Systemic treatments and outcomes in CIC‐rearranged Sarcoma: A national multi‐centre clinicopathological series and literature review

Abstract

CIC ‐rearranged sarcoma is a recently established, ultra‐rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC ‐rearranged sarcomas and explore clinical management including systemic treatments and outcomes. Methods A multi‐centre retrospective cohort study of patients diagnosed between 2014–2019. Results Eighteen patients were identified. The median age was 27 years (range 13–56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1‐, 2‐ and 5‐year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing‐based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1–20.1), 1‐year OS was 57%. Median progression‐free survival was 5.8 months (95% CI 4.5–7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib ( n = 1) and pembrolizumab ( n = 1) were not seen. Conclusion In this series, CIC ‐rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent.

CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers

“…The ultra-rare variant CIC-NUTM1 seems to have distinct anatomic tropism for the axial skeleton [ 13 ]. The most common metastatic sites are the lungs, bone, liver, brain, and lymph nodes and around 40% of cases are diagnosed at metastatic stage [ 14 ].…”

“…Although some sporadic cases of good response to chemotherapy or radiation therapy have been reported [ 15 , 16 ], the prognosis of CIC sarcomas is poor. The 5-year overall survival is around 50%, which is significantly lower than the 80% 5-year overall survival of EWS patients [ 4 , 14 , 17 ]. Around 40% of CIC sarcoma patients present metastasis at diagnosis, mainly involving the lung, and patients with metastatic disease at diagnosis display an unfavorable clinical outcome compared to patients with localized disease [ 4 , 14 , 17 ].…”

“…The 5-year overall survival is around 50%, which is significantly lower than the 80% 5-year overall survival of EWS patients [ 4 , 14 , 17 ]. Around 40% of CIC sarcoma patients present metastasis at diagnosis, mainly involving the lung, and patients with metastatic disease at diagnosis display an unfavorable clinical outcome compared to patients with localized disease [ 4 , 14 , 17 ]. No significant effect on survival has been observed when considering age, sex, and tumor size [ 4 , 14 , 17 ].…”

“…Around 40% of CIC sarcoma patients present metastasis at diagnosis, mainly involving the lung, and patients with metastatic disease at diagnosis display an unfavorable clinical outcome compared to patients with localized disease [ 4 , 14 , 17 ]. No significant effect on survival has been observed when considering age, sex, and tumor size [ 4 , 14 , 17 ]. Available data are limited to relatively small, single-institution retrospective series but they consistently indicate that CIC sarcomas are less chemo-sensitive than EWS.…”

“…In addition, histologic response to chemotherapy, evaluated according to tumor necrosis grade, indicated a minority of CIC patients (around 30%) displaying a good response to the treatment [ 4 ], which is lower than the 49% of good response in EWS [ 18 ]. Considering other non-cytotoxic therapeutic approaches, no signs of activity were identified for those few patients treated with tyrosine kinase inhibitors (regorafenib, pazopanib) or immunotherapy (pembrolizumab), who still experienced rapid disease progression [ 14 ]. Despite the limitation of these retrospective studies, the evidence from the clinic indicates that CIC-rearranged sarcoma represents a novel and discrete tumor entity, which displays a decreased histological response to standard chemotherapy compared to EWS.…”