# Clinical characteristics and outcomes for children, adolescents and young adults with “CIC-fused” or “BCOR-rearranged” soft tissue sarcomas: A multi-institutional European retrospective analysis

Monika Sparber-Sauer, Nadège Corradini, Maria Carmen Affinita, Giuseppe Maria Milano, Gaelle Pierron, Matthieu Carton, Franck Tirode, Daniel Pissaloux, Rita Alaggio, Christian Vokuhl, et al.

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## To cite this version:

Monika Sparber-Sauer, Nadège Corradini, Maria Carmen Affinita, Giuseppe Maria Milano, Gaelle Pierron, et al. Clinical characteristics and outcomes for children, adolescents and young adults with “CIC-fused” or “BCOR-rearranged” soft tissue sarcomas: A multi-institutional European retrospective analysis. Cancer Medicine, 2023, 12 (13), pp.14346-14359. 10.1002/cam4.6113. inserm-04320793

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Submitted on 4 Dec 2023

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# Clinical characteristics and outcomes for children, adolescents and young adults with “CIC-fused” or “BCOR-rearranged” soft tissue sarcomas: A multi-institutional European retrospective analysis

Monika Sparber-Sauer<fnref n="1" />,<fnref n="2" /> ID | Nadège Corradini<fnref n="3" /> | Maria Carmen Affinita<fnref n="4" /> ID |

Giuseppe Maria Milano<fnref n="5" /> | Gaelle Pierron<fnref n="6" /> | Matthieu Carton<fnref n="7" /> ID | Franck Tirode<fnref n="8" />,<fnref n="9" /> |

Daniel Pissaloux<fnref n="8" />,<fnref n="9" /> | Rita Alaggio<fnref n="10" /> | Christian Vokuhl<fnref n="11" /> | Gianni Bisogno<fnref n="4" /> |

Pablo Berlanga<fnref n="12" /> | Andrea Ferrari<fnref n="13" /> | Daniel Orbach<fnref n="14" /> ID

## Correspondence

Daniel Orbach, SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, France.

Email: daniel.orbach@curie.fr

## Funding information

Deutsche Kinderkrebsstiftung, Grant/Award Number: A2007/13DKS2009.08;

## Abstract

**Background:** In certain rare undifferentiated small round cell sarcomas new specific molecular *CIC-DUX4*/other partner, *BCOR-CCNB3*/other partner, *YWHAE* fusions, or *BCOR-ITD* (internal tandem duplication) were identified. These new “*CIC fused*” (CIC-fused/*ATXN1::NUTM1*) and “*BCOR rearranged*” (BCOR fused/ITD/ *YWHAE*) soft tissue sarcomas (STS) are not well described.

Findings were presented at the 54th Annual Congress of the international society of pediatric oncology SIOP Barcelona 2023, abstract number 233.

This is an open access article under the terms of the [Creative Commons Attribution](https://creativecommons.org/licenses/by) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2023 The Authors. *Cancer Medicine* published by John Wiley & Sons Ltd.

<footnote n="1">¹Klinikum der Landeshauptstadt Stuttgart gKAÖR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Stuttgart, Germany</footnote>

<footnote n="2">²Medizinische Fakultät der Universität Tübingen, Tübingen, Germany</footnote>

<footnote n="3">³Department of Pediatric Hematology and Oncology-IHOPe, Léon Bérard Center, Lyon, France</footnote>

<footnote n="4">⁴Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health University Hospital of Padova, Padova, Italy</footnote>

<footnote n="5">⁵Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy</footnote>

<footnote n="6">⁶Department of Somatic Genetics, Institut Curie, Paris, France</footnote>

<footnote n="7">⁷Department of Biometry, Institut Curie, DRCI, PSL Research University, Paris, France</footnote>

<footnote n="8">⁸Department of Biopathology, Centre Léon Bérard, Lyon, France</footnote>

<footnote n="9">⁹INSERM U1052, Cancer Research Centre of Lyon, Lyon, France</footnote>

<footnote n="10">¹⁰Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy</footnote>

<footnote n="11">¹¹Section of Pediatric Pathology, Department of Pathology, Bonn, Germany</footnote>

<footnote n="12">¹²Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France</footnote>

<footnote n="13">¹³Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy</footnote>

<footnote n="14">¹⁴SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, France</footnote>
Foerderkreis Krebskranke Kinder;
Fondazione Città della Speranza; S
Wisnia

**Methods:** Multi-institutional European retrospective analysis of young patients (0–24 years) with CIC-fused and BCOR rearranged STS.

**Results:** Overall, out of the 60 patients selected, the fusion status was CIC-fused (n=29), *ATXN1::NUTM1* (n=2), *BCOR::CCNB3* (n=18), *BCOR-ITD* (n=7), and *YWHAE* (n=3), *MAML::BCOR* STS (n=1). The main primaries were abdominal-pelvic (n=23) and limbs (n=18). Median age was 14 years (0.9–23.8) and 0.9 (0.1–19.1) for CIC-fused and BCOR-rearranged groups, respectively (n=29; *p* < 0.001). IRS stages were I (n=3), II (n=7), III (n=35), and IV (n=15). Overall, 42 patients had large tumors (>5 cm) but only six had lymph node involvement. Patients received mainly chemotherapy (n=57), local surgery (n=50), and/or radiotherapy (n=34). After a median follow-up of 47.1 months (range, 3.4–230), 33 (52%) patients had an event and 23 patients died. Three-year event-free survivals were 44.0% (95% CI 28.7–67.5) and 41.2% (95% CI 25.4–67.0) for CIC and BCOR groups (p=0.97), respectively. Three-year overall survivals were 46.3% (95% CI 29.6–72.4) and 67.1% (95% CI 50.4–89.3; p=0.24), respectively.

**Conclusions:** Pediatric patients often present with large tumors and metastatic disease, especially CIC sarcomas. Overall outcome is dismal. New treatment options are needed.

