Heterogeneity Of Soft Tissue Sarcomas Research Articles

Addressing Modern Diagnostic Pathology for Patient-Derived Soft Tissue Sarcosphere Models in the Era of Functional Precision Oncology

Responses to therapy often cannot be exclusively predicted by molecular markers, thus evidencing a critical need to develop tools for better patient selection based on relations between tumor phenotype and genotype. Patient-derived cell models could help to better refine patient stratification procedures and lead to improved clinical management. So far, such ex vivo cell models have been used for addressing basic research questions and in preclinical studies. As they now enter the era of functional precision oncology, it is of utmost importance that they meet quality standards to fully represent the molecular and phenotypical architecture of patients’ tumors. Well-characterized ex vivo models are imperative for rare cancer types with high patient heterogeneity and unknown driver mutations. Soft tissue sarcomas account for a very rare, heterogeneous group of malignancies that are challenging from a diagnostic standpoint and difficult to treat in a metastatic setting because of chemotherapy resistance and a lack of targeted treatment options. Functional drug screening in patient-derived cancer cell models is a more recent approach for discovering novel therapeutic candidate drugs. However, because of the rarity and heterogeneity of soft tissue sarcomas, the number of well-established and characterized sarcoma cell models is extremely limited. Within our hospital-based platform we establish high-fidelity patient-derived ex vivo cancer models from solid tumors for enabling functional precision oncology and addressing research questions to overcome this problem. We here present 5 novel, well-characterized, complex-karyotype ex vivo soft tissue sarcosphere models, which are effective tools to study molecular pathogenesis and identify the novel drug sensitivities of these genetically complex diseases. We addressed the quality standards that should be generally considered for the characterization of such ex vivo models. More broadly, we suggest a scalable platform to provide high-fidelity ex vivo models to the scientific community and enable functional precision oncology.

Nanomaterial Technology and Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are relatively rare heterogeneous solid tumors of the mesenchymal origin. They account for approximately 1% of all malignant tumors in adults and have more than 70 histological subtypes. Consequently, the rarity and heterogeneity of STSs make their diagnosis and treatment very challenging. Nanotechnology has attracted increasing attention from researchers due to the unique physicochemical and biological properties of nanomaterials with potential medical applications as nanoprobes, drug delivery systems, photosensitizers, radioenhancers, antitumor agents, and their combinations for cancer diagnosis and treatment. This review discusses the progress made in the use of nanotechnology for the diagnosis and treatment of STSs and highlights future prospects of the STS multimodality therapy.

Olaratumab’s failure in soft tissue sarcoma

Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26–75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3–37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28–10.45), and mean OS was 12.26 months (95% CI 8.47–16.05) Median OS was 9.8 months (95% CI 6.07–13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.

Heterogeneity of Soft Tissue Sarcomas and Its Implications in Targeted Therapy.

Soft tissue sarcomas are a set of malignancies of mesenchymal origin. Due to the rarity and similarity in clinical presentation, they are grouped together and treated similarly in clinic. The response rates for current chemotherapy are around 20% and the median overall survival for advanced soft tissue sarcoma are less than 2 years. Thus, the current strategy with identical treatment for all soft tissue sarcomas is far from satisfactory. In this study, we first reviewed the current clinical and genomic findings of soft tissue sarcoma, paying special attention to the heterogeneities among different tumors. Then we reviewed the state-of-art understanding of targeted therapy in soft tissue sarcoma. We observed tremendous heterogeneity both in clinical and genomic settings between different tumors. Individualized treatment plans demonstrated better response and disease control and should be advocated. In summary, heterogeneity of soft tissue sarcomas requires the development of individualized treatment plans such as targeted therapy.

Neoadjuvant Treatment Options in Soft Tissue Sarcomas.

Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is growing continuously. We may consider radiotherapy, chemotherapy, targeted therapy, radiosensitizers, hyperthermia, and their combinations. This review discusses possible neoadjuvant treatment options in STS with an emphasis on available evidence, indications for each treatment type, and related risks. Finally, we summarize current recommendations of the STS neoadjuvant therapy response assessment.

