Metastatic Ewing Sarcoma Research Articles

Establishment and characterization of a patient-derived metastatic extraskeletal Ewing sarcoma cell line ES-ZSS-1.

The methods available for treating metastatic Ewing sarcoma (ES) are inadequate; thus, innovative therapeutic approaches need to be developed. However, the lack of clinically relevant ES models has hindered the discovery of drugs for this disease. In this study, we established and characterized a patient-derived xenograft (PDX) cell line model, which was constructed using tumor tissue from a patient with metastatic extraskeletal ES. The cells were found to recapitulate the morphological and histopathological features of the patient tumor and were designated as ES-ZSS-1. The cells harbor the characteristic EWSR1-FLI1 infusion and underwent successive passages in vitro. By performing gene expression profiling, we found that the mutation in STAG2 was the most frequent. An increase in Twist1 and epithelial-to-mesenchymal transition (EMT) was recorded. These genetic features might be relevant to metastasis and resistance to chemotherapy. To summarize, the novel patient-derived ES cell line we developed closely mimics the phenotype and genotype of patient tumors, making it a reliable tool for research on metastatic ES.

Metastatic-Site Radiation Therapy for Ewing Sarcoma and Rhabdomyosarcoma: Consensus Guidelines From the National Pediatric Cancer Foundation

BackgroundDespite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities. MethodsWe gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address five key questions: 1) the role of whole lung irradiation (WLI) in treating lung metastases 2) number of metastatic sites warranting radiotherapy and the radicality of such an approach; 3) radiation techniques, including stereotactic body radiation therapy (SBRT); 4) the timing of metastatic-site radiation therapy; and 5) the utility of metastatic site radiation therapy for relapsed metastatic disease. ResultsAfter a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation with the goal of improving long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred. ConclusionsA consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy.

Ten‐year follow‐up of outcomes, patterns of care, and psychosocial burden in adolescent and young adult patients with bone sarcomas from a large cohort in a low‐income and middle‐income country

AbstractBackgroundThe care of adolescents and young adults (AYAs) with bone sarcomas involves unique challenges. The objectives of this study were to identify challenges and evaluate long‐term outcomes of these patients from India who received treatment with novel protocols.MethodsThis prospective cohort study included AYA patients (aged 15–39 years) with osteosarcoma and Ewing sarcoma (ES), who were treated uniformly at the authors' institute using unique protocols (OGS‐12 and EFT‐2001) from 2011 to 2021 and from 2013 to 2018, respectively.ResultsThe cohorts included 688 of 748 (91.9%) treatment‐naive AYA patients with osteosarcoma and 126 of 142 (88.7%) treatment‐naive AYA patients with ES. Among 481 of 561 patients (85.7%) who had nonmetastatic osteosarcoma treated according to protocol, at a median follow‐up of 59.7 months, the 5‐year event‐free survival (5‐EFS) rate was 58.6% (95% confidence interval, 54.1%–63.5%) and for 142 patients (20.6%) who had metastatic osteosarcoma, the 5‐EFS rate was 18.7%. The 5‐EFS rate was 66.4% and 21.9% for 104 patients (73%) with nonmetastatic ES and 38 patients (27%) with metastatic ES, respectively. Treatment‐naive patients had better outcomes, similar to compliance in the form of protocol completion (hazard ratio, 1.93 [p = .0043] and 2.66 [p &lt; .0001], respectively. Only 230 of 377 (61.0%) male patients and 10 of 134 (7.4%) female patients reached out to fertility specialists. In addition, 17 of 161 (10.6%) eligible male survivors and 14 of 61 (22.9%) eligible female survivors got married posttreatment. Furthermore, 14 of 17 (82.4%) males and 14 of 14 (100%) females conceived. Among 311 patients who were working or attending school during diagnosis, greater than 90% had interruptions.ConclusionsHomogenous treatment with the OGS‐12 and EFT‐2001 protocols resulted in internationally comparable long‐term outcomes in the cohorts with nonmetastatic and metastatic AYA bone sarcomas. Treatment compliance, timely referral to sarcoma reference centers (avoiding prior inadvertent treatment), and streamlining fertility‐preservation practices constitute unmet needs that demand prioritization.

