Retroperitoneal Soft Tissue Sarcoma: Emerging Therapeutic Strategies
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ABSTRACT:
SUBMITTER: de Bree E
PROVIDER: S-EPMC10670057 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Complete en bloc surgical resection offers the best opportunity for the cure of primary retroperitoneal sarcomas (RPS). The potential for disease recurrence, in the form of both loco-regional recurrence and distant metastases, underpins the rationale for postoperative surveillance. There is a paucity of high-quality evidence underpinning follow-up for RPS patients, and most practice guidelines draw from expert opinion and evidence from soft tissue sarcomas of the extremities. The available observational retrospective data analysis has failed to demonstrate that high-intensity radiological surveillance improves the overall survival in patients. The lack of a robust evidence base has given rise to variations in approaches to post-operative surveillance strategies adopted by specialist centres managing RPS across the world. More high-quality prospective research is needed and planned to more clearly support surveillance approaches that balance oncologic outcomes, patient-centric care, and health service value. Risk stratification tools exist and are available for use in routine practice. Their use will likely support more individualised post-operative surveillance moving forward. Surveillance will likely be underpinned by serial radiological imaging for the medium term. However, developments in genomics offer hope for biomarkers such as ctDNA to impact patient care positively in the future and further support individualised patient care pathways.
| S-EPMC10047263 | biostudies-literature
Project description:Soft tissue sarcomas (STS) are heterogeneous, mesenchymal malignancies with variable biologic behavior. The primary management for localized STS is surgical resection, which may be combined with neoadjuvant or adjuvant radiation therapy to increase the probability of achieving local control. Many patients with large, high-grade STS develop metastatic disease. Several clinical trials of immune checkpoint blockade for STS have produced promising responses in patients with metastatic disease. In this review, recent and ongoing clinical trials of immune checkpoint inhibition for STS are discussed. The authors explain the rationale for immune checkpoint inhibition and radiation therapy and highlight new studies testing this combination in the neoadjuvant setting for patients with high-risk STS. In addition, they describe novel combinations of immunotherapy with targeted therapies and chemotherapies being tested in the metastatic setting and discuss how these combinations have the potential to be integrated into adjuvant therapy in the future.
| S-EPMC6215523 | biostudies-literature
Project description:Soft tissue sarcomas are an uncommon and diverse group of more than 50 mesenchymal malignancies. The pathogenesis of many of these is poorly understood, but others have begun to reveal the secrets of their underlying mechanisms. With considerable effort over recent years, soft tissue sarcomas have increasingly been classified on the basis of underlying molecular alterations. In turn, this has allowed the development and application of targeted agents in several specific, molecularly defined, sarcoma subtypes. This review will focus on the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors. In addition, we will address some of the early successes in sarcoma-targeted therapy as well as a few challenges and disappointments in this field. Finally, we will discuss several possible opportunities represented by poorly understood, but potentially promising new therapeutic targets, as well as several novel biological agents currently in preclinical and early phase I/II trials. This will provide the reader with the context for understanding the current state of this field and a sense of where it may be headed in the coming years.
| S-EPMC3353406 | biostudies-other
Project description:PURPOSE:Local recurrence is the most common cause of failure in retroperitoneal soft tissue sarcoma patients after surgical resection. Postoperative radiotherapy (PORT) is infrequently used due to its high complication risk. We investigated the efficacy of PORT using modern techniques in patients with retroperitoneal soft tissue sarcoma. MATERIALS AND METHODS:Eighty patients, who underwent surgical resection for non-metastatic primary retroperitoneal soft tissue sarcoma at the Yonsei Cancer Center between 1994 and 2015, were retrospectively reviewed. Thirty-eight (47.5%) patients received PORT: three-dimensional conformal radiotherapy in 29 and intensity-modulated radiotherapy in nine patients. Local failure-free survival (LFFS), overall survival (OS), and RT-related toxicities were investigated. RESULTS:Median follow-up was 37.1 months (range, 5.8-207.9). Treatment failure occurred in 47 (58.8%) patients including local recurrence in 33 (41.3%), distant metastasis in eight (10%), and both occurred in six (7.5%) patients. The 2-year and 5-year LFFS rates were 63.9% and 47.9%, respectively. The 2-year and 5-year OS rates were 87.5% and 71.1%. The 5-year LFFS rate was significantly higher in PORT group than in no-PORT group (74.2% vs. 24.3%, p<0.001). In multivariate analysis, PORT was the only independent prognostic factor for LFFS. However, there was no significant correlation between RT dose and LFFS. OS showed no significant difference between the two groups. Grade ?2 acute toxicities were observed in 63% of patients, but no acute toxicity ?grade 3 was observed. CONCLUSION:PORT using modern technique markedly reduced local recurrence in retroperitoneal sarcoma patients, with low toxicity. The optimal RT technique, in terms of RT dose and target volume, should be further investigated.
