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, we investigated a cohort 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 number assays (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, cMET and PDGFRA, and SMAD4 gene (single cases, respectively). When compared with control tissues, 21 genes were over expressed and 19 genes under expressed by microarray assay (>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 indicates that a subset of ONBs exhibits molecular alterations, notably in the Wnt and cKIT/PDGFRA pathways, that are potentially treatable using novel targeted therapies. Optimization of cytotoxic chemotherapy approaches based on protein expression may be worthy of further investigation.

Clinical trial identification

Not applicable.

Legal entity responsible for the study

Caris Life Sciences, Phoenix, Arizona, USA

Funding

Caris Life Sciences, Phoenix, Arizona, USA

Disclosure

Z. Gatalica, A. Ghazalpour, J. Swensen, R. Bender, R. Feldman, S. Reddy: Employee of Caris Life Sciences. All other authors have declared no conflicts of interest.