Circumventing resistance within the Ewing sarcoma microenvironment by combinatorial innate immunotherapy

BackgroundPediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient...

Let it glow: Intraoperative visualization of pulmonary metastases using pafolacianine, a next-generation fluorescent agent, for young adults undergoing pulmonary metastasectomy.

A new generation of disease-specific molecular imaging agents is poised to revolutionize fluorescence-guided surgery. Pafolacianine has been approved for adult lung and ovarian cancers. We demonstrate a proof of concept for pediatric surgeons treating young adults with pulmonary metastatic sarcomas. Five successful fluorescence-guided pulmonary metastasectomy operations were performed in young adult patients with metastatic osteosarcoma or Ewing sarcoma following administration of pafolacianine. All osteosarcoma lesions identified using standard techniques were also markedly fluorescent in patients. Novel fluorescent molecular agents targeted to tumor-specific receptors have promise of increased sensitivity and specificity for detecting metastatic nodules and enhancing surgical clearance of disease.

Unusual testicular metastatic localization of Ewing’s sarcoma: case report

BackgroundEwing’s sarcoma is a rare form of bone cancer that can also affect soft tissues. In some cases, it can spread to other parts of the body, including the testicles, causing testicular metastases. To our knowledge, no testicular metastasis of Ewing’s sarcoma has been reported in the literature.SummaryWe report an original case of an 18-year-old patient who presented with bilateral testicular masses revealing an exceptional metastasis of metastatic bone Ewing sarcoma under chemotherapy for one year. It was difficult to diagnose synchronous bilateral testicular metastases of Ewing’s sarcoma due to the low frequency of these metastases. However, given the history of metastatic cancer, the data from the clinical examination, and the results of ultrasound, it should be considered and included in the differential diagnosis.ConclusionDespite the uncommon occurrence of secondary testicular metastasis, it should be considered in the differential diagnosis when encountering such a clinical presentation.

Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning “Two Keys” simultaneously

BackgroundMacrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here, we investigate the combination of a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal to induce macrophage phagocytosis of ES cells in vitro and inhibit tumor growth and metastasis in vivo.MethodsMacrophages were derived from human peripheral blood monocytes by granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Flow cytometry- and microscopy-based in-vitro phagocytosis assays were performed to evaluate macrophage phagocytosis of ES cells. Annexin-V assay was performed to evaluate apoptosis. CD47 was knocked out by CRISPR/Cas9 approach. ES cell-based and patient-derived-xenograft (PDX)-based mouse models were utilized to assess the effects of MAG and/or DOX on ES tumor development and animal survival. RNA-Seq combined with CIBERSORTx analysis was utilized to identify changes in tumor cell transcriptome and tumor infiltrating immune cell profiling in MAG and/or DOX treated xenograft tumors.ResultsWe found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (p < 0.01) and had significant effect on reducing tumor burden (p < 0.01) and increasing survival in NSG mouse model (p < 0.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (p < 0.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (p < 0.01) and significantly decreased tumor burden (p < 0.01) and lung metastasis (p < 0.0001) and extended animal survival in vivo in two different mouse models of ES (p < 0.0001). Furthermore, we identified CD38, CD209, CD163 and CD206 as potential markers for ES-phagocytic macrophages. Moreover, we found increased M2 macrophage infiltration and decreased expression of Cd209 in the tumor microenvironment of MAG and DOX combinatorial therapy treated tumors.ConclusionsBy turning “two keys” simultaneously to reactivate macrophage phagocytic activity, our data demonstrated an effective and highly translatable alternative therapeutic approach utilizing innate (tumor associated macrophages) immunotherapy against high-risk metastatic ES.

Association of elevated ctDNA burden following one cycle of chemotherapy with inferior outcomes for patients with metastatic Ewing sarcoma: A report from the Children’s Oncology Group (COG).

