Angiosarcoma Research Articles

Sarcomas in fluid cytology: Experience from a tertiary care centre in India

Cytological evaluation of fluids for sarcomatous exfoliation is extremely rare. However, recently studies have come up describing characteristics of sarcomatous malignancies exfoliating into fluids but study from an Indian experience is still lacking. Description of clinico-pathological landscape in known cases of sarcomas, involving body fluid with emphasis on cytomorphologic details. Study includes cases reported as positive for involvement by sarcoma on fluid cytology including pleural, ascitic and cerebrospinal fluid (CSF) specimens between Jan 2016 to June 2022. Cases were retrieved and reviewed for cytomorphologic features which were subsequently correlated with its parent histology and IHC. IHC was applied on cell blocks for two cases where involvement was doubtful. In total, 21 fluid samples/cases including 4 CSF, 6 ascitic and 11 pleural fluid specimens were incorporated. Case spectrum comprised of 6 cases of Ewing Sarcoma (ES), 3 cases of rhabdomyosarcoma (RMS), 3 cases of osteosarcoma (OS), 2 cases of malignant peripheral nerve sheath tumor (MPNST), 2 cases of synovial sarcoma (SS), a case each of chondrosarcoma (CS), leiomyosarcoma (LMS) angiosarcoma (AS) and two cases of other malignancies with exfoliation of their sarcomatous component. Two cases presented as isolated latent metastasis so an IHC panel was applied to exclude involvement by secondary malignancy and prove involvement by primary diagnosed sarcoma.Majority of exfoliated sarcomas presented with epithelioidto pleomorphic morphology where at times it becomes obligatory to rule out occurrence of a secondary malignancy. It’s the first study from an Indian institute’s perspective that reflects upon such diversity of sarcomas with variability in morphology on exfoliation which can be overwhelming for a cytopathologist at times. IHC panel might be used when clinical background is unknown or when involvement is uncertain. More studies are needed that can help come up with recommendations that address such problems.

Tumor Microenvironment and Its Clinicopathologic and Prognostic Association in Cutaneous and Noncutaneous Angiosarcomas.

We explored features of the angiosarcoma (AS) tumor microenvironment to discover subtypes that may respond to immunotherapy. Thirty-two ASs were included. Tumors were studied by histology, immunohistochemistry (IHC), and gene expression profile using the HTG EdgeSeq Precision Immuno-Oncology Assay. Comparing cutaneous and noncutaneous ASs, the second group showed 155 deregulated genes, and unsupervised hierarchical clustering (UHC) delineated two groups: the first mostly cutaneous AS and the second mainly noncutaneous AS. Cutaneous ASs showed a significantly higher proportion of T cells, natural killer cells, and naive B cells. ASs without MYC amplification revealed a higher immunoscore in comparison with ASs with MYC amplification. PD-L1 was significantly overexpressed in ASs without MYC amplification. UHC showed 135 deregulated genes differentially expressed when comparing ASs from the non-head and neck area with patients who had AS in the head and neck area. ASs from the head and neck area showed high immunoscore. PD1/PD-L1 content was significantly more highly expressed in ASs from the head and neck area. IHC and HTG gene expression profiling revealed a significant correlation between PD1, CD8, and CD20 protein expression but not PD-L1. Our HTG analyses confirmed a high degree of tumor and microenvironment heterogeneity. Cutaneous ASs, ASs without MYC amplification, and ASs located in the head and neck area seem to be the most immunogenic subtypes in our series.

