926P - Genetic alteration in olfactory neuroblastoma: Unraveling carcinogenesis mechanisms and chemotherapy resistance through whole exome sequencing analysis

Background

Olfactory neuroblastoma (ONB), a very rare sinonasal malignancy, is treated multimodally but is often observed to be insensitive to cytotoxic chemotherapy and radiotherapy, resulting in a recurrence mainly with locoregional relapse. While Hyams histological grading, the Kadish system, and staging traditionally aid clinical characterization and treatment planning, comprehensive genomic profiling via Whole Exome Sequencing (WES) and its link to therapy resistance remain poorly understood.

Methods

This retrospective study investigates tumor genomic alterations (GA) in patients with unresectable or metastatic ONB treated at the National Cancer Center Hospital from 2015 to 2023. Genetic changes pre- and post-treatment were also analyzed when these tissue samples were available.

Results

We identified 12 patients (6 females) with a median age of 50 (range 31-69). Eight of 12 patients initially received multimodal therapy, predominantly platinum-based chemotherapy, and WES was performed on the primary samples in all cases. Four patients received chemotherapy after postoperative recurrence; the primary samples were available in 2 cases. Among 24 samples from 12 cases subjected to WES, 75% exhibited significant GA, delineating two prevalent patterns: cell proliferation pathways and aberrant repair mechanisms. Tumor mutation burden (TMB) high status was noted in 33% of samples, and the median TMB score was 8.4 (range 1.8-92). The median homologous recombination (HR) deficiency (HRD) score was 12 (range 2-29), and HR-related genes were present in two cases (CHEK2 and RAD50), although not unequivocally linked to HRD score elevation but with elevated TMB. ZNRF3 was detected in two cases from primary samples, and both were responders to platinum-based chemotherapy. Exclusive genetic abnormalities in recurrent samples included concurrent NF1 and PRL5 mutations in two cases and TP53 mutation in one case.

Conclusions

Nine of 12 ONB cases demonstrated abnormalities in cell proliferation pathways or repair mechanisms. Newly discovered abnormalities in HRD and TMB mechanisms may offer future therapeutic avenues with novel agents in ONB.

Clinical trial identification

Editorial acknowledgement

Funding

Has not received any funding.

Disclosure

Y. Honma: Financial Interests, Personal, Advisory Board: Janssen, Rakuten Medical Japan; Financial Interests, Personal and Institutional, Coordinating PI: Taiho Pharmaceutical, Chugai Pharma, MSD, Jannsen, Merck Biopharma; Financial Interests, Institutional, Coordinating PI: GSK, Adlai Nortye Biopharma, Maruho, Genmab, Astellas pharma, AstraZeneca; Financial Interests, Institutional, Funding: Rakuten Medical Japan. All other authors have declared no conflicts of interest.