(P 449) CIC-DUX4 sarcomas: A single-center review of clinical features and molecular aberrations identified through DNA sequencing

Objective: CIC-rearranged sarcomas, a rare and distinct subtype of undifferentiated round cell sarcomas, harbor CIC-related gene fusions. While other fusion partners exist, a CIC-DUX4 fusion is present in 95% of cases. Despite a small blue round cell morphology, CIC-rearranged sarcomas appear more aggressive and less responsive to treatment with inferior outcomes when compared to Ewing sarcoma. Given the rarity of CIC-rearranged sarcomas, further investigation into these poorer outcomes is scarce, as are consensus treatment guidelines. The aim of this study is to summarize clinical and histological features of CIC-DUX4 sarcomas and to review additional molecular aberrations identified by DNA sequencing to facilitate targeted therapy.

Methods: A single-institution retrospective chart review using a free-text search engine and keywords “CIC-DUX4”, and “sarcoma” generated 25 patients of any age diagnosed from 2012-2022. Eligible patients had a confirmed diagnosis of CIC-DUX4 sarcoma based on immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), molecular profiling via next generation sequencing or the Michigan Oncology Sequencing Center (MI-ONCOSEQ), an integrative sequencing technique that detects point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes.

Results: 15 eligible patients (10M/5F) were identified with a median age of 23 years (range 10-85); 8 patients (53%) were 15-39 years at the time of diagnosis. 7 patients were non-white (5 black and 2 Hispanic). 8 patients (53%) presented with localized disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Sites of metastases included lung (n=7), adrenal (n=1), and bone (n=1). 10 patients (67%) received radiotherapy to the primary site, 6 as part of definitive treatment, 3 for palliation and 1 for pre-operative treatment. 9 patients (60%) underwent surgical resection of the primary site. 14 patients received chemotherapy, primarily Ewing sarcoma-based regimens, while one patient received pazopanib as primary therapy. 7 patients (47%) received additional lines of systemic therapy. 1-, 2-, and 5-year overall survival (OS) was 67%, 32%, and 7%, respectively. OS estimates for patients with localized disease were 76%, 39%, and 13% at 1, 2 and 5 years while patients presenting with metastases had OS estimates of 57%, 28% and 0% at these times points. 2 patients with metastatic disease and 1 patient with localized disease remain in follow-up without evidence of disease at 37, 45, and 85 months, respectively, following diagnosis. MI-ONCOSEQ in available specimens revealed aberrations in ETS family genes, cell cycle gene CCNE1, FGFR1 and FGF1 and others. Histology was reviewed in 13 cases to identify features to help distinguish these tumors from Ewing’s sarcoma. 13/13 showed necrosis, 10/13 (77%) had myxoid matrix, 10/13 (77%) showed cytoplasmic clearing and 2/13 (15%) had moderate nuclear pleomorphism. Spindle cell or rhabdoid features were noted in 6 cases (46%).

Conclusion: In this series, CIC-DUX4 sarcomas affected young adults although in lower incidence than in other series. Racial distribution differed from that seen with Ewing sarcoma, with a higher incidence in non-white persons. While overall prognosis with CIC-rearranged sarcomas is poor, survival duration of more than 3 years occurred in a small subset of patients treated with multimodality therapy. Evaluating specific histological features of these CIC-DUX4 sarcomas to distinguish from Ewing’s sarcoma can help guide a correct diagnosis when molecular testing is not readily available. DNA sequencing in our series revealed a non-homogenous pattern of outlier expressed genes which may inform targets for individualized therapy beyond standard Ewing sarcoma-based regimens.