Adult Sarcomas Research Articles

Abstract A025: Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis

Abstract Undifferentiated pleomorphic sarcoma (UPS) is among the most common soft tissue sarcomas (STS) in adults. For decades, little therapeutic progress has been made for STSs, including UPSs. Targeted therapies for tumors driven by specific genetic mutations have proven to be more effective than standard chemotherapies. However, the molecular pathogenesis of UPSs remains unknown, hindering the development of targeted therapies for UPSs. Approximately 65% of UPSs harbor TP53 mutations, but somatic mutation of Trp53 alone is insufficient to induce sarcomas in vivo. The addition of Rb1 mutation alongside a Trp53 mutation induces sarcomas in vivo, though with low frequency of tumor onset and slow growth. The role of other genes in facilitating Trp53-driven sarcomas is largely unknown. Through a customized in vivo CRISPR/Cas9 screen of 35 genes commonly mutated in UPSs, followed by individual gene validation in vivo, we discovered that Bap1 knockout cooperates with Trp53 knockout to induce sarcomas in vivo. Furthermore, we demonstrated that Fat1 deletion increased the onset frequency and growth of Trp53 and Rb1-driven sarcomas in a genetically engineered mouse model. Through multiplex immunohistochemistry and flow cytometry, we found that mouse sarcomas induced by Trp53 and Rb1 mutations are significantly enriched with immune cells compared to other mouse sarcomas we generated in vivo. Finally, we show that PARP inhibition may be a potential targeted therapy for RB1-loss STSs and BRD4 inhibition may be a potential targeted therapy for FAT1-loss STSs. Citation Format: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R Daniel, Zhaoyu Sun, Nerissa T Williams, Melissa J Kasiewicz, Yaping Wu, Diana M Cardona, Brian Piening, John T. Welle, Wesley K Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M Oristian, Omar Lopez, Nicholas E. S. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J Lazar, Corinne M Linardic, Brady Bernard, William L Redmond, Walter J Urba, David G Kirsch. Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A025.

135P Management of sarcomas in adolescents and young adults (AYAs) in Spain

135P Management of sarcomas in adolescents and young adults (AYAs) in Spain

99P Real-world insights on sarcomas in young adults: Data from two tertiary cancer centers in Brazil

99P Real-world insights on sarcomas in young adults: Data from two tertiary cancer centers in Brazil

Liposarcoma of the Upper Extremity in an Elderly Patient

Liposarcoma is a malignant mesenchymal tumor originating from adipose tissue and is among the most common soft tissue sarcomas in adults. However, its occurrence in the upper extremities is rare, leading to diagnostic and therapeutic challenges. This report presents the case of an 83-year-old female patient with a 20 cm, painless, slow-growing mass in the left arm. Imaging studies, including ultrasound and MRI, confirmed the absence of osteomuscular involvement. Surgical resection with wide margins was performed, achieving complete tumor removal without requiring flap reconstruction. Histopathological analysis confirmed free margins. Due to the anatomical constraints of the upper extremities, achieving adequate surgical margins while preserving function is complex. Although surgical excision remains the primary treatment, the risk of local recurrence and metastasis necessitates long-term surveillance. This case underscores the importance of early diagnosis, precise imaging, and a multidisciplinary approach to managing upper extremity liposarcomas, particularly in elderly patients with comorbidities. Further studies are required to refine treatment strategies and improve clinical outcomes.

Efficacy and Safety of the Topotecan-Cyclophosphamide Regimen in Adult Metastatic Ewing Sarcoma: A Large, Multicenter, Real-World Study.

There is an unmet need to improve outcomes in patients with metastatic Ewing sarcoma (ES). This retrospective, multicenter study aimed to evaluate the efficacy and safety of the topotecan-cyclophosphamide (TC) regimen in adult patients with metastatic ES who had previously been treated with chemotherapy. This study enrolled 75 patients who were treated at five oncology centers in Turkey between 2011 and 2020. Patients were treated with the TC regimen, consisting of topotecan at 0.75 mg/m2/day and cyclophosphamide at 250 mg/m2/day, given daily for 5 days and repeated every 21 days. The median progression-free survival was 3.06 months (95% CI, 2.91-3.22), and the median overall survival was 6.16 months (95% CI, 5.14-7.18). Patients who received the TC regimen in the second line demonstrated longer OS (7.55 months 95% CI, 5.37-14.17) compared to those who received it in the third line or later (5.70 months 95% CI, 4.07-6.60) (p = 0.005). When the TC regimen was used in the second line, the disease control rate was 50%, whereas in the third line or later, the DCR was 10.8%. In the entire group, the DCR was 30.7%. The most common toxicity was transient cytopenia. This study showed that the use of the TC regimen in the second line resulted in better efficacy and overall survival outcomes compared to its use in the third line or later. However, in the entire population, the TC regimen demonstrated only a modest effect on metastatic ES. TC can be considered one of the palliative treatment options for metastatic ES.