Skin lesions on a man's face and scalp

An 87-year-old male patient was admitted to our Clinic for diagnostic evaluation and treatment of extensive, confluent erythematous-livid areas that affected almost the entire skin of his face, scalp, and neck Figure (1). The patient also showed left eyelid ectropion and a palpable subcutaneous, painless nodule in the left mandibular region the size of an apple that bled easily. The patient had been treated for undiagnosed erythematous papules on his left cheek 2 years before and reported that his condition had dramatically worsened over the last few weeks. The patient was otherwise healthy and was only being treated for hypertension and hyperlipemia. Multiple computed tomography (CT) scans were performed which showed an extensive disease affecting the skin and subcutaneous tissue of almost the entire face, scalp and neck, with occasional involvement of muscle tissue as well. Numerous secondarily altered lymph nodes of the neck and multiple tumour infiltrates in the liver were also seen. A skin biopsy from the scalp was performed Figure (2). Histopathology showed a tumoral lesion composed of irregular, anastomosing vascular spaces and an increased number of surrounding endothelial cells with hyperchromatic, atypical nuclei. The clinical and pathological features corresponded to a typical presentation of angiosarcoma (AS). The patient had an inoperable disseminated disease and palliative chemotherapy with paclitaxel was initiated. After three cycles of therapy, the patient's general condition worsened, and was admitted to a palliative care facility. cAS is a rare vascular malignant tumour that has a high risk of both local and distant metastatic dissemination despite aggressive therapy. It is classified into primary AS that occurs sporadically, usually in the scalp or face, and secondary AS that is most often related to a history of radiation treatment and chronic lymphedema.1 This malignant tumour resembles a “spreading bruise” that varies from blue to red in colour. The diagnosis of cAS is often delayed due to its subtle initial clinical appearance as it is often mistaken for an ecchymosis or haematoma, especially in elderly patients on anticoagulants. Most patients are asymptomatic although some may present with bleeding, oedema, and/or ulceration. Diagnosis is based on clinical examination and histopathological and immunohistochemical analysis. The extent of the disease may be assessed with magnetic resonance imaging or CT.1, 2 AS represents less than 0.1% of all head and neck malignancies but is associated with the highest rate of lymphatic dissemination among all head and neck soft tissue sarcomas.3, 4 AS shows aggressive behaviour and carries a poor prognosis, thus early diagnosis is crucial. The optimal treatment is surgery followed by wide-field radiotherapy. Clear surgical margins are of paramount importance and correlate with better outcome, but the disease is often so extensive at the time of diagnosis that it is not possible to excise.5, 6 Despite inconsistent data regarding chemotherapy, this is usually employed for patients with metastatic or inoperable disease. Doxorubicin-based regimens are most recommended, but recent use of paclitaxel has shown better efficacy compared with doxorubicin.6, 7 Though involvement of the face and scalp is common in cAS, the extent of disease in our case was striking. AS should be considered in the differential diagnosis of violaceous or ecchymotic lesions on the head or scalp in the elderly. All authors contributed to the manuscript conception, design, and writing. All authors read and approved the final manuscript. The authors have not declared a specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. This article did not require the approval of the Ethics committee. The patient in this manuscript has given written informed consent to the publication of his case details. Due to privacy and ethical concerns, neither the data nor the source of the data can be made available.

MYC amplification in angiosarcoma depends on etiological/clinical subgroups – Diagnostic and prognostic value

Angiosarcomas (AS) are rare and heterogeneous malignant vascular tumors with a dismal prognosis. We undertook a retrospective study of AS cases with the intent of elucidating the prevalence of MYC amplification amongst different etiological/clinical subgroups and identifying MYC's potential as a prognostic biomarker.Retrospective collection of data and tumor samples from 110 patients diagnosed with AS in the Netherlands was conducted. Histopathological review and investigation of MYC gene amplification and MYC protein overexpression (using fluorescent in situ hybridization and immunohistochemistry, respectively) was performed.MYC amplification was identified in 50.9 % of cases and predominantly present in secondary AS (sAS) (especially radiotherapy-associated and Stewart-Treves AS, both 92.9 %). Within the primary AS (pAS) subgroup, skin non-UV-associated AS (69.2 %) and primary breast AS (29.4 %) demonstrated MYC amplification. MYC protein overexpression was observed in 47.7 % of all tumors with an overall sensitivity and specificity of 75 % and 81 % respectively. There was no significant difference in median overall survival (OS) between patients with MYC and non-MYC amplified AS. Patients with AS displaying MYC protein overexpression had significantly shorter OS than those without (p = 0.028).Although MYC amplification is characteristic for secondary radiotherapy-associated and Stewart-Treves AS, it is not exclusive to these groups and can also be found in a subset of pAS. Overall concordance of FISH and IHC is rather poor. Only primary breast AS showed 100 % concordance. Therefore MYC expression as surrogate marker should be used with caution. The role of MYC/MYC as a prognostic indicator is undefined, however resulting tailored treatment options could be considered.

