Molecular profiling of locally advanced/metastatic olfactory neuroblastomas
Background: Olfactory neuroblastoma (esthesioneuroblastoma) [ONB] is a rare malignant neoplasm arising from the olfactory epithelium in the nasal vault. It usually takes an aggressive clinical course for which there are no specific treatment guidelines. Pursuing the goals of personalized medicine, weinvestigated acohort of recurrent and/ or metastatic ONBs using multiplatform molecular profiling approach. Methods: Formalin-fixed paraffin-embedded tissue samples of twenty (10 male, 10 female patients, age range: 29-84 years) ONBs were profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger sequencing, massively parallel sequencing [Illumina NGS] and gene fusions [Archer FusionPlex]), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina), gene copy numberassays (chromogenic and fluorescent in situ hybridization) and immunohistochemistry. Results: Mutations were detected in 8/14 (57%) ONBs including TP53 (3 cases), CTNNB1 (2 cases), APC, cKIT, cMETand PDGFRA, and SMAD4 gene (single cases, respectively). When compared with control tissues, 21 genes were overexpressed and 19 genes under expressed by microarrayassay (>10x). Some of the upregulated genes included stem cell marker CD24, SCG2 (Secretogranin II) and Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2). None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. No case expressed PD-L1 (0/6) or IDO-1 (0/3). Multiple protein biomarkers of response or resistance to classic chemotherapy drugs were identified: low ERCC1 [cisplatin sensitivity] in 82% (9/11), high TOPO1 [irinotecan sensitivity] in 63% [12/19], high TUBB3 [vincristine resistance] in 92% (12/13) and high MRP1 (multidrug resistance) in 100% (6/6). Conclusions: Our study indicatesthata subset of ONBs exhibits molecularalterations, notably in the Wnt and cKIT/PDGFRA pathways, that are potentially treatable using novel targeted therapies. Optimization of cytotoxic chemotherapyapproaches based on protein expression may beworthy offurther investigation. study: Disclosure: ofCaris All declaredno ofinterest.