KEYWORDS

BCOR rearrangement, CIC-DUX fusion transcript, pediatric/adolescent oncology, soft tissue sarcoma, YWHAE fusion transcript

# 1 | INTRODUCTION

A new subset of round/ovoid cell sarcomas histologically resembling tumors of the Ewing sarcoma family (ESFT) has been recently characterized in unclassified/undifferentiated small round cell sarcoma (USRCS or SRCSs).¹⁻⁶ Previously known as “Ewing-like sarcomas” (ELS), these tumors are currently distinguished from Ewing sarcoma in the current WHO classification. With molecular assays these tumors have been genetically characterized and are now under assessment if these entities may represent distinct biologic tumor entities.⁷⁻¹⁰ Accordingly, a new subtype of bone sarcoma has been characterized by a *BCOR::CCNB3* gene fusion.¹¹ This discovery offers new insight into oncogenesis and future new therapeutic considerations. Rare *BCOR* sarcoma was described in a group of small round cell bone tumors lacking the canonical EWSR1 translocation: only 24 *BCOR::CCNB3* positive tumors could be identified in an analysis of 594 sarcoma.¹¹ Other “BCOR rearranged sarcomas” have been described with molecular characteristics as *BCOR-ITD* (internal tandem duplication).¹² These *BCOR-ITD* tumors are reported to be aggressive tumor entities with an ITD in the last exon of the *BCOR* gene. With location in the kidney, these

sarcomas are described as clear cell sarcomas of the kidney (CCSK).¹³ However, these sarcomas are also described as high-grade endometrial stromal sarcomas (HG-ESS)¹⁴,¹⁵ in bone and soft tissue, referred to as USRCS, but also occurring in infants as primitive mesenchymal myxoid tumor (PMMTI).¹⁶⁻¹⁸ *CIC::DUX4* sarcoma (CDS) or CIC-rearranged sarcomas seem a rare subcategory of another small round cell sarcoma with histological signs of Ewing sarcoma (ES).² For extracranial sites, “CIC fused sarcoma” group had biological homology as the “BCOR rearranged sarcoma” group.⁶ In recent analysis, *ATXN1* tumors clustered with CIC tumors and *YWHAE* fused tumors within the BCOR tumors group. For the *BCOR-ITD* tumors no radiological, clinical, nor pathological specificity could be found, except for location in the central nervous system but a common transcriptomic signature with other *BCOR* rearranged sarcomas.¹⁸ However, all these are described as a distinct entity from ES, and occur in various sites as soft tissue, visceral primaries and less often bone.³,¹⁹

Therapeutic options for such tumors frequently include chemotherapy (CHT) and local surgery with radiotherapy (RT) analogous to treatment of soft tissue sarcomas or ES.¹⁹ There are few data available regarding the clinical description of these tumors when the primary site is soft tissue. We describe the clinical characteristics, treatment,
outcomes, and prognostic factors of an European cohort of pediatric and young patients with *CIC*, *BCOR*, or *YWHAE* gene rearranged soft tissue sarcomas.

## 2 | METHODS

This retrospective multi-institutional study registered all patients aged ≤24 years at the time of diagnosis with USRCS in soft tissues identified from local coordinators as *CIC*, *BCOR*, or *YWHAE* gene rearranged sarcomas. Location in bone, central nervous system, or kidney were exclusion criteria. Patients diagnosed between 1996 and 2021 with available clinical data and at least 3 months of follow-up were included. All specimen were reviewed by expert pathologists or by central review for those that were enrolled on clinical trials. Available molecular data were mandatory for all cases.⁶ In clinical practice, diagnosis of the oncogenic fusion was performed using molecular techniques such as fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or targeted RNA sequencing.⁶ Depending on tumor tissue availability, RT-PCR, next-generation RNA sequencing (RNA seq) or clustering, and methylation profile were performed on paraffin-embedded and/or fresh frozen tissue.²,⁴,²⁰ Recently, all cases of tumors with pathological Ewing characteristics that do not harbor the canonic EWS fusion transcript, were systematically analyzed with RNA sequencing and/or RT-PCR with specific combination of primer sets for *CIC::DUX4* and *BCOR* and/or FISH analysis with probes for *CIC* (19q13.2), for *BCOR* a dual color break apart probe (Xp 11.4) and for *YWHEA* (17p13.3).¹¹,²¹,²² The order of this techniques varies according to each institutional organization. For some old cases, analysis could have been performed retrospectively.

Due to their biological homology, all sarcomas with *CIC::DUX4*, *CIC* break, or *ATXN1::NUTM1* fusion transcript were gathered in the “*CIC* fused sarcoma” group and sarcomas with *BCOR::CCNB3*, *BCOR*-ITD, *YWHAE::NUTM2B*, or *MAML::BCOR* fusion transcripts represent the “*BCOR* rearranged sarcoma” group.⁶

Guardians of included patients had consented to data collection and retrospective chart review. This was performed per the requirements of the Declaration of Helsinki and in accordance with the regulations of the respective ethical committee (Ethikkommission Tübingen 413/2022BO2 from August 18, 2022).

### 2.1 | Definition of terms

Clinical staging was defined according to the Tumor Node Metastases (TNM) system: T1 or T2 according to the

invasion of contiguous organs; N0/N1 according to the presence of lymph node metastases and M0/M1 of distant metastases.²³ Postsurgical staging was classified according to the International Rhabdomyosarcoma Study grouping (IRS-G) system. IRS-I corresponds to a complete tumor resection with microscopically complete margins, IRS-II corresponds to a macroscopic resection but invaded histologic margins and IRS-III corresponds to a macroscopic residual tumor after biopsy or immediate surgery. IRS-IV corresponds to metastatic disease.²⁴ Initial staging included imaging of the primary tumor and bone/lung metastases by magnetic resonance imaging (MRI) or computed tomography (CT). Whole body imaging was recommended with radionuclide bone scan or 18F-fluorodeoxyglucose positron emission tomography. Staging included bone marrow aspirate/biopsy. Tumor response was mainly assessed after 3–4 courses of CHT: complete response (CR), partial response (PR), or stable disease (SD).²⁵ Delayed surgical resection was defined if the resection took part after initiation of chemotherapy. “Extent of tumor resection” was defined as the best surgical result in the sum of any surgeries that were performed in one patient during the first-line therapy. Primary tumor resection was classified as microscopically complete (R0), microscopically incomplete (R1), or macroscopically incomplete (R2).²⁶ “Best tumor response” was the best available response at any time point after start chemotherapy. Progressive disease (PD) was defined as first event with in case of any increase in tumor volume in patients who did not achieve CR.²⁷

### 2.2 | Therapy

No dedicated protocols were available and the treatment strategy the individual decision of the treating physicians. Patients were classically treated according to Ewing's or soft tissue sarcoma (STS)/ rhabdomyosarcoma (RMS) protocols, with a combination of therapies including neoadjuvant and adjuvant CHT, surgical resection, and/or radiation therapy (RT) of the primary according to initial tumor extension and the response to initial chemotherapy.²⁸ Primary resection was performed if a non-mutilating procedure was possible. RT was given as individual decision of the treating center.