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

The remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STSs) limits the clinical benefit of targeted therapies. Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. Enforced FBP2 expression inhibits sarcoma cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect," thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic-activity-independent manner by inhibiting the expression of nuclear respiratory factor and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STSs, identifying a potential metabolic vulnerability of this malignancy and possible therapeutic target.

Clinical characteristics and outcomes of extremity soft tissue sarcomas at Thailand’s national tertiary referral center

Background: Due to the heterogeneity of soft tissue sarcomas, conflicting data have been reported regarding treatment outcomes. Moreover, factors such as histologic subtype, treatment compliance, and treatment tolerability may influence outcomes of treatment. The aim of this study was to investigate the clinical characteristics, prognostic factors, survival outcomes, and outcomes of treatment in patients with extremity soft tissue sarcoma who underwent complete tumor resection at Siriraj Hospital. Methods: Medical records of patients with extremity soft tissue sarcoma underwent total tumor resection at Siriraj Hospital during the January 2007 to December 2016 study period were included. Data collected included demographic data, tumor characteristics, type of surgery, and postsurgical intervention. Regimen, dose, cycle, and treatment compliance data were collected in patients who received adjuvant chemotherapy. Results: A total of 58 patients with a median age of 53.5 years were included. In total, 13 patients received adjuvant chemotherapy. Tumor grade 3 with size >10 cm was a baseline factor found to be a significant predictor of unfavorable disease-free survival (DFS) (p<0.001). Median DFS was 56.2 months in the chemotherapy group and 20.5 months in the non-chemotherapy group (p=0.29). Median OS was 77.2 months in the chemotherapy group and 66.6 months in the non-chemotherapy group (p=0.24). A total of 20% of patients in chemotherapy group developed grade 3-4 hematologic toxicity. Conclusion: Tumor grade 3 >10 cm was the only baseline characteristic found to be a significant predictor of unfavorable DFS in univariate analysis. No conclusive benefit of adjuvant chemotherapy in term of DFS and OS.

Understanding the patient experience with soft tissue sarcoma: A systematic review of the literature.

61 Background: Soft tissue sarcomas (STS) are a heterogenous group of rare tumors that involve the connective tissue in the body. As with many rare tumors, little is known about the impact of STS on patient well-being. The objective of this review was to understand patient experience and quality of life (QOL) following diagnosis of STS. Methods: This was a systematic review of English language articles published between 2005-2015 in PubMed/Medline, Embase, PsychINFO, and Evidence-Based Medicine. The review included recent conference proceedings and resources from advocacy websites. Articles were considered relevant if they included adult STS patient reported outcomes (PROs) or details on patient experience. Results: Of the 3,430 articles identified, 20 were eligible for inclusion. Of these, 14 were clinical studies that included PRO measures, 1 summarized PRO measures used in STS studies, and 5 described the STS patient experience. Patients with STS report a variety of concerns including emotional well-being (e.g. anxiety, depression), body image, functional deficit following surgery, and practical considerations such as obtaining child care and ability to work. Reports of patient experience vary widely given the heterogeneity of STS and individualized treatment. In clinical studies that used PROs, the European Organization for Research and Treatment of Cancer QOL Questionnaire Core 30 (EORTC QLQ-C30) was the most commonly used cancer-specific measure (N = 5) followed by the Functional Assessment of Cancer Therapy–General (N = 2). The generic EQ-5D was used in 5 publications but was limited to the visual analog scale portion of the measure in two of these studies. Similar to other cancers, STS patients report lower QOL when compared to the general population. Conclusions: Few studies have published either qualitative or quantitative data on the patient experience with STS. While STS has a measurable impact on QOL, there is a lack of detailed information in the published literature. Although PROs are often used in clinical studies of STS, they are not STS-specific tools and may not capture the unique needs of this population. There is a need for qualitative research to better understand the patient perspective of STS.

Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas.

