(P 293) CIC-REARRANGED SOFT TISSUE SARCOMAS: DOES CHEMOTHERAPY CHANGE NATURAL HISTORY AND PROGNOSIS? A CANADIAN SARCOMA RESEARCH AND CLINICAL COLLABORATION (CANSARCC) STUDY

Objective: CIC-rearranged soft tissue sarcomas (CRSTS) are a subtype of small round blue cell sarcomas. The CIC gene (19q13) is most commonly fused with DUX4 (4q35). CRSTS are very rare (< 1% of sarcomas) but aggressive. CRSTS most commonly present in adolescents and young adults but reported cases have shown a wide age range from childhood to late adulthood.
Many clinicians use chemotherapy in patients with CRSTS, but its role in this disease remains unclear. We therefore sought to clarify the role of chemotherapy in a national cohort of patients with CRSTS.

Methods: Data from patients with CRSTS diagnosed between 1990 and 2023 in 11 institutions in Canada were extracted from the REB-approved CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. An event was defined as relapse, progression, or death, whichever occurred first. Response to chemotherapy was evaluated by imaging. Surgical margins were defined by pathology as R0, if negative, or R1, if microscopic positive. Overall survival (OS) and Event-Free Survival (EFS) were estimated using the Kaplan Meier method and log-rank test. We used the Wilcoxon rank test to compare means and medians between groups. Chi-square or Fisher’s exact test were used for categorical variables. Univariate and multivariable cox regression models were performed to identify risk factors for an event. For all analyses, p value < 0.05 was considered statistically significant. Statistics were performed using SAS V9.4, R V4.3.3 and SPSS V25.

Results: Of 27 patients, 15 (56%) were male. The median age at diagnosis was 21.5 years (range 9-83). Twelve (44%) presented with distant metastases, 8/12 (67%) had only lung metastases; 10/12 (83%) received chemotherapy, of whom response was complete (CR), partial (PR), mixed and progressive disease (PD) in 1 (10%), 4 (40%), 2 (20%) and 1 (10%), respectively. Response was unknown for 2 (20%) who were still in treatment. 7/12 (58%) received local control, 3 (25%) with radiotherapy (RT) alone, 2 (17%) with surgery alone and 2 (17%) with both (2, R0; 2, R1). Of 14 patients (52%) with localized disease at diagnosis, 7 (50%) received chemotherapy (1, stable disease; 1 CR, 2 PR, 1 mixed response, 1 PD, 1 unknown) and 12 (86%) received local control, 2 (14%) with RT alone, 5 (36%) with surgery alone and 5 (36%) with both (8, R0; 2, R1).
Median follow-up was 0.82 years (range 0.18-8.21). Two-year EFS and OS with vs without metastases at diagnosis was 9% (95% CI 0-27%) vs 59% (95% CI 30-87%, P=0.027) and 26% (95% CI 0-57%) vs 64% (95% CI 36-93%, P=0.112), respectively.
Thirteen patients (48.1%) died - 12 of disease. One patient (CIC-DUX4) died 1 month after diagnosis of unclear cause, before receiving any treatment (metastasis unknown). Four (14.8%) patients were alive with disease at time of last follow up, all with metastatic disease. Currently, 10 (37%) patients are alive with no evidence of disease, of whom 9 had localized disease at presentation. The only patient with metastatic disease with no evidence of disease at data cutoff is an adult with non-DUX4 CIC-rearranged sarcoma and lung only metastases, who underwent surgery (R1) and had CR to adjuvant chemotherapy.
In a univariate analysis, male sex (HR 4.88, 95% CI 1.36-17.5, p=0.015), metastatic disease at diagnosis (HR 3.17, 95% CI 1.08-9.35, p=0.036) and lack of R0 resection (HR 5.14, 95% CI 1.15-22.9, p=0.032) were associated with a higher risk for an event (N=16, 59%). In a multivariable analysis no single factor remained statistically significant.

Conclusion: Almost all patients with metastatic or unresected disease die from disease. Although the benefit of systemic treatment on survival is unclear, there was one patient with metastatic disease and long-term survival, indicating that further investigation is required. In patients with localized disease, surgical resection is critical, but systemic therapy does not appear to impact survival. International collaborations are warranted due to the rare incidence of CRSTS. Novel and targeted therapies may be the only avenue to meaningfully improve outcomes.