Neuroinflammation and neovascularization in diabetic eye diseases (DEDs): identification of potential pharmacotherapeutic targets.

The goal of this review is to increase public knowledge of the etiopathogenesis of diabetic eye diseases (DEDs), such as diabetic retinopathy (DR) and ocular angiosarcoma (ASO), and the likelihood of blindness among elderly widows. A widow's life in North India, in general, is fraught with peril because of the economic and social isolation it brings, as well as the increased risk of death from heart disease, hypertension, diabetes, depression, and dementia. Neovascularization, neuroinflammation, and edema in the ocular tissue are hallmarks of the ASO, a rare form of malignant tumor. When diabetes, hypertension, and aging all contribute to increased oxidative stress, the DR can proceed to ASO. Microglia in the retina of the optic nerve head are responsible for causing inflammation, discomfort, and neurodegeneration. Those that come into contact with them will get blind as a result of this. Advanced glycation end products (AGE), vascular endothelial growth factor (VEGF), protein kinase C (PKC), poly-ADP-ribose polymerase (PARP), metalloproteinase9 (MMP9), nuclear factor kappaB (NFkB), program death ligand1 (PDL-1), factor VIII (FVIII), and von Willebrand factor (VWF) are potent agents for ocular neovascularisation (ONV), neuroinflammation and edema in the ocular tissue. AGE/VEGF, DAG/PKC, PARP/NFkB, RAS/VEGF, PDL-1/PD-1, VWF/FVIII/VEGF, and RAS/VEGF are all linked to the pathophysiology of DEDs. The interaction between ONV and ASO is mostly determined by the VWF/FVIII/VEGF and PDL-1/PD-1 axis. This study focused on retinoprotective medications that can pass the blood-retinal barrier and cure DEDs, as well as the factors that influence the etiology of neovascularization and neuroinflammation in the eye.

Immunological and Genomic Analysis Reveals Clinically Relevant Distinctions between Angiosarcoma Subgroups.

Angiosarcomas (AS) are extremely rare and aggressive vascular malignancies subdivided in de novo primary AS (pAS) and secondary AS (sAS). We hypothesize that the combination of immunological and genomic profiles significantly differs between primary and secondary AS, with potential impact on treatment strategies and a role for immunotherapy. Tumor-infiltrating lymphocytes were analyzed using multiplex immunohistochemistry from 79 pAS and 178 sAS. Median cell density was significantly higher in sAS for CD3+ T-cells (p < 0.001), CD8+ cytotoxic T-cells (p = 0.033), CD4+ T-helper cells (p < 0.001) and FoxP3+ T-regulatory cells (p < 0.001). CD20+ B-cell density was comparable (p = 0.417). Comprehensive genomic profiling was performed in 25 pAS and 25 sAS. A (likely) pathogenic mutation was detected in 80% of pAS vs. 88% of sAS (p = 0.702). Amplifications were found in 15% of pAS vs. 84% of sAS (p < 0.001). DNA damage response (DDR) pathway mutations (p = 0.021) and MYC amplifications (p < 0.001) were predominantly seen in sAS. In conclusion we observed a clear and clinical relevant distinction in immune infiltration and genomic profiles between pAS and sAS. The T-cell infiltrated tumor microenvironment and frequent DDR gene mutations, especially in sAS, warrant clinical trials with immunotherapy.

