1773P - Genomic and transcriptomic analysis of chondrosarcomas to explore new potential treatment options

Background

Chondrosarcoma (CS) is the second most common bone sarcoma. It is chemoradiotherapy-resistant, with few therapeutic options. Here, we performed comprehensive profiling of CS samples to explore new potential treatment options that may aid in treatment selection.

Methods

CS samples (n = 24) from an internal database (conventional (C, n = 13), dedifferentiated (D, n = 7), mesenchymal (n = 3), and clear cell (n = 1) subtypes) were analyzed by whole exome sequencing (WES) and RNA-seq as a part of BostonGene’s Tumor Portrait test. Results were analyzed retrospectively to detect genomic and transcriptomic changes and to classify tumor microenvironment (TME) subtypes.

Results

We found alterations in several receptor tyrosine kinases (RTKs), some of which are not targeted by current CS drugs (MET, EGFR; Table). Given the rarity of CS, the impact of other detected mutations is unknown and warrants further studies. Our analysis revealed 14 fibrotic (F), 7 immune-enriched (IE), and 3 immune-desert (ID) TME subtypes, with most of D CS being IE (4/7) and C CS being F (10/13). Moreover, IDH1/2 mutation was found in 11 samples; 9 had an F TME characterized by high prevalence of stromal components and weak immune infiltration. All samples exhibited microsatellite stability, and 23 had low tumor mutational burden. Table: 1773P

Molecular events in CS samples (n = 24)

Conclusions

Comprehensive profiling of a CS cohort identified alterations in targeted (PDGFR, VEGFR, FGFR) and untargeted (MET, EGFR) RTKs, indicating a possibility to expand TKI options for treating CS. This could lead to more clinical trials for which CS patients may be eligible. Moreover, other mutations uncovered may be potential biomarkers or drug targets that warrant further studies. High prevalence of non-IE TME subtypes in CS implies non-immunotherapeutic options to be more appropriate. Our findings form the basis for future research to improve treatment options and outcomes for CS patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

BostonGene, Corp.

Funding

BostonGene, Corp.

Disclosure

K. Zirov, M. Voropaeva, A. Aukhadieva, A. Makarova, A.E. Shevkoplias: Financial Interests, Full or part-time Employment: BostonGene, Corp. A. Novokreshchenova: Financial Interests, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Stocks/Shares: BostonGene, Corp. A. Dubrovskaya: Financial Interests, Full or part-time Employment: BostonGene, Corp. D. Lebedev: Financial Interests, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Stocks/Shares: BostonGene, Corp. S.T. Yong: Financial Interests, Personal, Stocks/Shares: BostonGene, Corp.; Financial Interests, Personal, Financially compensated role, Employment: BostonGene, Corp. J.H. Brown: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Stocks/Shares: BostonGene, Corp. S.P. Chawla: Financial Interests, Personal, Stocks/Shares, Own stocks.: Cellestia pharma; Financial Interests, Personal, Stocks/Shares, Stocks: Adi Biopharma; Financial Interests, Personal, Ownership Interest, Owner and stocks: Counterpoint; Financial Interests, Institutional, Local PI, Clinical research: Amgen; Financial Interests, Institutional, Local PI, Research: Adi bio, NK Gene, BMS, Rain Therapeutic, Shasqui, Monopar, Ayala, Boehringer Ingelheim; Financial Interests, Personal, Local PI, Research: Rain Therapeutic, Molleculin. G.M. Cote: Other, Honorarium: Gilead, BioAtla; Other, Consultant: Sonata Therapeutics, Chordoma Foundation; Other, Advisory Board: Ikena Oncology, C4 Therapeutics, Daiichi Sankyo, Inc; Financial Interests, Research Funding: Servier Pharmaceuticals, PharmaMar, MacroGenics, Eisai, Merck KGaA/EMD Serono Research and Development Institute, SpringWorks, Repare Therapeutics, Foghorn Therapeutics, SMP Oncology, Jazz Pharmaceuticals, RAIN Oncology, BioAtla, Inhibrx, Ikena Oncology, C4 Therapeutics, Kronos, Bavarian Nordic, Pyxis. J.A. Livingston: Financial Interests, Personal, Other, Nonprofit Strategic Advisory Board: Osteosarcoma Institute; Financial Interests, Institutional, Funding, Clinical trial funding and drug support: Genentech, Exelixis; Financial Interests, Institutional, Research Grant: Repare Therapeutics. V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/Loxo Oncology, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Institutional, Advisory Board, Scientific Advisory Board: Relay Therapeutics; Financial Interests, Institutional, Advisory Board: Regeneron; Financial Interests, Institutional, Advisory Board, Consultancy one time service: Novartis; Financial Interests, Personal, Invited Speaker, Invited speaker: Clinical Care Communications; Other, Other, I am an employee of Sarah Cannon Research Institute, Nashville, TN: Sarah Cannon Research Institute. A. Bagaev: Financial Interests, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Stocks/Shares: BostonGene, Corp.; Financial Interests, Leadership Role: BostonGene, Corp. L. Bednyagin: Financial Interests, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Stocks/Shares: BostonGene, Corp. A.P. Conley: Financial Interests, Research Funding: Eli Lilly, EpicentRx, Kronos Bio, Krystal Biotech, Inhbrx, NCI, Roche; Financial Interests, Research Grant: Chordoma Foundation; Financial Interests, Speaker, Consultant, Advisor: Aadi Biosciences, Guide Point. All other authors have declared no conflicts of interest.