Expanding the spectrum of neoplasms harboring EWSR1::CREM fusion as detected by a real-world clinical genomics platform.

Leticia Campoverde University of Miami Hospital/Jackson Memorial Hospital, Miami, FL info_outline Leticia Campoverde, Mark Gordon Evans, Andrew Elliott, Felipe Camacho, Jeremy Adler, Matthew James Oberley, George W. Sledge, Andrew E. Rosenberg, Jonathan C. Trent

Authors Leticia Campoverde University of Miami Hospital/Jackson Memorial Hospital, Miami, FL info_outline Leticia Campoverde, Mark Gordon Evans, Andrew Elliott, Felipe Camacho, Jeremy Adler, Matthew James Oberley, George W. Sledge, Andrew E. Rosenberg, Jonathan C. Trent Organizations University of Miami Hospital/Jackson Memorial Hospital, Miami, FL, Caris Life Sciences, Phoenix, AZ, University of Miami Hospital, Miami, FL, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL Abstract Disclosures Research Funding No funding received None. Background: Malignancies with various well-defined phenotypes and prognoses have been shown to possess gene fusions between Ewing Sarcoma Breakpoint Region 1 ( EWSR1 ) and one of the CREB family genes, specifically CREB1 and ATF1 . However, less is known about neoplasms that harbor EWSR1:CREM rearrangements, which are thought to result in constitutive activation of CREM and subsequent dysregulation of oncogenes, such as BCL-2 family genes, EGFR1 , and cyclins . EWSR1:CREM fusion has been identified in rare cases of angiomatoid fibrous histiocytoma, clear cell sarcoma, hyalinizing clear cell carcinoma of the head and neck, and intracranial myxoid mesenchymal tumor. Our study represents the largest to date and seeks to expand and further define the diversity of tumor subtypes that possess EWSR1:CREM fusions. Methods: Detection of EWSR1:CREM rearrangements by whole transcriptome sequencing was performed for > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ). Histological review of the identified tumors was performed by two board-certified pathologists (MGE, AER). Treatment and outcome information were collected, where available. Results: An EWSR1:CREM fusion was detected in 18 cases, which included one intracranial myxoid mesenchymal tumor, one mesothelioma, four hyalinizing clear cell carcinomas of the head and neck, two clear cell sarcomas, two small round and spindle cell sarcomas, and eight histologically malignant tumors having an epithelioid morphology. While the latter were in keeping with a disease entity recently reported in the medical literature (epithelioid neoplasm with predilection for mesothelial-lined cavities), several of these cases demonstrated unexpected neuroendocrine differentiation and were found at unusual sites, including the kidney, uterus, and cervical spine. Moreover, three cases had the features of squamous cell carcinoma. Surgical resection was performed in all patients, and pazopanib was utilized in two round and spindle cell sarcoma cases. This medication was shown radiographically to produce a partial response at 19 months and stable disease at 26 months, respectively, in heavily pretreated patients. Conclusions: By detecting an EWSR1:CREM rearrangement, molecular testing may aid in the diagnosis of a variety of rare tumor types, including a poorly understood malignant epithelioid neoplasm that arises in a variety of anatomic sites including mesothelial-lined cavities. Tumors harboring this fusion may ultimately be susceptible to treatment with tyrosine kinase inhibitor targeted therapy.