### 2.3 | Statistical analysis

Survival time was measured from the date of diagnosis (initial biopsy/surgery) to the time of last follow-up or event. Event-free survival (EFS) was defined as the time from diagnosis to the date of local relapse or any lymph node or metastatic tumor progression or death from any
cause. Overall survival (OS) was calculated from the date of biopsy/surgery to death from any cause. Patients alive without local recurrence or metastasis at last contact were censored at the date of last follow-up. Kaplan-Meier method was used for survival curves and log-rank test to calculate the differences between survivals. The prognostic role of risk factors (gender, age at diagnosis [± median of the cohort], tumor size [±5 cm] and site, TNM status, IRS groups [IRS I–II vs. III vs. IV] and type of tumor groups [CIC-fused vs. BCOR groups]) were considered for their impact on EFS and OS by comparing Kaplan-Meier curves using log-rank tests and Cox univariate and multivariate models. All risk factors significant at least at *p* 0.25 in univariate analysis were included in the multivariable model; type of tumor group was forced in every model.

## 3 | RESULTS

### 3.1 | Patients' characteristics and demography

Since 1996, 60 patients fulfilled the inclusion criteria. Patients were treated in France (n=31), Italy (n=18), Germany (n=10), and Switzerland (n=1). Patients' and tumors' characteristics are presented in Tables 1 and 2. Median age of patients at initial diagnosis with “CIC fused sarcoma” was 14years (range, 0.9–23.8), and 0.9years (range, 0–19.1) for “BCOR rearranged sarcomas”. Primary tumor was mainly located in trunk (53%) and specifically in abdomen/pelvic site (38%). Tumors were frequently large (>5 cm, 72%) and extensive T2 (60%) but only 11% had lymph node involvement. In 58% of patients, the primary tumor was unresectable at diagnosis (IRS-III, n=35) and metastatic disease was present in 25% (IRS-IV, n=15). Metastatic patients had mostly pulmonary metastases (n=9/15) and “CIC-fused sarcoma” (n=13/15).

Pathologic diagnosis was mainly USRCS (n=19), other undifferentiated type sarcoma (UDS, n=14), “ELS” (n=13) and various (n=14) (Table 2). Overall, 31 (52%) contained a molecular rearrangement of the “CIC fused sarcoma” group and 29 of the “BCOR rearranged sarcoma” group. “CIC fused sarcoma” group consisted of CIC::DUX4 (n=22), CIC break (FISH) (n=7) and ATXN1::NUTM1 (n=2). The “BCOR rearranged sarcoma” group consisted of BCOR::CCNB3 (n=18), BCOR-ITD (n=7), YWHAE::NUTM2B (n=3), and MAML::BCOR STS (n=1; Table 2).

### 3.2 | Treatment

Patients received chemotherapy (n=57), local surgery (n=50), and/or radiotherapy (n=34) (Table 3). Systemic

treatment was delivered according to STS/RMS protocols (IVA/VAC, VAIA, IVADO, Ifo-Doxo; n=33) or Ewing sarcoma protocol (VDC-IE/VIDE/VAI; n=19). No CHT was administered in three young patients (<3 years old) with localized BCOR rearranged tumor (2 IRS-II without any other therapy, and 1 IRS-III with adjuvant radiotherapy). Most patients received alkylating based CHT: ifosfamide (n=27) or cyclophosphamide (n=2) or both (n=15). Anthracyclines based regimen were frequently added (80%), especially for “CIC fused sarcomas”. Additional HD CHT, with busulfan and melphalan (n=4) or unspecified regimen (n=1), was delivered in IRS-III tumors (n=4) and IRS-IV (n=1). Maintenance treatment with cyclophosphamide/vinorelbine (n=5) or oral trofosfamide/idarubicine/etoposide (n=1) was given (unspecified regimen, n=2). Local primary tumor resection was performed at diagnosis (n=20), as delayed resection after CHT ± RT reduction (n=28) or both (n=2). Most patients with initial unresected/unresectable tumor (IRS group III) could benefit for a R0-R1 delayed resection in 22/35 cases (63%).

RT of the primary tumor was delivered (n=34): for localized disease (n=26) and metastatic disease (n=8) after best result R0 resection (n=17), R1 resection (n=6) and R2 resection (n=3) (details on resection not available [n=2]), or exclusively (n=6). Median radiation dose at primary tumor was 54 Gray (Gy; range, 42–60). Metastatic sites were irradiated on lung metastases at 18 Gy (n=6; missing data, n=2).

Patients with CIC sarcomas were more likely to receive primary surgery and irradiation, while BCOR tumors were more frequently treated with exclusive surgery (p=0.04, Table 3).

### 3.3 | Characteristics according to molecular group

In the cohort of 31 patients with “CIC fusion sarcoma”, median age was 14 years (range 0.9–23.8) and metastatic disease was present in 13/31 patients (42%, Table 1, Table S1). Most patients had no regional lymph node involvement (84%), were female (65%) with a primary tumor frequently located in limbs (45%). Maximum tumor size was mainly >5 cm (68%), and extensive (T2, 68%). In contrast, the 29 patients in the “BCOR rearranged sarcoma” group were younger (p<0.001) with a median age of 0.9 years overall (0.1–19.1) and specifically 4 years (range, 0.1–19.1) for BCOR::CCNB3 (n=18) and 1 year (0.3–18.3) for BCOR-ITD (n=7). Localized disease was present in 27/29 patients (93%, p=0.002), with metastasis or nodal involvement only present for two YWHAE::NUTM2B fused tumors. Most patients were
<table><caption>TABLE 1 Clinical characteristics of the population with CIC/BCOR rearranged sarcomas.</caption><thead><tr><th></th><th>CIC-fused<br>sarcomas 31 cases</th><th>BCOR<br>rearranged<br>tumors 29 cases</th><th>Total</th><th>p<br>value</th></tr></thead><tbody><tr><td>Median age (range)<br>years</td><td>14 (0.9–23.8)</td><td>0.9 (0–19.1)</td><td>60</td><td>&lt;0.001</td></tr><tr><td>Gender</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Male</td><td>11</td><td>23</td><td>34</td><td></td></tr><tr><td>Female</td><td>20</td><td>6</td><td>26</td><td></td></tr><tr><td>Tumor site</td><td></td><td></td><td></td><td>0.011</td></tr><tr><td>Head and neck</td><td>6</td><td>4</td><td>10</td><td></td></tr><tr><td>Limbs</td><td>14</td><td>4</td><td>18</td><td></td></tr><tr><td>Trunk (thorax,<br>pelvis, abdomen)</td><td>11</td><td>21</td><td>32</td><td></td></tr><tr><td>Tumor size</td><td></td><td></td><td></td><td>1</td></tr><tr><td>≤5 cm</td><td>8</td><td>8</td><td>16</td><td></td></tr><tr><td>&gt;5 cm</td><td>21</td><td>21</td><td>42</td><td></td></tr><tr><td>NA</td><td>2</td><td>0</td><td>2</td><td></td></tr><tr><td>T status</td><td></td><td></td><td></td><td>0.65</td></tr><tr><td>T1</td><td>10</td><td>11</td><td>21</td><td></td></tr><tr><td>T2</td><td>21</td><td>18</td><td>39</td><td></td></tr><tr><td>N status</td><td></td><td></td><td></td><td>1</td></tr><tr><td>N0</td><td>26</td><td>25</td><td>51</td><td></td></tr><tr><td>N1</td><td>3</td><td>3</td><td>6</td><td></td></tr><tr><td>NA</td><td>2</td><td>1</td><td>3</td><td></td></tr><tr><td>M status</td><td></td><td></td><td></td><td>0.002</td></tr><tr><td>M0</td><td>18</td><td>27</td><td>45</td><td></td></tr><tr><td>M1</td><td>13</td><td>2</td><td>15</td><td></td></tr><tr><td>IRS stage</td><td></td><td></td><td></td><td>0.006</td></tr><tr><td>IRS I–II</td><td>3</td><td>7</td><td>10</td><td></td></tr><tr><td>IRS III</td><td>15</td><td>20</td><td>35</td><td></td></tr><tr><td>IRS IV</td><td>13</td><td>2</td><td>15</td><td></td></tr></tbody></table>

