Objective – Chondrosarcomas are rare cancers of cartilage. Conventional chondrosarcoma, the most common subtype, has no known effective systemic therapies. Mesenchymal and dedifferentiated chondrosarcoma are treated with Ewing sarcoma or osteosarcoma regimens, although the efficacy of this approach is not firmly established. More effective systemic therapies are urgently needed. After the identification of IDH mutations in chondrosarcoma, IDH inhibitors are now being studied in this disease. Reports of patients responding to immune checkpoint inhibitors are published, but without a clear mechanism for why some chondrosarcoma patients respond to immunotherapy. Small
prospective studies of immune checkpoint inhibitors were negative. We sought to characterize the molecular and immune landscape of conventional, dedifferentiated, and mesenchymal chondrosarcomas using a large database of clinical-grade sequencing results.

Methods – A sample of de-identified records from patients with a histologic diagnosis of conventional chondrosarcoma, dedifferentiated chondrosarcoma, or mesenchymal chondrosarcoma in the Tempus database who had completed tissue DNA sequencing with the Tempus xT assay were included for this retrospective analysis (Tempus Labs, Chicago, IL). Tempus xT is a targeted, tumor/normal-matched panel that detects single-nucleotide variants, insertions and/or deletions, and copy number variants in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Microsatellite instability (MSI) and tumor mutational burden (TMB) were determined from sequencing data. Expression of PD-L1 and mismatch repair enzymes were evaluated in cases with available immunohistochemistry (IHC) data.

Results – There were 149 patient records identified consisting of 103 conventional chondrosarcoma, 31 dedifferentiated chondrosarcoma, and 15 mesenchymal chondrosarcoma samples. Out of the total cohort, 44% of patients had either an IDH1 or IDH2 mutation (n=65); there were no cases of co-occurring IDH1/2 mutations. No cases were MSI high. One conventional chondrosarcoma patient had a TMB >10 mut/Mb. Among 86 patients with available PD-L1 IHC data, 4% of conventional (n=4), 13% of dedifferentiated (n=4), and 13% of mesenchymal cases (n=2) were PD-L1 positive. The most common somatic alterations in conventional chondrosarcoma were IDH1 (34%),
TP53 (30%), CDKN2A (18%), TERT (15%), CDKN2B (14%), LRP1B (13%), MTAP (12%), and KMT2D (11%). The most common somatic alterations in dedifferentiated chondrosarcoma were TERT (71%), TP53 (68%), IDH2 (39%), CDKN2A (39%), IDH1 (39%), CDKN2B (35%), MTAP (19%), and PDGFRB (19%). The most common somatic alterations in mesenchymal chondrosarcoma were HEY1-NCOA2 fusions (87%), KMT2C (20%), CDKN2A (20%), EMSY (13%), PRKDC (13%), RBM10 (13%), CDKN2B (13%), and MTAP (13%).

Conclusions – These findings reinforce current therapeutic efforts to target IDH signaling in chondrosarcoma and provide insight into why some subpopulations of patients may respond to immune checkpoint inhibitors. Biomarker-driven trials are needed to understand the significance and potential applications of these results in clinical practice.

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