10018 Background: All patients with Ewing sarcoma (EWS) currently receive the same intensive chemotherapy and novel risk-adapted approaches to therapy are needed. We have previously shown that elevated baseline ctDNA burden is prognostic among patients with EWS. Here we investigate the prognostic impact of on-treatment ctDNA burden in patients with metastatic EWS treated on COG AEWS1221. Methods: AEWS1221 was a randomized phase 3 trial evaluating ganitumab plus interval compressed chemotherapy (vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide given every 2 weeks) for patients with newly diagnosed metastatic EWS. We evaluated 680 serial blood samples and data from 273 patients enrolled to AEWS1221. We utilized a custom NGS hybrid-capture assay for ctDNA quantification that detects EWSR1 and FUSfusions. We used log rank tests to compare event-free survival (EFS) from the designated timepoint according to ctDNA burden post cycle 1 of VDC (planned day 14) and post cycle 2 VDC+IE (planned day 28) of chemotherapy. We dichotomized patients by ≥0.5% ctDNA at each timepoint. A P-value of ≤0.05 was considered evidence of a significant association. Results: Of 298 eligible patients with metastatic EWS, 273 provided blood samples for ctDNA analysis. Three patients had non-FET-ETS family fusions ( CIC::DUX4, EWSR1::WT1 and EWSR1::GTDC1) and were excluded from further analysis. Eighty-five percent of patients were &lt; 21, 56% were male, 33% had pelvic bone primary tumors, and 40% had lung only metastatic disease. ctDNA was ≥0.5% in 86% of patients at baseline (median 25%, range 0-113%, n = 264), in 53% (median 0.53%, range 0-15%, n = 34) after 1 cycle (median day 14, range 11-20), and in 14% (median 0, range 0-53%, n = 130) after 2 cycles (median day 29, range 25-36). Baseline ctDNA burden ≥0.5% was associated with an increased risk of EFS-event (3-year EFS 35% [95% CI 29-41%] vs. 61% [95% CI 43-76%], HR = 2.2, P= 0.002). ctDNA ≥0.5% after cycle 1 was also associated with an increased risk of EFS-event (3-year EFS 6% [95% CI 0.4-22%] vs. 56% [95% CI 29-76%], HR = 6.0, P&lt; 0.0001). ctDNA ≥0.5% after cycle 2 was not associated with an increased risk of EFS-event (28% [95% CI 10-49%] vs. 34% [95% CI 25-43%], HR = 1.2, P= 0.55). Conclusions: ctDNA burden ≥0.5% following one cycle of chemotherapy identifies patients highly likely to relapse, albeit in a small cohort with available data at that timepoint. Conversely, ctDNA at a cutpoint of ≥0.5% after two cycles of chemotherapy was not prognostic, suggesting either more sensitive assays are needed or the prognostic value of ctDNA burden is diminished following additional therapy. These findings will enable novel trials of risk-adapted therapy focused on baseline and early ctDNA burden.

Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases.

Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). This retrospective cohort study included children under 20years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p=.04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p=.14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p=.13), or WLI (38.8%) versus no WLI (46.0%, p=.32). Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study

Background and purposePatients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. Materials and methodsForty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6–55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. ResultsThe 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). ConclusionIn conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

Abstract 5464: Galectin-3 expression in Ewing sarcoma: Modulation of the immune microenvironment in an immunocompetent model

