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Improving the survival of patients with osteosarcoma has long proved challenging, although the treatment of this disease is on the precipice of advancement. The increasing feasibility of molecular profiling together with the creation of both robust model systems and large, well-annotated tissue banks has led to an increased understanding of osteosarcoma biology. The historical invariability of survival outcomes and the limited number of agents known to be active in the treatment of this disease facilitate clinical trials designed to identify efficacious novel therapies using small cohorts of patients. In addition, trial designs will increasingly consider the genetic background of the tumour through biomarker-based patient selection, thereby enriching for clinical activity. Indeed, osteosarcoma cells are known to express a number of surface proteins that might be of therapeutic relevance, including B7-H3, GD2 and HER2, which can be targeted using antibody–drug conjugates and/or adoptive cell therapies. In addition, immune-checkpoint inhibition might augment the latter approach by helping to overcome the immunosuppressive tumour microenvironment. In this Review, we provide a brief overview of current osteosarcoma therapy before focusing on the biological insights from the molecular profiling and preclinical modelling studies that have opened new therapeutic opportunities in this disease.Despite being the most common primary bone cancer in children and young adults, osteosarcoma is a rare cancer, a fact that has complicated efforts to improve patient outcomes. Moreover, the molecular biology of disease is highly heterogeneous and most of the recurrent genetic alterations occur in tumour-suppressor genes that are challenging therapeutic targets. Herein, Gill and Gorlick discuss the new biological discoveries, technologies, and therapeutic agents and approaches that, through collaborative efforts, are poised to generate advances in the treatment of osteosarcoma after more than four decades of stagnation.

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs ( n  = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7–59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7–49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6–16.5) and 2.4% (95% CI, 0.1–12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients’ selection for pembrolizumab treatment. In a trial of patients with soft-tissue sarcomas, clinical outcome measures following anti-PD-1 treatment were better in a cohort prospectively selected for the presence of intratumoral tertiary lymphoid structures than in other cohorts where most patients lacked these structures.

This document is an update of the British Sarcoma Group guidelines (2016) and provides a reference standard for the clinical care of UK patients with primary malignant bone tumours (PMBT) and giant cell tumours (GCTB) of bone. The guidelines recommend treatments that are effective and should be available in the UK, and support decisions about management and service delivery. The document represents a consensus amongst British Sarcoma Group members in 2024. Key recommendations are that bone pain, or a palpable mass should always lead to further investigation and that patients with clinical or radiological findings suggestive of a primary bone tumour at any anatomic site should be referred to a specialist centre and managed by an accredited bone sarcoma multidisciplinary team. Treatment recommendations are provided for the major tumour types and for localised, metastatic and recurrent disease. Follow-up schedules are suggested.

When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.Gastrointestinal stromal tumour (GIST) is the most common form of sarcoma and has become a paradigm of precision medicine owing to the fact that almost all patients harbour one of several known molecule drivers, most of which can be targeted therapeutically. Nevertheless, novel therapeutic strategies are required to overcome the intrinsic resistance of certain subtypes of GIST to existing treatments as well as the acquired resistance that eventually arises in initially sensitive subtypes. This Review describes the biology of GIST, the evolution of the current treatments for this cancer, and the emerging therapeutic agents and approaches that might overcome the remaining clinical challenges.

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients ( N  = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies. In a phase 1 dose-escalation trial in patients with nine different types of solid tumors, MAGE-A4-specific T cells had an acceptable safety profile and exhibited an encouraging overall response rate in patients with synovial sarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti- VEGFR , anti- MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS. Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.

Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2 -related gene fusions, a MYOD1 -mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1 -mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1 -mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2–94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases  showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.

Background Hepatic metastases of GIST might be the dominant site of progression and resistant to available tyrosine kinase inhibitors (TKIs). Selective internal radiation therapy (SIRT) offers treatment by intratumoral radiation up to 200 Gy. We analyzed the hepatic progression-free survival (H-PFS) in a consecutive patient cohort. Methods Twenty-six patients (median age 57.6 years) with biopsy proven liver metastases of GIST were treated by SIRT. All had RECIST documented tumor progression, and 24/26 patients had up to four lines of pretreatment. Mutational status was ‘quadruple wildtype’ (q-wt, n  = 5), KIT exon 11/9/13 in n  = 15/4/1 cases and PDGFRα ( n  = 1). Median follow-up of this retrospective analysis of a prospectively kept database is 33.6 months. Results Median H-PFS was 16 months (range, 4–54+ months, 95% CI 6.5–25.4 months) and OS after SIRT was 28 months (95% CI 17.2–28.7 months). Best H-PFS was observed in patients with ‘q-wt’ at 25 months (range, 6+–54 months, 95% CI 16.2–33.8 months). The worst outcome was for KIT exon 11 mutations plus secondary mutations with 7 months (range, 4–33 months, 95% CI, 4.2–9.8 months). Conclusions 90Y-SIRT is a potent treatment for patients with liver metastases of GIST resistant to TKI therapy. In patients with ‘q-wt’ GIST, SIRT is an option for first-line use.

Solitary fibrous tumor (SFT) is composed of spindled to ovoid cells in a patternless architecture with prominent stromal collagen and hemangiopericytoma-like vessels. Some tumors show hypercellularity, nuclear atypia, and significant mitotic activity; the latter feature in particular often portends an aggressive clinical course. SFT can sometimes be difficult to distinguish from other benign mesenchymal tumors and sarcomas. The most characteristic (albeit nonspecific) immunohistochemical finding in SFT is CD34 expression. A NAB2–STAT6 gene fusion, resulting in a chimeric protein in which a repressor domain of NGFI-A binding protein 2 (EGR1 binding protein 2) (NAB2) is replaced with a carboxy-terminal transactivation domain from signal transducer and activator of transcription 6, interleukin-4 induced (STAT6), was recently identified as a consistent finding in SFT. However, as these genes are located in close proximity on 12q13, this fusion can only rarely be detected by conventional chromosomal banding or fluorescence in situ hybridization analysis. Nuclear expression of the carboxy terminal part of STAT6 is a consistent finding in SFT of the meninges (so-called ‘meningeal hemangiopericytoma'). We investigated STAT6 expression by immunohistochemistry in SFTs and other soft tissue tumors arising outside the central nervous system to validate the diagnostic utility of this novel marker. Whole-tissue sections of 231 tumors were evaluated, including 60 cases of SFT as well as other benign and malignant mesenchymal neoplasms and sarcomatoid mesotheliomas. Fifty-nine of 60 SFT cases (98%) showed nuclear expression of STAT6, which was usually diffuse and intense. All other tumor types were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. In conclusion, STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics.

Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4 , which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies. While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4 , which encodes an ATPase subunit of BAF chromatin-remodeling complexes 1 , 2 . Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4 -mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs) 3 , 4 , 5 , SMARCB1 -inactivated malignant rhabdoid tumors 6 (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations 7 ). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4 -deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.