Efficacy and safety of apatinib in advanced refractory soft tissue sarcoma and association with histologic subtypes: a multicenter retrospective study.

BackgroundAntiangiogenic therapy is a potential strategy against advanced refractory soft tissue sarcoma (STS). This retrospective study aimed to assess the efficacy and safety of apatinib in patients with advanced refractory STS and explore its clinical effect on the different histologic subtypes.MethodsPatients with pathologically diagnosed and metastatic STS who had failed at least standard chemotherapy and were naive to angiogenesis inhibitors were enrolled in this multicenter respective study. Apatinib was administered orally at a dosage of 250 to 850 mg/day. The primary endpoints were objective response rate (ORR) and disease control rate (DCR). The secondary endpoints were progression free survival (PFS) and overall survival (OS). Tumor assessment was done after the first 4 weeks and every 8 weeks thereafter.ResultsTwenty-six patients were enrolled from seven centers between December 2015 and December 2020, consisting of 9 leiomyosarcomas (LMS), 4 rhabdomyosarcomas (RMS), 3 undifferentiated pleomorphic cell sarcomas (UPS), 3 fibrosarcomas (FS), 3 alveolar soft part sarcomas (ASPS), 2 angiosarcomas (AS) and 2 synovial sarcomas (SS). The median age was 49.0 [26–77] years, 15 females and 11 males. The ORR was 34.62% [9/26, 95% confidence interval (CI): 19.42–53.78%] and DCR was as high as 84.62% (22/26, 95% CI: 66.47–93.85%). The median progression-free survival and overall survival were 6.0 months (95% CI: 2.42–9.58) and 19.3 months (95% CI: 7.31–31.29) respectively. Furthermore, 181 patients from seven studies as well as this trial were included for pooled analysis of apatinib efficacy dependency on histology. In terms of ORR, RMS (41.7%), ASPS (78.6%), and Ewing sarcoma (40.7%) seemed to benefit more than the other histologic subtypes. Common adverse events (AEs) included hand-foot skin reaction (n=13, 50.0%), hypertension (n=12, 46.15%), proteinuria (n=10, 38.46%). Seven patients (7/26, 26.92%) had grade 3 AEs and no grade 4 AEs occurred. 2 patients (2/26, 7.69%) and 15 patients (15/26, 57.69%) experienced dose withdrawal and dose reduction respectively.ConclusionsApatinib showed promising efficacy and a manageable safety profile in patients with advanced refractory STS. In addition, the response to apatinib in STS seemed to be dependent on histology.

Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients.

Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer’s clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within an individual patients’ cancer can shape the use of mutations as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 43 dogs (27 HSA, 15 benign masses, and 1 stromal sarcoma) presenting for emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal targeted sequencing panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/27 (52%) HSAs. Among recurrent candidate driver mutations, TP53 was most commonly mutated (30%) followed by PIK3CA (15%), AKT1 (11%), and CDKN2AIP (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspectives on the genomic landscape of this veterinary cancer and suggest a cross-species value for using HSA in pet dogs as a naturally occurring model of intratumoral heterogeneity.

Impaired Fanconi anemia pathway causes DNA hypomethylation in human angiosarcomas.

Angiosarcomas (AS) is a rare soft tissue sarcomas with poor treatment options and a dismal prognosis. The abnormal DNA methylation pattern has been determined as the certain clinical relevance with different angiosarcoma subtypes. However, the profound mechanism is not clear. In present study, we studied thirty-six AS with or without chronic lymphedema, and reported that DNA damage was an important factor causing DNA methylation abnormality. Furthermore, we determined that the impaired Fanconi anemia (FA) pathway contributed to severe DNA damage in AS with chronic lymphedema. We also observed that the activated FANCD2 could facilitate DNMT1 recruitment on genomic DNA. Our study uncovers a novel regulatory mechanism of FA pathway on DNA methylation, and is a benefit to advanced understanding the pathogenesis of AS, as well as providing the potential therapeutic targets for AS treatment.