BackgroundThe biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment. In earlier studies, gene expression patterns that distinguish two subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF) were used to separate 73 STS into two or four groups with different probabilities of developing metastatic disease (PrMet). This study was designed to confirm our earlier observations in a larger independent data set.MethodsWe utilized these gene sets, hierarchical clustering (HC), and Kaplan-Meier analysis, to examine 309 STS, using Affymetrix chip expression profiling.ResultsHC using the combined AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p = 0.048), and also among the four different clusters defined by the second branch points (p < 0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UPS) (p = 0.0004). HC of both the LipoD and UPS sample sets divided the samples into two groups with different PrMet (p = 0.0128, and 0.0002, respectively). HC of the UPS samples also showed four groups with different PrMet (p = 0.0007). HC found no subgroups of the LMS samples.ConclusionsThese data confirm our earlier studies, and suggest that this approach may allow the identification of more than two subsets of STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.

Prediction of metastatic behavior in high-grade pleomorphic soft tissue sarcomas by gene expression.

10561 Background: The biologic heterogeneity of soft tissue sarcomas (STS) complicates treatment. Metastatic propensity may be determined by gene expression patterns that do not correlate well with morphology. In earlier studies, gene expression patterns were identified that distinguish 2 subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF). We reported the use of a gene set derived from these three studies to separate 73 high grade STS into groups with different probabilities of developing metastatic disease (PrMet). We wished to confirm our findings using an independent data set. Methods: We utilized these gene sets, hierarchical clustering (HC), Kaplan-Meier, and log-rank analyses to examine the Affymetrix HU_133 expression profiles of 309 STS. Results: HC using a pooled gene set derived from the AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Kaplan-Meier analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p=0.048), and also among the 4 different clusters defined by the second branch points (p&lt;0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UDS) (p=0.0004). HC of the LipoD and UDS samples with the pooled probe set divided the samples into 2 groups with different PrMet (p=0.013, and 0.0002, respectively). HC of the UDS samples also showed 4 groups with different PrMet (p=0.0007). In contrast, HC found no subgroups of the LMS samples. Each individual gene set (AF-, RCC-, and OVCA-) separated the UDS samples into subsets of different metastatic outcome, but only the AF- gene set separated the LipoD samples, and no gene set identified LMS subsets. Conclusions: These data confirm our earlier studies and suggest that this approach may allow the identification of more than 2 subsets of high grade STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.

Gene expression identifies heterogeneity of soft tissue sarcomas

9574 Background: Soft tissue sarcomas (STS) exhibit heterogeneity in their clinical behavior, even within histological subtypes. Histological appearance is determined by gene expression. However, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two broad classes of clear cell renal carcinoma (ccRCC) independent of histological appearance, and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA). Methods: In this study, gene expression in 41 samples of STS (including malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarcoma, and synovial sarcoma), 12 samples of fibromatosis, and 17 normal tissues was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software. Results: Hierarchical clustering using two gene sets, one that distinguished two subsets of ccRCC, and a second set that distinguished two subsets of OVCA, both generated subgroups within the STS that for some, but not all, subtypes correlated with histology, and also suggested the existence of subsets of MFH. Both gene sets also identified the same two subsets of the fibromatosis samples. In addition, genes expressed uniquely in MFH, leiomyosarcomas, and liposarcomas among these and 512 samples from 17 other normal tissue types were identified. Conclusions: The ability to sub-classify histological subtypes of STS, including identifying possible subsets of MFH, using gene sets derived from studies of two different carcinomas suggests that these subgroups may have biological significance. Some of the genes identified as over-expressed in particular subsets of STS compared with a variety of normal tissues may reflect possible targets to which anti-tumor therapy could be directed, and may also be useful for sub-classification of STS. No significant financial relationships to disclose.

Intraarterial chemotherapy of soft‐tissue sarcomas

This review compares the results of preoperative intraarterial chemotherapy delivered by various methods, such as intraarterial injection/infusion, tourniquet infusion, and isolation perfusion, with the results achieved by pre- and postoperative radiotherapy. The histological heterogeneity of soft tissue sarcomas adds to the inherent difficulties of comparing results across studies. There is a clear need for randomized studies to directly compare these treatment modalities in similar patient populations. Patients with these rare tumors would benefit from the expertise of multidisciplinary teams available at the larger centers. Metastatic spread, which even with the highest rates of local control, occurs in approximately 30% of high grade soft tissue sarcomas, represents a continuing challenge, and innovative approaches are needed to control systemic disease.