Incidence and survival of European adolescents and young adults diagnosed with sarcomas: EUROCARE-6 results.

Incidence and survival of European adolescents and young adults diagnosed with sarcomas: EUROCARE-6 results.

ASO Visual Abstract: Surgical Margins and Oncologic Outcomes Following Wedge Resection of Pulmonary Metastases in Pediatric and Young Adult Sarcoma Patients.

ASO Visual Abstract: Surgical Margins and Oncologic Outcomes Following Wedge Resection of Pulmonary Metastases in Pediatric and Young Adult Sarcoma Patients.

A rare case of primary pulmonary embryonal rhabdomyosarcoma in children

Rhabdomyosarcoma is one of the most common soft tissue sarcomas in adolescence and young adults. Histologically, rhabdomyosarcoma has many subgroups, including embryonal, alveolar, pleomorphic, and spindle cell/sclerosing rhabdomyosarcomas. More than 50% of embryonal rhabdomyosarcomas occur in the head and neck region. The retroperitoneum and pelvis are less common sites of involvement. Primary pulmonary embryonal rhabdomyosarcoma is extremely rare. A 3-year-old girl presented with symptoms of cough and shortness of breath. A mass lesion with regular contours, approximately 3x3 cm in size, containing millimetric air densities within, and having soft tissue density was detected in the upper lobe of the right lung. According to the results of bronchoscopy and biopsy, a right thoracotomy and right upper lobectomy were performed with the diagnosis of embryonal rhabdomyosarcoma. We present a case whose pathology confirmed the diagnosis of embryonal rhabdomyosarcoma.

Surgical Margins and Oncologic Outcomes Following Wedge Resection of Pulmonary Metastases in Pediatric and Young Adult Patients with Sarcoma.

Children and young adults diagnosed with sarcoma often present with pulmonary metastases requiring wedge resection. It is important to balance the risk of pulmonary recurrence against the desire to limit resection of benign parenchyma. This study aims to determine the impact of resection margins on survival and recurrence among pediatric and young adult sarcoma patients. We conducted a retrospective cohort study of patients ages 25 years and younger with primary or recurrent osteogenic, Ewing's, or soft tissue sarcoma who underwent pulmonary metastasectomy (2006-2022). Margins were categorized as > 1mm, ≥ 5mm, or ≥ 10mm length. Two-year overall survival (OS), disease-free survival (DFS), and regional disease-free survival, consisting of pulmonary recurrence following metastasectomy, were analyzed using the Kaplan-Meier method. Cox analysis utilized patient, tumor, and treatment factors to predict risk of death and/or recurrence. In total, 122 patients were identified for analysis. The median number of wedge resections was 3.5, median nodule size was 12.5mm, and median margin length was 3mm. A 5-mm margin was associated with improvements in DFS and regional-DFS (10.6% vs. 29.7%, p = 0.01 and 10.7% versus 31.1%, p = 0.005, respectively). On Cox analysis, margin length was not associated with OS (p > 0.05); however, 5mm (HR 0.46, p = 0.005) and 10-mm margins (HR 0.39, p = 0.04) were associated with improvements in regional DFS. Margin length was not associated with development of postoperative complications (p = 0.20). Among pediatric and young adult sarcoma patients with pulmonary metastases, increased margin length was associated with decreasing risk of local recurrence but not the development of postoperative complications.

A Patient of Secondary Malignant Fibrous Histiocytoma of the Head Following Trauma and Review of the Literature.

Malignant fibrous histiocytoma (MFH) is a malignancy originating from soft tissues and ranks among the most prevalent soft tissue sarcomas in adults. The considerable complexity and heterogeneity of MFH contribute to an obscure pathogenesis, presenting with atypical clinical manifestations and pathologic features that complicate the clinical diagnostic process. Typically, MFH manifests in the extremities, trunk, and retroperitoneum, while occurrences in the head and neck regions are exceedingly rare. A thorough review of extant literature indicates that fewer than 5 cases of MFH secondary to a documented history of trauma have been reported globally. This article delineates an exceptionally rare instance of secondary MFH of the head subsequent to trauma, elaborating on the diagnostic and therapeutic procedures undertaken. It seeks to enrich the understanding of MFH treatment and pathogenesis and, by reviewing pertinent literature, aims to elucidate the clinical characteristics and prognostic outlook of MFH.

