带有EWSR1::CREM融合的软组织肉瘤是罕见且具有挑战性的治疗。帕唑帕尼,一种多酪氨酸激酶抑制剂,被FDA批准用于晚期软组织肉瘤,但其疗效的预测生物标志物仍未被确定。我们对提交给卡利斯生命科学(凤凰城,AZ)使用全转录组测序检测重排。两个肉瘤经历过,董事会认证的病理学家进行了组织学审查,收集治疗/结果信息。在确定的病例中(n=18),我们观察到各种各样的肉瘤和其他癌症,包括颅内黏液样间质瘤,间皮瘤,头颈部透明细胞癌,透明细胞肉瘤,和未分化的圆形细胞肉瘤,以及具有上皮样形态的组织学恶性肿瘤。值得注意的是,两个未分化的,转移性,用帕唑帕尼治疗的腹部圆形细胞肉瘤病例显示出显著的持续部分反应和临床获益。探讨这些病例中与帕唑帕尼疗效相关的遗传因素。我们通过下一代测序和荧光原位杂交分析了肿瘤的改变.基因组分析提供了令人信服的证据,证实了两种情况下EWSR1::CREM融合的存在,没有检测到其他致病基因变异或拷贝数改变。这些病例证明了帕唑帕尼作为EWSR1患者的有希望的治疗选择的潜力::CREM融合阳性软组织肉瘤,包括转移性未分化圆形细胞肉瘤。在这些病例中观察到的持续临床益处和部分反应值得进一步研究以验证这些发现,并探索帕唑帕尼在这种罕见且具有挑战性的软组织肉瘤子集中的更广泛用途。案例研究:案例1:一名49岁男子出现腹痛,减肥,慢性咳嗽.胸部计算机断层扫描(CT),腹部,和骨盆显示多个肺结节和肿块以及右直肌肿块,活检并显示未分化的圆形细胞肉瘤,并伴有罕见的EWSR1-CREM融合。没有检测到额外的致病基因变体或拷贝数改变。他接受了三个周期的长春新碱新辅助化疗,阿霉素,和异环磷酰胺(VAI)和七个周期的长春新碱/伊立替康和泰莫达(VIT)。在VIT的第7周期之后,他接受了腹部肿块的手术切除,并接受了肺转移的放射治疗。他完成了13个周期的VIT,此后他出现了疾病进展,并改用帕唑帕尼单药治疗。在进行此分析时,他的病情稳定了28个月。病例2:一名75岁的女性,表现为盆腔疼痛和新发作的便秘。腹部CT显示盆腔大肿块和腹膜内肿瘤扩散。剖腹探查术显示盆腔肿块破裂和小肠肿瘤。两种肿瘤都被证明是高级别肿瘤,低分化肉瘤。基因组分析表明EWSR1::CREM融合,但没有其他致病基因变体或拷贝数改变。她最初接受了四个周期的长春新碱/阿霉素/Cytoxan/Olaratumab的原始神经外胚层肿瘤(PNET)治疗,但在进展后拒绝了额外的化疗。两年后,她表现为复发性腹部肿块,接受了一个周期的Temodar/Irinotecan,然后她开始使用Pozapanib,并对整个骨盆进行了姑息性放疗。她已经服用帕唑帕尼23个月,病情稳定。
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.