Novel genomic alterations and transcriptomic-based tumor microenvironment classification of sarcoma and their impact on treatment decision making.
Authors: Zhuk Irina , Novokreschchenova Anna , Aukhadieva Aida , Degryse Sandrine , Shevkoplias Aleksei , Belozerova Anna , Nomie Krystle , Kotlov Nikita , Sagaradze Georgy , Bedniagin Lev , Balabanian Linda , Postovalova Ekaterina , Bagaev Alexander , Fowler Nathan , Livingston J Andrew Andrew , Ravi Vinod , Chawla Sant P. , Cote Gregory Michael 
Published: June 2023

11547 Background: Sarcomas are rare tumors of mesenchymal origin, with over 50 different histological sarcoma subtypes. The heterogeneous molecular and immunologic characteristics of sarcomas present many challenges for diagnostics and treatment plans. We aim to provide a more comprehensive molecular testing and immune profiling of sarcoma patients. Methods: The cohort consisted of samples from 200 patients diagnosed with sarcomas. WES and whole transcriptome analysis were performed on all samples. Tumor Portrait test identified genomic alterations of sarcomas and classified tumor microenvironment (TME) subtypes. The actual response to immune checkpoint inhibitor (ICI) treatment was determined using RECIST criteria and compared to response predictions by the Tumor Portrait test. Results: Across sarcoma subtypes, the most common mutations were in tumor suppressors including TP53, RB1, CDKN2A, and TSC1/2. We report fusions in 20.5% of cases, with commonly described diagnostic fusions accounting for 34/41 cases. In one case, the detection of the ZC3H7B-BCOR fusion suggested a change in diagnosis from uterine leiomyosarcoma to endometrial stromal sarcoma. Several previously unreported fusions were detected, including potentially targetable ( ARID1A-NUDC, MICAL3-MAPK) and prognostic ( YWHE-CIC) fusions. DNA damage response related genes were mutated in 12% of cases. Other less commonly detected targetable alterations were found in the following genes: MDM2, CDK4, SMARCB1, NF1, PIK3CA, NTRK1-3, FGFR1-4. Transcriptomic-based TME classification found that 52% of patients had an Immune-Enriched (IE) TME, with 26.5% and 25.5% grouped in the IE-Fibrotic and IE-non-Fibrotic subtype, respectively, which we previously showed is associated with good response to ICI treatment. In contrast, 48% of the patients presented with a Fibrotic (F, 30%) or Desert (D, 18%) subtype, are predicted to have a poor response to ICI treatment. Our classification of sarcomas based on TME subtypes conforms well with predicted responses of tumors to ICI therapy found in previous reports. Soft-tissue angiosarcomas, undifferentiated pleomorphic sarcoma, and myxofibrosarcomas presented TMEs of the IE subtype in 75% of cases, significantly more compared to 34% of the bone neoplasm cases, which are known for their favorable and unfavorable response to ICI therapy, respectively (Chi-squared test, p = 0.001). In retrospective chart review, we had response data on 24 patients who received ICI treatment. The disease control rate, defined as CR+PR+SD as best response, was significantly higher in the IE subtype compared to the F/D subtype (85.7% vs 20%, Chi-squared test, p < 0.003). Conclusions: Together, our findings identify actionable and diagnostic alterations in diverse mesenchymal tumors and suggest that ICI treatment may be beneficial in immune-enriched sarcomas.