1774P - Immunological-molecular profiling of chondrosarcoma (ChS)

Background

There is still no effective systemic treatment of ChS. ChS are considered as cold tumors with poor response to immunotherapy. Immunophenotype of ChS and characterization of immune markers, as well as molecular background of this tumors are still poorly understood. The aim of this study was both immunological and molecular profiling of ChS and correlation these features with clinical outcomes. This study may also help in selection of patients (pts) who can benefit from targeted therapy.

Methods

We enrolled 99 pts diagnosed with primary ChS (28 G1, 37 G2, 24 G3 and 10 dedifferentiated cases). For immune cells infiltrates evaluation, tissue microarrays of central and peripheral region of the tumors were prepared from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemical analysis covered 20 markers defining e.g. effector T cells, antigen-presenting cells, and M1/M2 macrophages, T cells exhaustion, PD-L1 expression. Molecular profiling and tumor mutational burden were obtained by next-generation sequencing of 409 genes. Additionally, microsatellite instability was evaluated. Multiparametric analysis was performed using LASSO-based Cox regression.

Results

Median overall survival of all pts was 64.6 (95%CI: 44.2 -) months. We identified 3 different immunophenotypes among ChS pts which can be described as “cold”, “hot” and “intermediate”. The most frequently mutated genes (detected in >10% of pts) were IDH1/2, TP53, TAF1, and RNF213. The presence of IDH1/2 or TP53 mutation was significantly correlated with tumor grade and these were observed more frequently in high grade ChS. In multivariate Cox analysis the presence of “hot” (HR: 3.36, CI:1.12-10.1, p<0.05) or “intermediate” phenotype (HR: 3.07, CI:1.01-9.4, p<0.05), and IDH1 mutations (HR: 3.34, CI:1.56-7.2, p<0.01) were poor prognostic factors, as well as tumor grade and size.

Conclusions

Immune phenotypes related to higher immune cell infiltrates inside the tumor and occurrence of IDH1 mutation are independent poor prognostic factors and predict worse outcomes in ChS pts. These finding indicated that it is possible to identify a group of pts with a poor prognosis, in whom the use of immunotherapy and inhibitors of IDH-mutant could potentially provide clinical benefit.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Maria Sklodowska-Curie National Research Institute of Oncology.

Funding

Polish National Science Centre.

Disclosure

P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfizer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Member of Board of Directors: Polish Society of Surgical Oncology; Non-Financial Interests, Member of Board of Directors, President: Polish Oncological Society. E. Palmerini: Financial Interests, Personal, Advisory Board: SynOx, Daiichi Sankyo, Deciphera Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Peer View Educational. J. Blay: Financial Interests, Institutional, Invited Speaker: MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022.: Innate pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. A.M. Czarnecka: Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre. All other authors have declared no conflicts of interest.