Abstract 2184: Landscape of genomic alterations of ultra-rare sarcomas (URS) from 1,079 patients in the AACR GENIE real world database: Clinical implications
Authors: Moyers Justin Tyler , Brazel Danielle , Kumar Priyanka , Doan Hung , Roszik Jason , Valerin Jennifer B. , Pestana Roberto Carmagnani , Chow Warren A. , Subbiah Vivek K. 
Published: June 2022

Abstract
Introduction: Sarcomas are heterogenous tumors of more than 150 different tumor types. Recently, 56 soft tissue (ST-URS) and 21 bone (B-URS) sarcomas were classified as URS based on incidence of less than 1 in a million by the Connective Tissue Oncology Society. There is only one histology-based treatment approved in URS.
Methods: AACR GENIE database cBioPortal were accessed. Individual alterations annotated by OncoKB therapeutic evidence level, TCGA PanCancer pathway alterations, and demographic data were gathered. Detailed cancer type was reclassified into genomically distinct diseases as appropriate.
Results: From 112, 222 patients, 3,424 soft tissue sarcomas and 832 bone sarcomas were identified. 1,079 of 4,251 (25.4%) sarcomas were URS including 950 ST-URS and 129 B-URS. Patients included were 54.1% (n=584) female and identified race as 66.1% (n=713) white, 8.5% (n=92) black, and 6.8% (n=73) Asian. 39/56 ST-URS and 11/21 B-URS subtypes had cases in database. The median number of alterations was 3.0 (SD 5.94, Range 0-81), 3.0 for B-URS and 4.0 for ST-URS. Oncogenic alterations were present in 63.6% of B-URS versus 74.0% of ST-URS (p=0.01). Genomic sequencing identified Level 1 (L1) (FDA-approved drug) in 4.9% (n=53) of URS; 5.6% (n=53) of ST-URS and 0 B-URS (p=0.006). Level 2 (L2) (Standard of care) alterations were seen in 1.6% (n=15) ST-URS and no B-URS. 19.5% (n=210) of all URS and 19.9% (n=189) of ST-URS versus 16.3% (n=21) of B-URS (p=0.3) had an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). Level 3A gene mutations included BRAF (n=12), NRAS (n=2), TSC2 (n=8). 100 level 3B gene alterations were observed; NRAS (n=21), PIK3CA (n=16), IDH1 (n=8), IDH2 (n=4), TSC2 (n=9), HRAS (n=8), TSC1 (n=5), ATM (n=7), BRCA1/2 (n=4). All L1 (n=36) fusions involved NTRK alterations and all L2 fusions (n=14) involved ALK fusion products in inflammatory myofibroblastic tumors. 17 L1 SMARCB1 copy number alterations (CNA) were seen in epithelioid sarcomas. 1 L3A TSC2 CNA was observed in PECOMA; 29 L3B CNAs were observed including SMARCB1 del (n=7), FGFR1 amp (N=6), BRCA2 del (n=4), and Met amp (n=2). 62.9% of cases had PanCancer pathways altered; TP53 (32.7%), RTK-RAS (33.5%), and cell cycle (33.2%) pathway alterations were most common. TP53 (40.3% versus 31.7%, p=0.05) and cell cycle (41.1% versus 32.1%, p=0.04) alterations were more common in B-URS, while RTK-RAS (34.5% versus 25.6%, p=0.04) alterations were more common in ST-URS.
Conclusions: Genomic sequencing of URS reveals actionable alterations, their co-alterations, and key clinical characteristics using a large multi-institution publicly accessible registry of real-world patient data opening additional treatment options. Sequencing should be routine care in URS. Increased racial diversity in genetic samples and public databases is warranted.
Citation Format: Justin Tyler Moyers, Danielle Brazel, Priyanka Kumar, Hung Doan, Jason Roszik, Jennifer B. Valerin, Roberto Carmagnani Pestana, Warren A. Chow, Vivek K. Subbiah. Landscape of genomic alterations of ultra-rare sarcomas (URS) from 1,079 patients in the AACR GENIE real world database: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2184.