Soft tissue sarcoma incidences and clinical characteristics are significantly different in France and Taiwan.

The incidence of different soft tissue sarcoma (STS) histotypes among ethnic and geographic populations has not been comprehensively investigated. Data from 2013 to 2016 were obtained from national cancer registry databases in France and Taiwan. Liposarcoma (LPS), leiomyosarcoma (LMS), angiosarcoma (AS), synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST) were selected as index STSs to estimate the age-standardized incidence rates (ASRs) and other clinical features between patients. In total, 9398 patients (7148 from France and 2250 from Taiwan) were included. The ASRs of AS (5.4 vs. 2.8) and MPNST (2.0 vs. 1.0) were significantly higher in Taiwan; France had significantly higher ASRs for LPS (12.0 vs. 10.0), LMS (9.7 vs. 7.6), and SS (1.7 vs. 1.2). Patients in Taiwan with LMS or LPS were younger than their French counterparts. With regard to the distribution according to primary anatomic site, French patients had higher odds for extremity and truncal LMS (odds ratio [OR], 2.84; p < .001), AS (OR, 2.67; p < .001), MPNST (OR, 1.55; p=.027), and LPS (OR, 1.38; p < .001) and for breast AS (OR, 10.58; p < .001). Taiwanese patients had higher odds for liver AS (OR, 10.72; p < .001) and uterine LMS (OR, 3.21; p < .001). SS age and distribution according to primary anatomic site did not differ significantly between the French and Taiwanese populations. Significant differences in the incidence and clinical characteristics of index STS suggested that geographic (environmental) and ethnicity factors likely play a vital role in the pathogenesis of STS.

Abstract LB140: The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas

Abstract Background: Angiosarcomas (AS) are a rare heterogenous group of soft tissue sarcomas (STS) that form in the lining of blood vessels or lymphatic vessels. They comprise of primary (de novo) AS and secondary AS. The etiology of primary AS is unknown. Secondary AS arise due to DNA damaging factors like prior radiotherapy (RT), ultraviolet (UV) light exposure or chronic lymphedema (Stewart Treves syndrome). Treatment options are limited and their prognosis is poor. Development of new treatment strategies is difficult due to the rarity of these subgroups of STS. Genomic profiling of primary and secondary AS may provide a rationale for targeted treatment strategies. Method: Tumor samples were retrospectively collected from patients diagnosed with AS in the Netherlands. Patients were categorized as primary/secondary AS. Genomic profiles were analyzed using “TruSight Oncology 500”, a Next Generation Sequencing panel that analyzes variants in 523 cancer relevant genes. Results: Tumor DNA from 51 treatment naive AS patients was analyzed. The cohort comprised of 26 patients with a primary AS, divided in 5 subgroups: Heart (n=5, 10%), primary breast (n=5, 10%), skin not UV associated (n=4, 8%), soft tissue (n=5, 10%) and visceral (n=7, 14%) AS. The other 25 patients had a secondary AS, subdivided in RT-associated (n=13, 25%), Stewart Treves (n=5, 10%) and UV-associated (n=7, 14%) AS. Mean Tumor Mutational Burden (TMB) was 7.1 mutations per Mb for all patients (4.2 mut/Mb in primary AS vs 10.1 in secondary AS, p = 0.91). High TMB (≥10 mut/Mb) was found in 6 patients (12%) divided over 3 subgroups: UV associated AS (n=3/7 (43%)), visceral AS (n=2/7 (28%)) and skin not UV associated AS (n=1/4 (25%)). No patients were microsatellite instable. A pathogenic mutation, amplification or deletion was identified in 82% of all patients (n=42, 70% of primary AS vs 100% of secondary AS (p=&amp;lt;0.01)). In 36 patients (71%) at least one (likely) pathogenic mutation was detected (54% primary vs 88% secondary AS, (p=0,013)). In 20 patients (39%) a mutation in the DNA damage response (DDR) pathway was detected (12% primary vs 68% secondary AS (p=&amp;lt;0.01)). The most frequently found mutations were TP53 (10%), BRAF (6%), ERCC4 (6%), PTPRD (6%), WETD2 (6%), SETD2 (6%) and PIK3CA (4%). Amplifications were found in 49% (n=25) of all patients (15% primary vs 84% secondary AS, (p=&amp;lt;0,01)). MYC amplifications were detected in 41% of all patients (15% of primary vs 68% of secondary AS), including 100% of Stewart Treves AS, 92% of RT associated AS and 75% of skin not UV associated AS. FLT4 (20%) and CRKL (12%) amplifications occurred only in secondary AS. FLT4 was seen in 31% of RT-associated AS. Conclusion: We showed a clear distinction in genomic profiles of AS subgroups with specific pathogenic alterations. Especially secondary AS may benefit from treatment with ICI based on frequent MYC amplifications, DDR mutations, and high TMB. These data show clear evidence for the development of future treatment strategies with targeted therapy and ICI for this rare heterogeneous group of STS. Citation Format: Stefan G. van Ravensteijn, Yvonne M. Versleijen-Jonkers, Melissa H. Hillebrandt-Roeffen, Maikel Nederkoorn, Mark A. Gorris, Kiek Verrijp, Leonie I. Kroeze, Tessa J. de Bitter, Richarda M. de Voer, Uta E. Flucke, Ingrid M. Desar. The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB140.