Diagnostic and Prognostic Role of Neutrophil/Lymphocyte Ratio, Platelet/Lymphocyte Ratio and Lymphocyte/Monocyte Ratio in Pediatric Sarcomas.

The correlation between the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) with prognosis has been observed in different types of adult sarcomas. However, there is insufficient evidence in pediatric tumors. Our study aimed to examine if alterations in these characteristics serve as prognostic indicators in juvenile sarcomas. A cohort group of 138 patients including Ewing sarcoma (n = 62), osteosarcoma (n = 52), and rhabdomyosarcoma (n = 24), the most common pediatric sarcomas diagnosed and treated in our institute between January 2006 and December 2022, were retrospectively evaluated. Pre-treatment values of NLR, PLR, and LMR were calculated for all patients. These values were then evaluated about overall survival (OS) and disease-free survival (DFS), along with other established prognostic variables. In terms of area under the ROC curve (AUC) values, NLR and LMR in osteosarcoma, NLR and PLR in Ewing sarcoma, and NLR in rhabdomyosarcoma were statistically significant. In patients with osteosarcoma (OS), NLR ≥ 3 and LMR < 5.3 were found to be an independent prognostic factor for overall survival in multivariate analysis (HR, 2, 95% [CI], 1.1-8; P = 0.049 and HR, 2.1, 95% [CI], 1.3-8.3; P = 0.046, respectively). Furthermore, positive surgical margins were found to be an independent prognostic factor in OS patients (HR, 2.7, 95% CI, 1-9.2; P = 0.045). In multivariate analysis, cut-off values of NLR ≥ 2.1 and PLR ≥ 194 were determined as prognostic factors for overall survival in patients with Ewing sarcoma (ES) (HR, 2.2, 95% [CI], 1-6.8; P = 0.048, HR, 3.2, 95% [CI], 1.1-9; P = 0.035, respectively). Metastatic disease was found to be correlated with poorer overall and disease-free survival rates in patients with ES. The hazard ratio for overall survival was 4 (95% confidence interval: 2.1-17.4; P = 0.03), while the hazard ratio for disease-free survival was 2.3 (95% confidence interval: 2-4.9; P = 0.024). In the rhabdomyosarcoma (RMS) group, surgical margin positivity and NLR ≥ 4.6 were associated with worse overall survival rates in univariate analysis (HR, 4, 95% CI, 1.6-27.2; P = 0.029 and HR, 2.2, 95% CI, 1.05-6.9; P = 0.046, respectively). Our study revealed that elevated NLR hurt OS and DFS in patients with osteosarcoma and Ewing sarcoma. Low LMR and high PLR were also associated with poor prognosis in these diseases, even in the presence of heterogeneity. In the rhabdomyosarcoma group, however, none of the markers provided a significant prognostic contribution.

Targeted transcriptomic analysis of well-differentiated and dedifferentiated liposarcoma reveals multiple dysregulated pathways including glucose metabolism, TGF-β, and HIF-1 signaling.

Liposarcoma is the most prevalent sarcoma in adults representing 20% of all sarcomas with well-differentiated/dedifferentiated among the most common subtypes represented. Despite multimodality treatment approaches, there has not been any appreciable change in survival benefit in the past 10 years. The future of targeted therapy for WD/DDLPS is promising with the intention to spare multi-visceral removal due to radical surgical resection. Therefore, there is a need to expand upon the molecular landscape of WDLPS and DDLPS which can help identify potential therapeutic targets for the treatment of this disease. Targeted transcriptome analysis using the NanoString tumor signaling 360 panel revealed a dysregulation in glucose metabolism and HIF1 signaling pathways in both WDLPS and DDLPS when compared to normal fat controls. WDLPS, however, demonstrated upregulation of HIF-1A and TGF-β when compared to DDLPS by targeted transcriptome analysis and orthogonal validation by RT-qPCR suggesting activation of EMT pathway in WDLPS when compared to DDLPS. Our findings implicate a putative role for dysregulation in glucose metabolism, TGF-β and HIF1 signaling in the pathogenesis of both WD/DDLPS suggesting a possible proinflammatory tumor environment within WDLPS and subsequent activation of the TGF-β signaling pathway.