Abbreviations: IRS, Intergroup Rhabdomyosarcoma Staging; M, metastasis; N, node; NA, not available; R0, complete resection (IRS-I); R1, incomplete microscopic resection (IRS-II); R2, macroscopic residue (IRS III); T, tumor.

male (79%, *p* < 0.001), with frequent abdomen/ pelvis primary (72%, *p* = 0.011). Tumor size was also frequently large (>5 cm; 72%) and T2 (62%) (Table 1, Table S2).

Patients with “CIC fused sarcoma” had been treated more often with CHT including anthracyclines (94% vs. 66%, respectively; *p* = 0.01), had more complete surgery (R0 vs. R1/R2; 65.4% vs. 31.8%, *p* = 0.007) and received more frequently RT (71% vs. 41%, *p* = 0.02) than patients with “BCOR rearranged sarcomas” (Table 3).

## 3.4 | Outcome

Median follow-up of the complete cohort was 47.1 months (range, 0.3–229.9), CI 95% [30.8–66.0].

Thirty-two events occurred after a median delay of 8.2 months (range, 0.5–115): local progressive disease (n = 5), local relapse (n = 8), metastatic progressive disease (n = 10), metastatic relapse (n = 7), and combined progressive disease (n = 2). All deaths were due to tumor progression, but one patient had a chemotherapy-related death. Among the 45 patients with initially localized disease, 30 (67%) patients were alive at the end of follow-up: in CR (n = 22), with PR (n = 3), on treatment (n = 2) and with PD (n = 1) (tumor status unspecified, n = 2). Among the 15 patients with metastatic disease, seven patients (47%) were still alive: in CR (n = 5), in PR (n = 1) and on therapy (n = 1). Overall, the 3 year-EFS were 44.0% (95% CI 28.7–67.5) and 41.2% (95% CI 25.4–67.0) for “CIC fused sarcoma” and “BCOR rearranged
<table><caption>TABLE 2 Tumor characteristics.</caption><thead><tr><th></th><th>CIC tumors group N=31</th><th>BCOR tumors group N=29</th></tr></thead><tbody><tr><td>Initial pathologic diagnosis</td><td></td><td></td></tr><tr><td>Undifferentiated small round cells sarcoma</td><td>13</td><td>6</td></tr><tr><td>Other undifferentiated sarcoma</td><td>5</td><td>9</td></tr><tr><td>Ewing-like sarcoma</td><td>9</td><td>4</td></tr><tr><td>MPNST</td><td>1</td><td>-</td></tr><tr><td>Primitive myxoid mesenchymal tumor of infancy</td><td>1</td><td>1</td></tr><tr><td>Malignant sarcomatoid tumor</td><td>-</td><td>1</td></tr><tr><td>Adamantinoma</td><td>1</td><td>-</td></tr><tr><td>Angiosarcoma</td><td>-</td><td>4</td></tr><tr><td>Congenital fibrosarcoma</td><td>-</td><td>1</td></tr><tr><td>Synovial sarcoma</td><td>-</td><td>1</td></tr><tr><td>Clear cell sarcoma</td><td>1</td><td>-</td></tr><tr><td>Germ cell tumor</td><td>-</td><td>2</td></tr><tr><td>Pathology findings</td><td></td><td></td></tr><tr><td>Necrosis</td><td></td><td></td></tr><tr><td>Presence</td><td>23</td><td>5</td></tr><tr><td>Absence</td><td>2</td><td>10</td></tr><tr><td>Not mentioned</td><td>6</td><td>14</td></tr><tr><td>Mitotic rate</td><td></td><td></td></tr><tr><td>High</td><td>17</td><td>8</td></tr><tr><td>Intermediate/low</td><td>5</td><td>1</td></tr><tr><td>Not done</td><td>9</td><td>20</td></tr><tr><td>Immunohistochemistry</td><td></td><td></td></tr><tr><td>Nuclear CD99 staining</td><td></td><td></td></tr><tr><td>Strong</td><td>9</td><td>3</td></tr><tr><td>Absence</td><td>17</td><td>13</td></tr><tr><td>Not done</td><td>5</td><td>13</td></tr><tr><td>Cytoplasmic CD99 staining</td><td></td><td></td></tr><tr><td>Strong</td><td>14</td><td>10</td></tr><tr><td>Absence</td><td>12</td><td>6</td></tr><tr><td>Not done</td><td>5</td><td>13</td></tr><tr><td>BCOR expression</td><td></td><td></td></tr><tr><td>Presence</td><td>0</td><td>6</td></tr><tr><td>Absence</td><td>11</td><td>6<sup>a</sup></td></tr><tr><td>Not done</td><td>20</td><td>17</td></tr><tr><td>Cyclin D1 expression</td><td></td><td></td></tr><tr><td>Presence</td><td>-</td><td>2</td></tr><tr><td>Absence</td><td>-</td><td>4</td></tr><tr><td>Not done</td><td>-</td><td>23</td></tr><tr><td>Vimentin expression</td><td></td><td></td></tr><tr><td>Strong</td><td>9</td><td>3</td></tr><tr><td>Absence</td><td>-</td><td>3</td></tr><tr><td>Not done</td><td>22</td><td>23</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 (Continued)</caption><thead><tr><th></th><th>CIC tumors group N=31</th><th>BCOR tumors group N=29</th></tr></thead><tbody><tr><td>Molecular analysis<sup>a</sup></td><td></td><td></td></tr><tr><td>FISH</td><td>8</td><td>6</td></tr><tr><td>RT-PCR/dd PCR</td><td>14</td><td>4</td></tr><tr><td>RNA seq</td><td>5</td><td>6</td></tr><tr><td>NGS</td><td>3</td><td>1</td></tr><tr><td>Methylation profile</td><td>2</td><td>1</td></tr><tr><td>Unknown</td><td>1</td><td>12</td></tr><tr><td>Type of molecular rearrangement</td><td>22 CIC::DUX4<br>7 CIC break (FISH)<br>2 ATXN1::NUTM1</td><td>18 BCOR::CCNB3<br>7 BCOR-ITD<br>3 YWHAE::NUTM2B<br>1 MAML::BCOR</td></tr></tbody></table>

