Case report: The activity of multi-kinase VEGF inhibitor, Pazopanib, in metastatic undifferentiated round cell sarcomas harboring EWSR1::CREM fusion: clinicopathological series of two cases and literature review

Our plain-English summary of Case report: The activity of multi-kinase VEGF inhibitor, Pazopanib, in metastatic undifferentiated round cell sarcomas harboring EWSR1::CREM fusion: clinicopathological series of two cases and literature review, by L. Campoverde, F. Camacho, F. Alessandrino, et al (Frontiers in Oncology, 2023).

The study

• Authors: L. Campoverde, F. Camacho, F. Alessandrino, M.G. Evans, A. Elliot, A. Rosenberg, J. Trent
• Journal: Frontiers in Oncology
• Published: 2023;13:1215003
• Type of article: Case report
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Soft tissue sarcomas harboring EWSR1::CREM fusion are rare and challenging to treat. Pazopanib, a multi-tyrosine kinase inhibitor, is FDA-approved for advanced soft tissue sarcomas, but predictive biomarkers for its efficacy remain unidentified. We conducted a study on > 240,000 neoplasms submitted to Caris Life Sciences (Phoenix, AZ) to detect rearrangements using whole transcriptome sequencing. Two sarcoma-experienced, board-certified pathologists performed histological reviews, and treatment/outcome information was collected. Among the identified cases (n = 18), we observed a diverse range of sarcoma and other cancers, including an intracranial myxoid mesenchymal tumor, mesothelioma, hyalinizing clear cell carcinomas of the head and neck, clear cell sarcomas, and undifferentiated round cell sarcomas, as well as histologically malignant tumors with epithelioid morphology. Notably, two undifferentiated, metastatic, abdominal round cell sarcoma cases treated with pazopanib demonstrated significant sustained partial response and clinical benefit. To explore the genetic factors associated with the efficacy of pazopanib in these cases, next-generation sequencing and fluorescence in situ hybridization were analyzed for alterations in the tumors. The genomic analysis provided compelling evidence confirming the presence of EWSR1::CREM fusion in both cases, with no other pathogenic gene variants or copy number alterations detected. These cases demonstrate the potential of Pazopanib as a promising therapeutic option for patients with EWSR1::CREM fusion-positive soft tissue sarcomas, including metastatic undifferentiated round cell sarcomas. The sustained clinical benefit and partial responses observed in these cases warrant further research to validate these findings and explore the wider utility of Pazopanib in this rare and challenging subset of soft tissue sarcomas. Case studies: Case 1: A 49-year-old man presented with abdominal pain, weight loss, and chronic cough. A computed tomography (CT) of the chest, abdomen, and pelvis showed multiple lung nodules and masses and a right rectus mass that was biopsied and revealed an undifferentiated round cell sarcoma with a rare fusion EWSR1-CREM. No additional pathogenic gene variants or copy number alterations were detected. He received neoadjuvant chemotherapy with three cycles of Vincristine, Adriamycin, and Ifosfamide (VAI) and seven cycles of Vincristine/Irinotecan and Temodar (VIT). After cycle 7 of VIT, he had surgical resection of the abdominal mass and received radiation for lung metastasis. He completed 13 cycles of VIT after which he presented with progression of disease and switched to monotherapy with Pazopanib. At the time of this analysis he had stable disease for 28 months. Case 2: A 75-year-old woman presented with pelvic pain and new onset constipation. CT abdomen showed a large pelvic mass and intraperitoneal tumor spread. Exploratory laparotomy revealed a ruptured pelvic mass and a small bowel tumor. Both tumors were proved to be high-grade, poorly differentiated sarcoma. Genomic analysis demonstrated an EWSR1::CREM fusion but no other pathogenic gene variants or copy number alterations. She was treated initially for a primitive neuroectodermal tumor (PNET) with four cycles of Vincristine/Adriamycin/Cytoxan/Olaratumab but declined additional chemotherapy after progression. Two years later, she presented with recurrent abdominal mass and received one cycle of Temodar/Irinotecan, then she began Pozapanib and underwent palliative radiation to the entire pelvis. She has been on Pazopanib for 23 months with stable disease.

Copyright © 2023 Campoverde, Camacho, Alessandrino, Evans, Elliot, Rosenberg and Trent.

In plain English

This article reports two patients' cases after a laboratory screen; it does not study asbestos. The authors searched more than 240,000 tumor samples submitted to Caris Life Sciences for a gene fusion called EWSR1::CREM. Eighteen tumors carried it, including one mesothelioma, about which no further details are given. The report then describes two patients with undifferentiated round cell sarcomas in the abdomen that had already spread when they were diagnosed. Both tumors carried the fusion, and no other disease-causing gene variants or copy number alterations were detected. A 49-year-old man was switched to the drug pazopanib alone after his disease progressed on chemotherapy. Imaging every 3 months showed stable disease for at least 28 months. A 75-year-old woman received pazopanib and radiation to the pelvis after chemotherapy. She had stable disease for 23 months, after which imaging showed progression and she had severe anemia. The authors concluded that these cases demonstrate the potential of pazopanib for EWSR1::CREM fusion-positive soft tissue sarcomas, and that further research is needed to validate the findings.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case report of two patients, preceded by a molecular screen of tumor samples for the EWSR1::CREM fusion; the title also describes a literature review, which consists of discussion of earlier published cases
• Who was studied: More than 240,000 tumor samples submitted to Caris Life Sciences (Phoenix, AZ) were screened. 18 carried the EWSR1::CREM fusion. Two patients were described in detail: a 49-year-old man and a 75-year-old woman, both with metastatic undifferentiated round cell sarcomas of the abdomen. Dates of the screen are not given.
• Exposure: No asbestos or other fiber exposure is reported. What the article examines is treatment with pazopanib, a multi-tyrosine kinase inhibitor drug, given after chemotherapy in the two patients.
• Main results:
  • Of the screened tumors, 18 had the EWSR1::CREM fusion: one intracranial myxoid mesenchymal tumor, one mesothelioma (site and type not stated), four hyalinizing clear cell carcinomas of the head and neck, two clear cell sarcomas, two undifferentiated round cell sarcomas, and eight histologically malignant tumors with epithelioid morphology
  • In both described patients, no other pathogenic gene variants or copy number alterations were detected besides the fusion
  • Case 1 (49-year-old man): on pazopanib alone, imaging every 3 months showed stable disease for at least 28 months
  • Case 1: CT 28 months after starting pazopanib showed mildly decreased size and enhancement of lung lesions, which the authors read as suggesting tumor regression
  • Case 2 (75-year-old woman): stable disease for 23 months on pazopanib, followed by progression of disease on imaging and severe anemia
• The authors' conclusion: The authors concluded that these cases demonstrate the potential of pazopanib as a therapeutic option for patients with EWSR1::CREM fusion-positive soft tissue sarcomas, including metastatic undifferentiated round cell sarcomas
• Limitations the authors state:
  • The authors stated that further research is needed to validate the findings

Topics

Medical terms in this study, explained in our Lexicon: Sarcoma, Tyrosine Kinase Inhibitor, Biomarker, Neoplasm, Mesenchymal Tumor, Mesothelioma, Carcinoma, Epithelioid.

Related studies

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• Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review — R.N. Prasad, U.G. Gardner, et al. (2021)
• EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities — P. Argani, I. Harvey, et al. (2020)
• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)
• RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12) — I. Panagopoulos, J. Thorsen, et al. (2013)
• Malignant Mesothelioma With EWSR1-ATF1 Fusion in Two Adolescent Male Patients — H. Ren, S.R. Rassekh, et al. (2021)

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