EPCO-09. DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA: ASSESSING THE ONCOGENIC ROLE OF MIRNA DYSREGULATION

Abstract Cross-cancer profiling has shown that mutations in human DICER1 are recurrent in diverse cancers including intracranial sarcoma. Due to the rarity of these tumors, treatment options for these patients remain poorly defined. DICER1 encodes an endoribonuclease that processes the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs. In particular, hotspot mutations in the RNase IIIb domain of DICER1 are predicted to confer an oncogenic role although the precise mechanism is unknown. In a case of a 28-year-old male who presented with multicentric right frontal dural and parenchymal enhancing masses and underwent partial resection, pathology showed a DICER1-mutant primary intracranial sarcoma with a hotspot E1813G mutation in the RNase IIIb domain. Additionally, due to a family history of an unknown fatal brain tumor in his mother, the patient had additional molecular testing which revealed a germline BRCA2 mutation. After surgery, the patient received intensity-modulated radiation therapy followed by 6 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy with significant radiographic response and clinical improvement. He remains progression-free on radiological surveillance for 13 months since diagnosis. The treatment was well tolerated with clinically manageable myelosuppression (including grade 3 thrombocytopenia). This is the first reported case of an adult DICER1-mutant primary intracranial sarcoma patient with a germline BRCA2 mutation although the interaction between these oncogenic mechanisms is unclear. Based on the role of DICER1 in miRNA processing and to test the hypothesize that DICER1 mutations drive primary intracranial sarcoma through dysregulation of miRNA function, we have established a multi-institutional collaboration that is collecting and profiling DICER 1 mutant primary intracranial sarcoma cases from across the United States preliminary results of which will be presented. Identification of a miRNA-driven oncogenic mechanism in these tumors may yield novel targeted approaches beyond intensive chemotherapy for these patients.

ASO Visual Abstract: Adult Prostate Sarcoma: Demographics, Treatment Patterns, and Survival.

ASO Visual Abstract: Adult Prostate Sarcoma: Demographics, Treatment Patterns, and Survival.

Adult Prostate Sarcoma: Demographics, Treatment Patterns, and Survival

BackgroundThis study aimed to examine clinicopathologic characteristics, treatment patterns, and survival rates in a contemporary population-based cohort of adult prostate sarcoma patients.MethodsIn the Surveillance, Epidemiology, and End Results database (2004–2020), adult patients with prostate sarcoma were identified. Descriptive statistics, Kaplan–Meier analyses, smoothed cumulative incidence plots, and Cox regression models were used.ResultsOf 125 patients, 45 (36%) harbored leiomyosarcoma, 17 (14%) had rhabdomyosarcoma, 15 (12%) had stromal sarcoma, 17 (14%) had sarcoma not otherwise specified (NOS), and 31 (25%) had other sarcoma subtypes. Metastatic stage was most common in the rhabdomyosarcoma patients (44%) and least common in the leiomyosarcoma (21%) and stromal sarcoma (20%) patients. Most of the rhabdomyosarcoma patients received the combination of systemic and radiation therapy with (24%) or without radical surgery (35%), whereas most of the leiomyosarcoma and stromal sarcoma patients underwent radical surgery with (22 and 13%) or without (22 and 47%) radiation. In the overall population, the median overall survival was 27 months. The 5-years overall versus cancer-specific versus other-cause mortality rates were respectively 71 versus 58 versus 13%. In the multivariable Cox regression models, the highest overall mortality was exhibited by the patients with metastatic disease (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.55–5.31; p < 0.001) or unknown disease stage (HR 2.94; 95% CI 2.20–7.21; p = 0.019). Conversely, of all the histologic subtypes, only stromal sarcoma distinguished itself by lower overall mortality (HR 0.41; 95% CI 0.18–0.96; p = 0.039).ConclusionsFour major histologic subtypes were identified. Among most adult sarcoma patients, treatment patterns vary according to histology, from multimodal therapy to radical prostatectomy alone. These treatment differences reflect equally important heterogeneity in survival patterns.

1748P A prospective, phase II study of tislelizumab administered in combination with eribulin and anlotinib for patients (pts) with advanced adult oft tissue sarcoma (TEASTS)

1748P A prospective, phase II study of tislelizumab administered in combination with eribulin and anlotinib for patients (pts) with advanced adult oft tissue sarcoma (TEASTS)

Harmonization of the Upfront Osteosarcoma Treatment Paradigm for Adolescents and Young Adults.