Abbreviations: FISH, fluorescence in situ hybridization; N, number; NGS, next-generation sequencing; RNA seq, RNA sequencing; RT-PCR, reverse transcriptase polymerase chain reaction; RT-PCR dd, reverse transcription polymerase chain reaction droplet digital.

sarcoma" groups, respectively (p = 0.97). Three-year OS were 46.3% (95% CI 29.6–72.4) and 67.1% (95% CI 50.4–89.3; p = 0.24), respectively. There was no significant difference of the 3-year EFS and OS between the two groups (Figures 1 and 2).

## 3.5 | Statistical analysis and prognostic factors

In term of clinical characteristics, age > 13 years was the only clinical factor significantly associated with a better EFS in univariate and multivariate analysis (Table 4). Notably, these risk factors were only present in BCOR/YWHA tumors (p = 0.012) and not in CIC sarcomas (p = 0.84). Presence of metastases was the only factor significantly associated with a worse OS in univariate and multivariate analysis (Table 5; Figures S1 and S2). Males showed a significantly better OS in univariate analysis but not after adjustment for other risk factors (Table S3A,B).

## 4 | DISCUSSION

We reported the first clinical data of a European cohort of young patients with the novel genetically defined "CIC fused sarcomas" and "BCOR rearranged sarcomas" in soft tissues.

"CIC fused sarcomas" were described in a cohort of 115 patients as often found in soft tissue sarcoma (86%) and mainly occurring in adults (median age 32 years).<sup>9,22</sup> This analysis includes data on children, adolescents and young

adults. The definition of young adults (AYA) varies and mostly includes patients up to 24 years. However, inclusion of data of older patients in cooperation with the adult oncologists are undoubtedly needed to get an overview on a larger cohort concerning age and this data do not reflect the overall age at diagnosis.

In our study, "CIC fused" STS were mainly located in the trunk and are often presenting with metastatic disease.<sup>29</sup> In contrast, "BCOR rearranged sarcomas" are described as occurring more frequently in bone (64%) and in pediatric patients (76%):<sup>30</sup> BCOR::CCNB was described more often in adolescents in contrast to BCOR-ITD, more frequently occurring in infants.<sup>30–32</sup> In our study, we cannot demonstrate any difference in the age of occurrence comparing BCOR::CCNB to other genetic alterations as BCOR-ITD or the YWHAE alteration in contrast to data referring to all locations.<sup>31</sup>

Our cohort of patients harboring the BCOR rearrangement frequently had localized tumor, located in limbs and significantly younger at diagnosis than patients with "CIC fused" STS, confirming observations including locations in bone.<sup>30</sup> Interestingly, we confirm that age was a significant factor for EFS, especially for BCOR/YWHA tumors, but not the biological entity itself. The precise reason to explain this difference is not totally clear. However, as this finding was only present in BCOR/YWHA sarcomas, one hypothesis could be that, in some way, therapy differences may influence the outcome of patients. Patients with BCOR tumors are more frequently younger and may have received different therapy (i.e., less radiotherapy for instance) that may explain such difference.

<footnote><sup>a</sup>4 BCOR::CCNB3, 1 BCOR-ITD and 1 YWHAE::NUTM2B.</footnote>
<table><caption>TABLE 3 Summary of delivered therapy.</caption><thead><tr><th></th><th>CIC tumors group N=31</th><th>BCOR tumors group N=29</th><th>Total N=60</th><th>p value</th></tr></thead><tbody><tr><td>Local treatment</td><td></td><td></td><td></td><td>0.04</td></tr><tr><td>Surgery alone</td><td>7</td><td>15</td><td>22</td><td></td></tr><tr><td>Radiation alone</td><td>3</td><td>3</td><td>6</td><td></td></tr><tr><td>Both</td><td>19</td><td>9</td><td>28</td><td></td></tr><tr><td>None<sup>c</sup></td><td>2</td><td>2</td><td>4</td><td></td></tr><tr><td>Primary tumor resection</td><td></td><td></td><td></td><td>1</td></tr><tr><td>No</td><td>5</td><td>5</td><td>10</td><td></td></tr><tr><td>Yes</td><td>26</td><td>24</td><td>50</td><td></td></tr><tr><td>Best tumor resection</td><td></td><td></td><td></td><td>0.007</td></tr><tr><td>R0</td><td>17</td><td>7</td><td>24</td><td></td></tr><tr><td>R1</td><td>4</td><td>16</td><td>17</td><td></td></tr><tr><td>R2</td><td>5</td><td>2</td><td>7</td><td></td></tr><tr><td>NA</td><td>5</td><td>7</td><td>12</td><td></td></tr><tr><td>Chemotherapy regimens</td><td></td><td></td><td></td><td></td></tr><tr><td>Anthracyclines based<sup>a</sup></td><td>29</td><td>19</td><td>48</td><td>0.011</td></tr><tr><td>Platinum based<sup>a</sup></td><td>3</td><td>3</td><td>6</td><td>1</td></tr><tr><td>High dose<sup>b</sup></td><td>2</td><td>3</td><td>5</td><td>1</td></tr><tr><td>Maintenance therapy</td><td>5</td><td>3</td><td>8</td><td>0.75</td></tr><tr><td>Overall chemotherapy regimen</td><td></td><td></td><td></td><td>Not performed</td></tr><tr><td>According to Ewing protocols (VDCy-IE/VIDE+VAI)</td><td>13</td><td>6</td><td>19</td><td></td></tr><tr><td>According to RMS-NRSTS protocols (IVA/VAC, VAIA, IVADO, Ifo-doxo)</td><td>15</td><td>17</td><td>32</td><td></td></tr><tr><td>Other regimens</td><td>3</td><td>3</td><td>6</td><td></td></tr><tr><td>None</td><td>-</td><td>3</td><td>3</td><td></td></tr><tr><td>Radiotherapy</td><td></td><td></td><td></td><td>0.021</td></tr><tr><td>No</td><td>9</td><td>17</td><td>26</td><td></td></tr><tr><td>Yes</td><td>22</td><td>12</td><td>34</td><td></td></tr></tbody></table>

Abbreviations: IE, ifosfamide-etoposide; Ifo-doxo, ifosfamide-doxorubicin; N, number; NA, not available; R0, complete resection; R1, microscopic incomplete resection; R2, macroscopic residue; Rx, data not available; VAC, vincristine-D actinomycin-cyclophosphamide; VAI/IVA, vincristine-D actinomycin-ifosfamide; VAIA, IVADO, IVA with doxorubicin; VDCy, vincristine-doxorubicin-cyclophosphamide; VIDE, vincristine-ifosfamide-doxorubicin-etoposide.