Abstract Objective: Ewing sarcoma is an aggressive cancer of adolescents. Patients with metastatic Ewing sarcoma often receive radiation as part of their treatment protocol. We have demonstrated that both Ewing tumor cells and T cells infiltrating Ewing tumors express Galectin-3 (Gal3), an immunosuppressive protein in the tumor microenvironment. Here, we utilize an immunocompetent, humanized mouse model of Ewing sarcoma to investigate the role of Galectin-3 in the Ewing tumor immune microenvironment both at baseline and following radiation. Specifically, we sought to determine the influence of Galectin-3 on post-radiation inflammation in Ewing sarcoma. Methods: Human Ewing cells -/+ Gal3 expression were generated using CRISPR/Cas 9 technology. Cells -/+ Gal3 were orthotopically injected into humanized mice and allowed to established tumors over ~3 weeks. Tumors were then treated with radiation (or no radiation controls). To also address immune cell expression of Gal3, galectin inhibitors were utilized. Tumors were analyzed by bulk RNA sequencing and flow cytometry analysis (Cytek Aurora) for human CD45, CD3, CD4, CD20, CD8, CD56, CD14, CD16, etc. Peripheral blood controls were also collected and analyzed to ensure consistent baseline immune reconstitution. Results: CHLA10 and TC32 Ewing sarcoma cell lines both demonstrate Gal3 expression at baseline by western blot. CRISPR/Cas 9 knock-out of Gal3 in both cell lines showed successful knock down. Impact on growth and sensitivity to radiation in vitro was assessed by live cell Incucyte assays. Tumors in humanized mice were established utilizing these cells (or Gal3 expressing non-targeting controls) and changes in the post-radiation transcriptional profiles were assessed. Immune cells infiltrating these tumors were also quantified. Ongoing work focuses on additional characterization of these tumor infiltrating immune cell populations following radiation therapy and the impact of broader galectin inhibition on this effect. Conclusion: This work contributes to the understanding of radiation-induced tumor inflammatory responses in Ewing sarcoma by defining the role of tumor and T cell galectin-3 expression inn Ewing immunobiology. Next steps will explore translational opportunities based on these findings. Citation Format: Yunash Maharjan, Sreya Dey, Elina Mukherjee, Jessica Daley, Kelly M. Bailey. Galectin-3 expression in Ewing sarcoma: Modulation of the immune microenvironment in an immunocompetent model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5464.

Abstract 150: Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase

Abstract Outcomes for patients with recurrent and metastatic Ewing sarcoma (EwS) are dismal and novel therapies are needed. As EwS are initiated and maintained by the EWS::FLI1 transcription factor, agents that target aberrant gene transcription are of interest and bromodomain inhibitors (BETi) have shown promise in preclinical models. Nevertheless, despite initial efficacy, BETi tolerance emerges across tumor types, often via transcriptional rewiring. We reasoned that the therapeutic potential of BETi in EwS could be augmented by identifying and targeting mechanisms of drug resistance. To investigate this, we performed transcriptional and phenotypic profiling of BETi-naïve, responsive, and drug-tolerant (DT) EwS cells and used these data to nominate biologically-informed drug combinations. EwS cells (A673, CHLA10, TC32) were exposed for 72 hrs or 20 days to BMS-986158, a clinical grade BETi being tested in a phase I pediatric clinical trial (NCT0393465). A profound cytostatic effect was observed at 72 hrs but in all cell lines proliferation was restored by 20 days. RNA-seq confirmed reversion of the EWS::FLI1-dependent gene signature at 72 hrs and this was maintained at 20 days, demonstrating continued on-target effects despite restored growth of DT cells. Interrogation of differentially expressed genes between drug naïve, cytostatic, and DT cells indicated that that DT cells had been transcriptionally rewired to more mesenchymal states, with notable upregulation of genes involved in integrin signaling. In support of this, DT populations displayed more fibroblastic morphologies, increased F-actin filaments, and enhanced invasion in collagen-rich 3D culture. In parallel, an unbiased kinase inhibitor screen that exploits mathematical modeling revealed that, while BETi-treated cells were overall more resistant than parent cells to kinase inhibitors, their viability depended on focal adhesion kinase (FAK) activity. Western blot confirmed increased phospho-FAK in DT cells. We next tested BMS-986158 and the FAK-inhibitor Defactinib singly or in combination in vitro and in vivo. Defactinib induced cell death in 2D cultures and blocked invasion of 3D spheroids in collagen. Conversely, BMS-986158 enhanced invasive potential in 3D. The combination of Defactinib and BMS-986158 in naïve and DT populations was highly synergistic in 2D assays. In 3D collagen assays, viability and invasion of DT tumor spheroids were significantly reduced by the combination. Finally, ongoing studies show that the combination of FAK and BET inhibition prolongs survival of mice with EwS tumor xenografts. Thus, our studies reveal that exposure of EwS cells to BETi induces transcriptional rewiring that activates integrin and FAK signaling, restoring proliferation. This work supports further investigation of FAKi as agents that could prevent or reverse the BETi tolerant state in EwS. Citation Format: Shireen S. Ganapathi, Emma Wrenn, Nicolas Garcia, Neerja Katiyar, Aya Miyaki, Yuqi Kang, Marina Chan, Taran S. Gujral, Elizabeth R. Lawlor. Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 150.