| S-EPMC6192889 | biostudies-literature
Project description:ObjectiveSoft-tissue sarcoma is a heterogeneous disease that frequently includes the development of pulmonary metastases. The purpose of this study is to determine factors associated with improved survival among patients with soft-tissue sarcoma to help guide selection for pulmonary metastasectomy.MethodsWe reviewed a prospectively maintained database and identified 803 patients who underwent pulmonary metastasectomy for metastatic soft-tissue sarcoma between September 1991 and June 2014; of these, 539 patients undergoing 760 therapeutic-intent pulmonary metastasectomies were included. Clinicopathologic variables and characteristics of treatment were examined. The outcomes of interest were overall survival and disease-free survival. Survival was estimated with the Kaplan-Meier method and compared between variables with the log-rank test. Factors associated with hazard of death and recurrence were identified via the use of univariable and multivariable Cox proportional hazards models.ResultsMedian overall survival was 33.2 months (95% confidence interval, 29.9-37.1), and median disease-free survival was 6.8 months (95% confidence interval, 6.0-8.0). In multivariable analyses, leiomyosarcoma histologic subtype (P = .007), primary tumor size ≤10 cm (P = .006), increasing time from primary tumor resection to development of metastases (P < .001), solitary lung metastasis (P = .001), and minimally invasive resection (P = .023) were associated with lower hazard of death. Disease-free interval ≥1 year (P = .002), and 1 pulmonary metastasis (P < .001) were associated with lower hazard of disease recurrence.ConclusionsIn a large single-institution study, primary tumor histologic subtype and size, numbers of pulmonary metastases, disease-free interval, and selection for minimally invasive resection are associated with increased survival in patients undergoing pulmonary metastasectomy for soft-tissue sarcoma.
| S-EPMC5521256 | biostudies-literature
Project description:Soft-tissue sarcoma (sts) represents a heterogeneous group of rare tumours, and a significant number of affected patients will develop metastatic disease. Outcomes in the population with metastatic disease are generally poor, especially after progression on standard chemotherapy. The advent of personalized medicine has permitted oncologists to offer targeted treatment, thus addressing the limited treatment options and poor prognosis after progression on first-line chemotherapy. In this review, we delineate the existing data and therapeutic successes with respect to existing and emerging molecular targets in sts and options for immunotherapy in sts. Our review also summarizes emerging clinical trials that are currently recruiting patients.
| S-EPMC7050044 | biostudies-literature
Project description:BackgroundSoft-tissue sarcoma (STS) is a rare solid malignant tumor with numerous histologic subtypes. Current studies on targeted therapy for STS are in preclinical and early-phase trials. Genomic differences largely influence the prognosis of patients even with the same subtype. To investigate the genomic alterations (GAs) and the potential of targeted therapy in STS, we analyzed the genomic landscape, the therapeutic GAs, and biomarkers of immunotherapy in Chinese STS patients.MethodsTargeted sequencing covering 425 genes was performed, from which we obtained the results of tissue samples from 351 Chinese STS patients of all ages covering different histologic subtypes. Bioinformatics analysis of altered genes with nonsynonymous mutations, copy-number variations, and gene fusions were performed. OncoKB therapeutic GAs and relevant biomarkers including TMB, MSI, and HRD were further examined for potential targeted therapy.ResultsIn total, 2743 GAs were identified in 330 genes with a median of 6 (1-38) per case. The top 11 frequently altered genes were: TP53, MCL1, MDM2, CDK4, MYC, CDKN2A, GNAS, RB1, ATRX, CDKN2B, and FGFR1. OncoKB defined therapeutic GAs were found in 23 genes in 43% of the patients. In general, 9.4% of the patients had high-TMB, 2.8% had MSI, and 13.7% had HRD. A significant difference in the percentage of patients with OncoKB therapeutic GAs were observed between the most frequent two subtypes, leiomyosarcoma and liposarcoma. Altogether, 54% of the patients had the potential to respond to a targeted therapy.ConclusionThis study indicated the potential efficacy of targeted therapy on many STS patients, and also provided insight for novel precision therapy. The clinical efficacy of combining targeted therapy and immunotherapy can be further investigated.
| S-EPMC9636498 | biostudies-literature
Project description:BackgroundSeveral studies have investigated the molecular drivers and therapeutic targets in adult soft tissue sarcomas. However, such studies are limited by the genomic heterogeneity and rarity of sarcomas, particularly in those with complex and unbalanced karyotypes. Additional biomarkers are needed across sarcoma types to improve therapeutic strategies. To investigate the molecular characteristics of complex karyotype sarcomas (CKSs) for therapeutic targets, we performed genomic profiling.ResultsThe mutational landscape showed that TP53, ATRX, and PTEN genes were highly mutated. CKS samples were categorized into three groups based on copy number variations that were associated with CDK4 and RB1 signatures. Integrated analysis of genomic and transcriptomic data revealed several pathways related to PDGFR, which could be a strategic target for anti-sarcoma therapy.ConclusionsThis study provides a detailed molecular classification of CKSs and proposes several therapeutic targets. Targeted or combinational therapies for treating CKS should be considered before chemotherapy.
| S-EPMC6311917 | biostudies-literature
Project description:Defects in homologous recombination repair (HRR) in tumours correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harbouring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.
| S-SCDT-10_15252-EMMM_202216863 | biostudies-other
Project description:Soft-tissue sarcoma (sts) is a rare mesenchymal malignancy that accounts for less than 1% of all adult tumours. Despite the successful advancement of localized therapies such as surgery and radiotherapy, these tumours can, for many, recur-often with metastatic disease. In the advanced setting, the role of systemic therapies is modest and is associated with poor survival. With the discovery of immunotherapies in other tumour types such as melanoma and lung cancer, interest has been renewed in exploring immunotherapy in sts. The biology of some stss makes them ripe for immunotherapy intervention; for example, some stss might have chromosomal translocations resulting in pathognomonic fusion products that have been shown to express cancer/testis antigens. Here, we present a targeted review of the published data and ongoing clinical trials for immunotherapies in patients with sarcoma, which comprise immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines.
| S-EPMC7050043 | biostudies-literature