These different genetic alterations seem to have a prognostic impact as patients with *BCOR* altered tumors are reported to have an overall poor prognosis. *BCOR::CCNB3* fused tumors are reported to have a 5-year OS of 68%, in contrast to patients with *BCOR-ITD* or *ZC3H7B::BCOR* tumors that have low survival rates, with more than 50% of patients in each group dying of

relapse of their disease.³¹ In our experience we report a much higher number of IRS group IV tumors in the “CIC fused sarcomas” and only two in the “BCOR rearranged sarcomas” at diagnosis. Yet, the EFS of “BCOR rearranged sarcomas” as a group is lower than that of the “CIC fused sarcoma” group. This suggests that effective therapy was likely not delivered due to the younger

<footnote><sup>a</sup>One missing data.</footnote>

<footnote><sup>b</sup>2 missing data.</footnote>

<footnote><sup>c</sup>1 toxic death, 3 early progressive disease.</footnote>
<figure><img src="image_3.png" /><figcaption>FIGURE 1 Kaplan-Meier estimates presenting EFS of 60 patients with CIC-fused sarcoma (n = 31) and BCOR rearranged sarcoma (n = 29).</figcaption></figure>

<caption>FIGURE 2 Kaplan-Meier estimates presenting OS of 60 patients with CIC-fused sarcoma (n = 31) and BCOR rearranged sarcoma (n = 29).</caption>

age in the “BCOR rearranged sarcoma” group and also probably explains the higher salvage rate at relapse given the better overall survival compared to that seen in the “CIC fused sarcoma” group.

We recommend imaging guidelines developed for rhabdomyosarcoma as specific guidelines for CIC and BCOR sarcoma need to be developed.33 The initial extent

of the disease and the patients age at the time of diagnosis might be responsible for the inhomogeneous treatment.34 The outcome of these patients is unsatisfactory with a 3-year OS of 46.3% and 67.1%, respectively, but not statistically different (p = 0.24). These data correlate to the rare published data on these patient groups including bone primary: 5-year OS 43% for “CIC fused sarcoma” and 72%
<table><caption>TABLE 4 Risk factors in univariate and multivariate analysis for event-free survival for the population with CIC and BCOR sarcomas.</caption><thead><tr><th rowspan="2">Risk factors</th><th rowspan="2">Number of patients</th><th colspan="4">Univariate</th><th colspan="3">Multivariate</th></tr><tr><th>3y-EFS % (95% CI)</th><th>HR</th><th>95% CI</th><th>p value</th><th>HR</th><th>95% CI</th><th>p value</th></tr></thead><tbody><tr><td>Tumor type</td><td></td><td></td><td></td><td></td><td>0.98</td><td></td><td></td><td>0.94</td></tr><tr><td>CIC-fused</td><td>31</td><td>44.0 (28.7-67.5)</td><td>1</td><td>[0.50; 1.95]</td><td></td><td>1</td><td></td><td></td></tr><tr><td>BCOR rearranged</td><td>29</td><td>41.2 (25.4-67.0)</td><td>0.99</td><td></td><td></td><td>1.03</td><td>[0.44; 2.42]</td><td></td></tr><tr><td>Median age</td><td></td><td></td><td></td><td></td><td>0.06</td><td></td><td></td><td>0.04</td></tr><tr><td>&lt;13 yo</td><td>30</td><td>33.5 (18.8-59.9)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>&gt;13 yo</td><td>30</td><td>51.9 (35.9-75.2)</td><td>0.52</td><td>[0.26; 1.03]</td><td></td><td>0.45</td><td>[0.21; 0.95]</td><td></td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td><td>0.84</td><td></td><td></td><td>-</td></tr><tr><td>Female</td><td>26</td><td>43.2 (26.1-71.4)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>Male</td><td>34</td><td>41.7 (27.1-64.3)</td><td>0.93</td><td>[0.47; 1.84]</td><td></td><td></td><td></td><td></td></tr><tr><td>Tumor site</td><td></td><td></td><td></td><td></td><td>0.50</td><td></td><td></td><td>-</td></tr><tr><td>Head and neck</td><td>10</td><td>40.0 (18.7-85.5)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>Limbs</td><td>18</td><td>36.1 (17.7-73.7)</td><td>0.62</td><td>[0.24; 1.65]</td><td></td><td></td><td></td><td></td></tr><tr><td>Others</td><td>32</td><td>47.1 (31.5-70.6)</td><td>0.58</td><td>[0.24; 1.41]</td><td></td><td></td><td></td><td></td></tr><tr><td>Tumor size</td><td></td><td></td><td></td><td></td><td>0.61</td><td></td><td></td><td>-</td></tr><tr><td>≤5 cm</td><td>16</td><td>57.4 (36.2-91.1)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>&gt;5 cm</td><td>42</td><td>40.6 (27.4-60.2)</td><td>1.23</td><td>[0.55; 2.75]</td><td></td><td></td><td></td><td></td></tr><tr><td>T status</td><td></td><td></td><td></td><td></td><td>0.321</td><td></td><td></td><td>-</td></tr><tr><td>T1</td><td>21</td><td>46.3 (26.4-81.2)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>T2</td><td>39</td><td>40.5 (27.1-60.5)</td><td>1.46</td><td>[0.68; 3.13]</td><td></td><td></td><td></td><td></td></tr><tr><td>N status</td><td></td><td></td><td></td><td></td><td>0.28</td><td></td><td></td><td>-</td></tr><tr><td>N0</td><td>51</td><td>46.1 (33.4-63.6)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>N1</td><td>6</td><td>50.0 (22.5-100.0)</td><td>0.92</td><td>[0.28; 3.07]</td><td></td><td></td><td></td><td></td></tr><tr><td>Nx</td><td>3</td><td>33.3 (6.7-100.0)</td><td>3.05</td><td>[0.92; 10.1]</td><td></td><td></td><td></td><td></td></tr><tr><td>M status</td><td></td><td></td><td></td><td></td><td>0.21</td><td></td><td></td><td>0.12</td></tr><tr><td>M0</td><td>45</td><td>46.6 (32.8-66.2)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>M1</td><td>15</td><td>29.3 (12.9-66.5)</td><td>1.64</td><td>[0.78; 3.41]</td><td></td><td>2.06</td><td>[0.83; 5.09]</td><td></td></tr><tr><td>IRS stage</td><td></td><td></td><td></td><td></td><td>0.45</td><td></td><td></td><td>-</td></tr><tr><td>IRS I-II</td><td>10</td><td>43.8 (20.0-95.7)</td><td>1</td><td></td><td></td><td>NI</td><td>-</td><td></td></tr><tr><td>IRS III</td><td>35</td><td>47.1 (31.6-70.1)</td><td>1.10</td><td>[0.41; 2.96]</td><td></td><td></td><td></td><td></td></tr><tr><td>IRS IV</td><td>15</td><td>29.3 (12.9-66.5)</td><td>1.76</td><td>[0.60; 5.19]</td><td></td><td></td><td></td><td></td></tr></tbody></table>

