2K) pathway. However, many complex paediatric cranio-spinal AVMs are not amenable to surgical resection due to the high risk of bleeding. An alternative method of identifying such mutations is via a liquid biopsy. Liquid biopsy involves sampling of blood, either from the draining vein of the AVM or from a peripheral vein, to obtain circulating cell-free DNA (from necrotic endothelial cells). Liquid biopsy has been used successfully to identify mutations in peripheral body AVMs. We hypothesized that liquid biopsy would be a feasible method of identifying somatic mutations in complex paediatric cranio-spinal AVMs, including Vein of Galen Malformation. <h3>Methods</h3> Our Paediatric AVM Somatic Mutation Study received institutional ethics approval. Enrolled paediatric patients (age &lt;/= 18 years) underwent endoluminal liquid biopsy from the draining vein of the AVM at the time of planned embolization, with matched peripheral blood samples; or via peripheral blood alone if no endovascular treatment was being undertaken. Cell-free DNA was extracted and underwent next generation sequencing (NGS) for our bespoke panel of genes associated with vascular malformations: <i>KRAS</i>, <i>HRAS</i>, <i>NRAS</i>, <i>RASA1</i>, <i>BRAF</i>, <i>MAP2K1</i>, <i>MAP2K2</i>, <i>EPHB4</i>, <i>ACVRL1</i>, <i>SMAD4</i>, <i>ENG</i>, <i>GNAQ</i>, <i>PTEN</i>, <i>PIK3CA</i>, <i>TEK</i>, and <i>MAP3K3.</i> Orthogonal confirmation of positive results was undertaken using digital droplet PCR testing. Patients with identified mutations underwent consultation with our paediatric oncology team for consideration of genotype-directed pharmacotherapy. <h3>Results</h3> Of n=18 patients enrolled, n=11 patients had AVMs involving the cranio-spinal axis, and n=7 have completed NGS testing. At this preliminary stage, three patients have been identified with somatic mosaic mutations, all involving the KRAS gene. Patient 1 was diagnosed antenatally with Vein of Galen Malformation and underwent staged embolization as a neonate and infant. Liquid biopsy of the draining vein (via a microcatheter advanced across an AV fistula into the venous sac) identified a somatic activating mutation of KRAS (G12S). Patient 2 is a teenager with cervical spinal arterio-venous metameric syndrome who presented with progressive paraparesis and became wheelchair-dependent. Peripheral blood liquid biopsy identified a somatic KRAS mutation (G12D). They were commenced on the MEK inhibitor trametinib and after six months was walking independently. Patient 3 is a teenager with extensive deforming AVM of the nose and periorbital tissues. Draining vein liquid biopsy identified a somatic KRAS mutation (G12D). They were also commenced on trametinib and demonstrated marked reduction in AVM size and reduced pain. <h3>Discussion</h3> Our preliminary results support our hypothesis that liquid biopsy is a feasible method of identifying somatic mutations in complex cranio-spinal AVMs. They also suggest that somatic activating KRAS mutations play a role in a variety of AVM phenotypes, including Vein of Galen Malformation. These results highlight potential use of genotype-directed pharmacotherapy for these disabling lesions. <h3>Disclosures</h3> <b>K. Bhatia:</b> 1; C; Sydney Aneurysm Pty Ltd. 4; C; Sydney Aneurysm Pty Ltd. <b>D. Lord:</b> None. <b>G. McCowage:</b> None. <b>D. Sylvester:</b> None. <b>J. Karpelowsky:</b> None. <b>G. Olsson:</b> None. <b>C. Bateman:</b> None. <b>B. Padhye:</b> None. <b>P. Muthusami:</b> None. <b>T. Krings:</b> None. <b>S. Kahana-Edwin:</b> None.