1963P - Comprehensive profiling of chordoma reveals tumor microenvironment subtypes and unique molecular findings

Background

Chordoma is a rare type of bone cancer with limited treatment options. Encouraging results showing the efficacy of pembrolizumab, a PD1 checkpoint inhibitor, in chordomas have recently been reported. Here, we performed comprehensive molecular testing to dissect the immune profile of these tumors and elucidate mechanisms of therapy response in chordomas.

Methods

Whole exome sequencing (WES) and whole transcriptome analysis was performed on samples from 14 patients (n = 6 samples from skull base, n = 8 samples from spine) with chordoma. Retrospective analysis of BostonGene’s Tumor Portrait® test results identified genomic and transcriptomic alterations of chordomas and classified tumor microenvironment (TME) subtypes according to methods from Bagaev, et al., 2021.

Results

The median age of patients was 54.5 years (range: 26-76 years). The histologic subtypes were conventional (n = 13) and dedifferentiated (n = 1). The median number of prior therapies was 1 (range: 0-3). Transcriptomic-based TME classification revealed 93% (n = 13) of patients had an immune-enriched (IE) TME subtype characterized by high levels of B cells and CD4+ T cells and low levels of tumor-associated macrophages. Only one patient had a fibrotic TME characterized by minimal immune infiltration and a high prevalence of stromal elements. High CD274 (PD-L1) expression was observed in 57% of samples. EGFR expression was high in all samples. In three cases, a 22q deletion was identified. Other clinically actionable events included SMARCB1 loss (n = 3), TP53 alteration (n = 2), BRCA1 loss (n = 1), a combination of PTEN, NF2, and TRAF2 loss (n = 1), and CDKN2A/B loss (n = 1). All samples were microsatellite stable and had low tumor mutational burden (range: 0.31-1.32 mut/Mb). From this cohort, 50% of patients were matched with at least one clinical trial based on their molecular profiles.

Conclusions

The prevalence of IE TME subtypes in chordomas supports the previously reported response to immune checkpoint inhibitors in chordomas. Together, these findings indicate next-generation sequencing could be a useful tool for informing treatment selection in advanced chordomas.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

BostonGene, Corp.

Funding

BostonGene, Corp.

Disclosure

M. Voropaeva, I. Zhuk, A. Aukhadieva, K. Zirov, A. Makarova, L. Bednyagin: Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. A. Bagaev: Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Personal, Stocks/Shares: BostonGene, Corp.