Abbreviations: EFS, event free survival; 95% CI, 95% confidential intervals; HR, Hazard Ratio; yo, year old; IRS-I, complete resection; IRS-II, microscopic incomplete resection; IRS-III, macroscopic residue; IRS-IV, presence of distant metastasis; T, tumor; T1, tumor localized to tissue/organ of origin; T2, tumor beyond tissue/organ of origin; yo, year old; N0, absence of nodal involvement; N1, presence of nodal involvement; Nx, data not specified; M0, localized tumor; M1, presence of distant metastasis.

for "BCOR rearranged sarcoma".22,35 As in other STS, metastatic status was a clear prognostic factor for OS.

We are able to contribute detailed data on CHT and local treatment: Patients of both entities were more likely to be treated in Europe according to an STS protocol as (non-) rhabdomyosarcoma, rather than an Ewing one. However, the main drugs are similar in these protocols and the main difference lies on the total number of CHT courses. Multimodal strategy seems important but larger cohort are needed to evaluate the value of each therapy in such patients.

The main weaknesses of these data are their retrospective character, extracted from different databases or centers. As a limitation, the timing of the testing could not be evaluated. However, as patients are included diagnosed before 2015, few patients were included with the molecular diagnosis made some years after initial histologic diagnosis. The frequency of these biologically distinct cancers is extremely rare. Considering CWS patients from the European countries Germany, Switzerland, Austria, Poland, Sweden, and Finland, 11 patients with CIC-fused/
<table><caption>TABLE 5 Risk factors in univariate and multivariate analysis for overall survival for the population with CIC and BCOR sarcomas.</caption><thead><tr><th rowspan="2">Risk factors</th><th rowspan="2">Number of patients</th><th colspan="4">Univariate</th><th colspan="4">Multivariate</th></tr><tr><th>3y-OS % (95% CI)</th><th>HR</th><th>95% CI</th><th>p value</th><th>HR</th><th>95% CI</th><th>p value</th></tr></thead><tbody><tr><td>Tumor type</td><td></td><td></td><td></td><td></td><td>0.23</td><td></td><td></td><td>0.72</td></tr><tr><td>CIC-fused</td><td>31</td><td>46.3 (29.6-72.4)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>BCOR rearranged</td><td>29</td><td>67.1 (50.4-89.3)</td><td>0.59</td><td>[0.25; 1.42]</td><td></td><td>1.23</td><td>[0.39; 3.92]</td><td></td></tr><tr><td>Median age</td><td></td><td></td><td></td><td></td><td>0.92</td><td></td><td></td><td>—</td></tr><tr><td>&lt;13 yo</td><td>30</td><td>49.8 (30.0-82.0)</td><td>1</td><td></td><td></td><td>NI</td><td>—</td><td></td></tr><tr><td>&gt;13 yo</td><td>30</td><td>57.2 (40.8-80.1)</td><td>0.96</td><td>[0.42; 2.18]</td><td></td><td></td><td></td><td></td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td><td>0.24</td><td></td><td></td><td>0.16</td></tr><tr><td>Female</td><td>26</td><td>45.0 (26.1-77.3)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>Male</td><td>34</td><td>62.8 (47.2-83.4)</td><td>0.61</td><td>[0.27; 1.40]</td><td></td><td>0.52</td><td>[0.21; 1.31]</td><td></td></tr><tr><td>Tumor site</td><td></td><td></td><td></td><td></td><td>0.67</td><td></td><td></td><td>—</td></tr><tr><td>Head and neck</td><td>10</td><td>61.7 (34.9-100.0)</td><td>1</td><td></td><td></td><td>NI</td><td>—</td><td></td></tr><tr><td>Limbs</td><td>18</td><td>61.0 (40.6-91.7)</td><td>1.22</td><td>[0.31; 4.73]</td><td></td><td></td><td></td><td></td></tr><tr><td>Others</td><td>32</td><td>52.2 (35.1-77.5)</td><td>1.63</td><td>[0.46; 5.73]</td><td></td><td></td><td></td><td></td></tr><tr><td>Tumor size</td><td></td><td></td><td></td><td></td><td>0.63</td><td></td><td></td><td>—</td></tr><tr><td>≤5 cm</td><td>16</td><td>44.2 (21.1-92.8)</td><td>1</td><td></td><td></td><td>NI</td><td>—</td><td></td></tr><tr><td>&gt;5 cm</td><td>42</td><td>57.4 (42.8-77.1)</td><td>0.80</td><td>[0.33; 1.96]</td><td></td><td></td><td></td><td></td></tr><tr><td>T status</td><td></td><td></td><td></td><td></td><td>0.24</td><td></td><td></td><td>0.53</td></tr><tr><td>T1</td><td>21</td><td>76.2 (58.1-99.9)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>T2</td><td>39</td><td>47.2 (32.3-69.0)</td><td>1.77</td><td>[0.65; 4.77]</td><td></td><td>1.39</td><td>[0.50; 3.88]</td><td></td></tr><tr><td>N status</td><td></td><td></td><td></td><td></td><td>0.88</td><td></td><td></td><td>—</td></tr><tr><td>N0</td><td>51</td><td>57.4 (43.8-75.1)</td><td>1</td><td></td><td></td><td>NI</td><td>—</td><td></td></tr><tr><td>N1</td><td>6</td><td>26.7 (5.1-100.0)</td><td>1.37</td><td>[0.40; 4.66]</td><td></td><td></td><td></td><td></td></tr><tr><td>Nx</td><td>3</td><td>100 (100-100.0)</td><td>0.88</td><td>[0.12; 6.63]</td><td></td><td></td><td></td><td></td></tr><tr><td>M status</td><td></td><td></td><td></td><td></td><td>0.04</td><td></td><td></td><td>0.07</td></tr><tr><td>M0</td><td>45</td><td>62.4 (47.7-81.7)</td><td>1</td><td></td><td></td><td>1</td><td></td><td></td></tr><tr><td>M1</td><td>15</td><td>35.0 (15.5-78.8)</td><td>2.59</td><td>[1.08; 6.22]</td><td></td><td>2.88</td><td>[0.93; 8.97]</td><td></td></tr><tr><td>IRS stage</td><td></td><td></td><td></td><td></td><td>0.07</td><td></td><td></td><td>—</td></tr><tr><td>IRS I-II</td><td>10</td><td>87.5 (67.3-100.0)</td><td>1</td><td></td><td></td><td>NI*</td><td>—</td><td></td></tr><tr><td>IRS III</td><td>35</td><td>55.5 (38.9-79.1)</td><td>2.10</td><td>[0.47; 9.33]</td><td></td><td></td><td></td><td></td></tr><tr><td>IRS IV</td><td>15</td><td>35.0 (15.5-78.8)</td><td>4.74</td><td>[1.01; 22.5]</td><td></td><td></td><td></td><td></td></tr></tbody></table>