IL-1 Family Members in Bone Sarcomas.

IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.

Detection of early prognostic biomarkers for metastasis of Ewing's sarcoma in pediatric patients

AimsEwing's Sarcoma is an extremely aggressive tumor in children. The disease is associated with highly metastatic rate, especially at the time of diagnosis, contributing to a lower survival rate and poor prognosis. The study aimed to identify predictive biomarkers for metastatic Ewing's sarcoma through in-depth analysis of the plasma proteome profile of pediatric Ewing's sarcoma patients. Main methodsPlasma samples from Ewing's sarcoma patients and control individuals were profiled using both shotgun and dimethyl-labeled proteomics analysis. Subsequently, Ewing's sarcoma patients were further stratified according to their metastatic state and chemotherapy response. Western blot was used for validation. Univariate and multivariate analyses were performed to determine proteome metastasis predictors. Receiver operating characteristic (ROC) analysis was done to assess the diagnostic significance of the potential plasma Ewing's sarcoma biomarkers. Key findingsOur results revealed a set of proteins significantly associated with the metastatic Ewing's sarcoma disease profile. These proteins include ceruloplasmin and several immunoglobulins. Additionally, our study disclosed significant differentially expressed proteins in pediatric Ewing's sarcoma, including CD5 antigen-like, clusterin, and dermcidin. Stable isotope dimethyl labeling and western blot further confirmed our results, strengthening the impact of such proteins in disease development. Furthermore, an unbiased ROC curve evaluated and confirmed the predictive power of these biomarker candidates. SignificanceThis study presented potential empirical predictive circulating biomarkers for determining the disease status of pediatric Ewing's sarcoma, which is vital for early prediction.

Does primary tumor resection improve survival for patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at diagnosis ?

Recent studies demonstrated that primary tumor resection (PTR) improves survival of patients with metastatic bone sarcomas. However, it remains quite unclear regarding the role of PTR in the treatment of sarcomas of pelvic bones with synchronous metastasis at diagnosis. Using the Surveillance, Epidemiology, and End Results Program, we enrolled a total of 385 patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at initial diagnosis, including 139 patients with osteosarcoma, 176 with Ewing sarcoma, and 70 with chondrosarcoma. Association between PTR and disease-specific survival (DSS) were investigated using the univariable and multivariable Cox regression models. Hazard ratio (HR) and 95% confidence interval (CI) were reported. Representative institutional PTR strategies and clinical outcomes for patients with metastatic pelvic sarcomas from our cancer center were displayed. The usage rate of PTR was 28.1% (39/139) in osteosarcoma, 13.6% (24/176) in Ewing sarcoma, and 41.4% (29/70) in chondrosarcoma with synchronous metastatic lesions. PTR was not associated with an improved DSS for metastatic pelvic osteosarcoma (HR = 0.686, 95% CI = 0.430 ~ 1.094, P = 0.113) and Ewing sarcoma (HR = 0.580, 95% CI = 0.291 ~ 1.154, P = 0.121). The use of PTR was associated with an improved DSS for metastatic pelvic chondrosarcoma (HR = 0.464, 95% CI = 0.225 ~ 0.954, P = 0.037). Primary lesion resection may provide a survival benefit for metastatic chondrosarcoma, but not for osteosarcoma and Ewing sarcoma of pelvic bones, sacrum, and coccyx. This population-based study recommends an active surgical intervention for metastatic chondrosarcoma while non-surgical treatment for metastatic osteosarcoma and Ewing sarcoma of the pelvis in terms of survival improvement.

Histone Methyltransferases G9a/Ehmt2 and GLP/Ehmt1 Are Associated with Cell Viability and Poorer Prognosis in Neuroblastoma and Ewing Sarcoma.