Limited guidance exists on streamlining cancer therapy for adolescent and young adult (AYA) patients 15-39 years of age, as much of the current data are extrapolated from pediatric or adult counterparts and can differ significantly between the two care models. Harmonization of standard treatment approaches has the potential to improve outcomes and establish a foundation for the development of future clinical trials. We present our experience harmonizing treatment and supportive care regimens for AYA patients with osteosarcoma receiving treatment with methotrexate, doxorubicin, and cisplatin (MAP) therapy on the pediatric and adult sarcoma services at the Memorial Sloan Kettering Cancer Center.

Neurotrophic tyrosine receptor kinase gene fusions in adult and pediatric patients with solid tumors: a clinicogenomic biobank and record linkage study of expression frequency and patient characteristics from Finland.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes. We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis. Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing's sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy. NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.

Adult genitourinary sarcomas: A single-centre experience over 25 years.

e23532 Background: Genitourinary sarcomas are a rare entity. This study is a retrospective review of the patient characteristics, types of adult GU sarcomas, treatments and outcomes in a single institution over the past 25 years. Methods: Survival probabilities were estimated and plotted using the Kaplan-Meier method. Estimates along with 95% pointwise confidence intervals were reported. Recurrence-free survival (RFS) is defined as time from when the patient was disease-free to recurrence. Otherwise, patients were censored at last disease evaluation. OS was defined as time from when the patient was disease-free to death due to any cause. Patients still alive were censored at last known alive. Results: 29 patients presented with various types of GU sarcomas, with the majority being paratesticular tumors (n = 22, 75.9%). Others included bladder leiomyosarcomas (n = 5), prostatic leiomyosarcoma (n = 1), renal leiomyosarcoma (n = 1). Median age for diagnosis was 51 years (range: 21-79) for leiomyosarcoma vs 61 (range: 36-89) for liposarcoma. Among the paratesticular tumors majority were (n = 16) were liposarcoma, remaining 5 being leiomyosarcoma and 1 being rhabdomyosarcoma. Majority tumors were stage III and above (n = 16, 55.17%), high and intermediate grade (65.51%). All tumors were resected ± adjuvant therapy (n = 4). Leiomyosarcomas had a higher stage (66%) and grade (83%) at diagnosis, recurrence rate was also higher at 37.5% (vs 6.6% for liposarcoma) along with a higher mortality (41.6%). Commonest site of recurrence for leiomyosarcoma was the lungs (n = 3, 100%). Treatment for recurrence commonly involved radiotherapy, pembrolizumab etc. Paratesticular liposarcomas were found to be associated with a lipomatosis syndrome with n = 5 (31.25%) having lipomas elsewhere in the body and n = 2 (12.5%) patients having had previously resected spermatic cord lipoma. Paratesticular sarcomas often required (n = 15, 68%) revision surgery due to being initially diagnosed as a hernia, cord lipoma or hydrocele and requiring high ligation of the cord with hemiscrotectomy and radical orchiectomy ± LND on revision surgery, which often demonstrated a focus of residual tumor in liposarcomas (n = 5, 31%). N = 4 patients (25%) had positive margins in spite of revision surgery. Majority of these were MDM2+ positive on FISH (n = 9, 56%). Overall, GU sarcomas had an RFS of 63% (53-94%) and OS of 82% (53-94%) at 36 months since NED was achieved. The median length of follow-up was 19.9 months for leiomyosarcoma, 33.8 months for liposarcoma. Conclusions: Leiomyosarcomas in adults have worse outcomes compared to other GU sarcomas especially if it originates in the bladder. [Table: see text]

Promise and Perils of Precision Oncology for Patients With Pediatric and Young Adult Sarcomas.

The completion of multiple national pediatric precision oncology platform trials and the incorporation of standardized molecular profiling into the diagnostic care of pediatric and young adult patients with sarcomas have proven the feasibility and potential of the approach. In this work, we explore the current state of the art of precision oncology for pediatric and young adults with sarcoma. We highlight important lessons learned and the challenges that should be addressed in the next generation of trials. The chapter outlines current efforts to improve standardization of molecular assays, harmonization of data collection, and novel molecular tools such as cell-free DNA analyses. Finally, we discuss the impacts and psychosocial outcomes experienced by patients and communication strategies for providers.