Abbreviations: CI, confidence interval; CT, chemotherapy; HR, hazard ratio; IRS, Intergroup Rhabdomyosarcoma Staging; M, metastasis; N, node; NI*, not introduced in multivariate model since IRS stage IV was equivalent to M1 status; NI, not introduced in multivariate model; R0, localized complete resection (IRS-I); R1, microscopic incomplete resection (IRS-II); R2, macroscopic residue (IRS III); Rx, data not available; T, tumor; yo, year old.

BCOR rearranged STS of the total cohort of 247 patients with the histologic diagnosis of USRCC/UDS/ES of STS irrespective of the molecular diagnosis were registered in the European CWS studies and the STS registry SoTiSaR in this time. As further limitation we are not able to report on numbers of patients with “CIC fused sarcoma” and “BCOR rearranged sarcoma” in bone, kidney, and CNS from all the institutions. To get a sense of the frequency and clinical data of these biologically distinct cancers larger international retrospective studies including studies and registries of bone, kidney, and CNS are necessary.

An international common strategy based on the somatic genetic background is undoubtedly required and a new international risk stratification considering the overall unfavorable prognostic of these entities needs to be built up.

These data also stress the need to perform additional molecular testing in case of any tumor with Ewing characteristics that do not harbor the canonic EWS fusion transcript.36 Tumor genomic sequencing and assignment of genotype-based groups should be incorporated to help understanding of different clinical outcomes.37 Finally, new treatment options need to be developed. Since some
of them start to seem promising, international collaborations, to develop trials including new treatment strategies, are of highest importance in these rare diseases.38,39 Applying a distinctive signature of 537 deregulated genes in CIC-rearranged sarcoma with RNA seq, Palmirini et al. in a recent paper showed that the CIC::DUX4 transcriptional profile compared that of ES was enriched in gene sets including DUSP4, ETV1/4, IGF2, and IGF2BPs, PTX 1 and 3 that are associated with activity of irinotecan, proteasome inhibitors (bortezomib and MG262), and histone deacetylase inhibitors (scriptaid and vorinostat).40 Future common analyses on patients with these rare diseases occurring in bone and soft tissue sarcoma are needed to better compare different treatment regimen, to define prognostic factors and to develop new treatment strategies.

## AUTHOR CONTRIBUTIONS

**Monika Sparber-Sauer:** Conceptualization (lead); data curation (equal); formal analysis (equal); resources (equal); validation (equal); writing – original draft (equal); writing – review and editing (lead). **Nadege Corradini:** Resources (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal). **Maria Carmen Affinita:** Resources (equal); writing – original draft (equal); writing – review and editing (equal). **Giuseppe Maria Milano:** Resources (equal); writing – original draft (equal); writing – review and editing (equal). **Gaëlle Pierron:** Formal analysis (equal); methodology (equal); resources (equal); writing – original draft (equal); writing – review and editing (equal). **Matthieu Carton:** Data curation (lead); formal analysis (lead); methodology (lead); resources (equal); software (equal); supervision (equal); validation (equal); writing – original draft (equal); writing – review and editing (equal). **Franck Tirode:** Resources (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal). **Daniel Pissaloux:** Resources (equal); writing – original draft (equal); writing – review and editing (equal). **Rita Alaggio:** Resources (equal); validation (equal); writing – review and editing (equal). **Christian Vokuhl:** Resources (equal); validation (equal); writing – review and editing (equal). **Gianni Bisogno:** Resources (equal); validation (equal); writing – review and editing (equal). **Pablo Berlanga:** Resources (equal); validation (equal); writing – review and editing (equal). **Andrea Ferrari:** Conceptualization (equal); data curation (equal); methodology (equal); project administration (equal); resources (equal); validation (equal); visualization (equal); writing – review and editing (equal). **Daniel Orbach:** Conceptualization (lead); data curation (lead); formal analysis (lead); funding acquisition (lead); investigation (equal); methodology (equal); project administration (equal); resources (equal); supervision (lead); validation (equal); visualization (equal); writing – original draft (equal).

(equal); visualization (equal); writing – original draft (lead); writing – review and editing (lead).

## ACKNOWLEDGMENTS

Authors gratefully thank parents who allow sharing their children's clinical data, and specifically the French GSF-GETO group, and are very grateful for the continuous cooperation of the contributing hospitals. This work could not have been done without the excellent data management of all persons involved.

## FUNDING INFORMATION

The Soft Tissue Sarcoma Registry (SoTiSaR) was supported by the Deutsche Kinderkrebsstiftung, Bonn, Germany, grant no. A2007/13DKS2009.08 and by the Foerderkreis Krebskranke Kinder Stuttgart, Germany. The data collection of Padua has been supported by Fondazione Città della Speranza, Padova, Italy. The authors wish to thank S Wisna for the financial help.

## CONFLICT OF INTEREST STATEMENT

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## DATA AVAILABILITY STATEMENT

Not applicable.

## CONSENT STATEMENT

Informed consent has been obtained from all CWS and participating patients and/or their parents/guardians according to the legal requirements.

## ORCID

Monika Sparber-Sauer https://orcid.org/0000-0001-9551-2399

Maria Carmen Affinita https://orcid.org/0000-0003-1680-0240

Matthieu Carton https://orcid.org/0000-0002-6793-3273

Daniel Orbach https://orcid.org/0000-0002-2520-139X

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SUPPORTING INFORMATION

Additional supporting information can be found online
in the Supporting Information section at the end of this
article.

**How to cite this article:** Sparber-Sauer M, Corradini N, Affinita MC, et al. Clinical characteristics and outcomes for children, adolescents and young adults with “CIC-fused” or “BCOR-rearranged” soft tissue sarcomas: A multi-institutional European retrospective analysis. *Cancer Med.* 2023;12:14346-14359. doi:[10.1002/cam4.6113](https://doi.org/10.1002/cam4.6113)