Changes in epigenetic programming have been proposed as being key events in the initiation and progression of childhood cancers. HMT euchromatic histone lysine methyltransferase 2 (G9a, EHMT2), which is encoded by the G9a (Ehmt2) gene, as well as its related protein GLP, which is encoded by the GLP/Ehmt1 gene, participate in epigenetic regulation by contributing to a transcriptionally repressed chromatin state. G9a/GLP activation has been reported in several cancer types. Herein, we evaluated the role of G9a in two solid pediatric tumors: neuroblastoma (NB) and Ewing sarcoma (ES). Our results show that G9a/Ehmt2 and GLP/Ehmt1 expression is higher in tumors with poorer prognosis, including St4 International Neuroblastoma Staging System (INSS) stage, MYCN amplified NB, and metastatic ES. Importantly, higher G9a and GLP levels were associated with shorter patient overall survival (OS) in both NB and ES. Moreover, pharmacological inhibition of G9a/GLP reduced cell viability in NB and ES cells. These findings suggest that G9a and GLP are associated with more aggressive NB and ES tumors and should be further investigated as being epigenetic targets in pediatric solid cancers.

Surface and Global Proteome Analyses Identify ENPP1 and Other Surface Proteins as Actionable Immunotherapeutic Targets in Ewing Sarcoma.

Ewing sarcoma is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. Although the survival rate of patients diagnosed with localized disease is approximately 70%, this decreases to approximately 30% for patients with metastatic disease and only approximately 10% for treatment-refractory disease, which have not changed for decades. Therefore, new therapeutic strategies are urgently needed for metastatic and refractory Ewing sarcoma. This study analyzed 19 unique Ewing sarcoma patient- or cell line-derived xenografts (from 14 primary and 5 metastatic specimens) using proteomics to identify surface proteins for potential immunotherapeutic targeting. Plasma membranes were enriched using density gradient ultracentrifugation and compared with a reference standard of 12 immortalized non-Ewing sarcoma cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on each model to complement the surfaceome data. All models were analyzed by Tandem Mass Tags-based mass spectrometry to quantify identified proteins. The surfaceome and global proteome analyses identified 1,131 and 1,030 annotated surface proteins, respectively. Among surface proteins identified, both approaches identified known Ewing sarcoma-associated proteins, including IL1RAP, CD99, STEAP1, and ADGRG2, and many new cell surface targets, including ENPP1 and CDH11. Robust staining of ENPP1 was demonstrated in Ewing sarcoma tumors compared with other childhood sarcomas and normal tissues. Our comprehensive proteomic characterization of the Ewing sarcoma surfaceome provides a rich resource of surface-expressed proteins in Ewing sarcoma. This dataset provides the preclinical justification for exploration of targets such as ENPP1 for potential immunotherapeutic application in Ewing sarcoma. See related commentary by Bailey, p. 934.

1968P Metastatic Ewing sarcoma, patterns of care and outcomes of patients in a real-life setting: The Metabone national observational study

1968P Metastatic Ewing sarcoma, patterns of care and outcomes of patients in a real-life setting: The Metabone national observational study

Children's Oncology Group's 2023 blueprint for research: Bone tumors.

The Children's Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biological research on localized, metastatic, and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard-of-care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biological features associated with poor outcomes including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations-MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are under way. Clinical trials evaluating the addition of multitargeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are under way in osteosarcoma and planned in EWS. In addition, the Committee has data analyses and a clinical trial under way to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data-sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

Birth characteristics and risk of Ewing sarcoma

PurposeThe incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely unknown.MethodsWe compared the birth characteristics of a population-based series of 556 Ewing sarcoma cases born in California in 1978–2015 and diagnosed in 1988–2015 with those of 27,800 controls selected from statewide birth records and frequency-matched to cases on the year of birth, using multivariable logistic regression models. We also assessed whether Ewing sarcoma clustered within families.ResultsCompared to non-Hispanic White subjects, Black (odds ratio [OR] = 0.07, 95% confidence interval [CI] 0.03–0.18), Asian (OR = 0.57, 95% CI 0.41–0.80), and Hispanic (OR = 0.73, 95% CI 0.62–0.88) individuals had a significantly lower risk of Ewing sarcoma. Race and ethnicity differences were more profound for metastatic Ewing sarcoma. Birthweight was also identified as a significant risk factor (OR = 1.09, 95% CI 1.00–1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles.ConclusionsThis population-based study with minimal selection bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial and ethnic variations in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.