Which angiosarcoma subtypes may benefit from immunotherapy?

11572 Background: Angiosarcomas (AS) are aggressive mesenchymal tumors arising from cells with endothelial properties. They include de novo primary AS (pAS), and secondary AS (sAS) due to prior radiotherapy, UV exposure or chronic lymphedema. Treatment options are limited and their prognosis is poor. Development of new treatment strategies is difficult due to the heterogeneity and rarity of AS. We hypothesize that immunological and genomic profiles are significantly different between pAS and sAS and may result in different immune checkpoint inhibition (ICI) based treatment strategies. Methods: Tumor samples from AS patients were retrospectively collected. Patients were categorized as pAS or sAS. Lymphocytes were analyzed using multiplex immunohistochemistry on tissue microarrays. Genomic profiling was performed in a selected subgroup with “TruSight Oncology 500”, a Next Generation Sequencing panel containing 523 cancer related genes. Results: Immunological data were analyzed from 257 AS patients. The cohort comprised 80 pAS patients and 177 sAS patients. The median density of CD3+ T cells was 250 cells/mm2 in pAS vs 452 cells/mm2 in sAS (p&lt; 0.001). Median CD4+ T helper cell density was 128 cells/mm2 in pAS vs 246 cells/mm2 in secondary AS (p&lt; 0.001). The median density of CD8+ cytotoxic T cells was 85 cells/mm2 in pAS vs 111 cells/mm2 in sAS ( p= 0.057). Density of FoxP3+ T regulatory cells was higher in sAS (median 42 cells/mm2) compared to pAS (median 23 cells/mm2) (p&lt; 0.001). The median count of CD20+ B cells in pAS was 24 cells/mm2 compared to 32 cells/mm2 in sAS ( p= 0.533). Genomic analysis was performed on tumor DNA from 51 patients (25 pAS and 26 sAS). Median tumor mutational burden (TMB) was 3.2 (range 0.8-11.9) mutations per megabase (mut/Mb) in pAS vs 3.9 (range 0.0-99.6) in sAS ( p= 0.485). No microsatellite instability was detected. A pathogenic mutation, gene amplification or gene loss was identified in 82% of all patients (n = 42, 70% of pAS vs 100% of sAS ( p&lt; 0.01)). In 36 patients (71%) at least one (likely) pathogenic mutation was detected (54% pAS vs 88% sAS, ( p= 0.013)). In 20 patients (39%) mutations in the DNA damage response (DDR) pathway were detected (12% pAS vs 68% sAS ( p&lt; 0.01)). The most frequently found mutated genes were TP53 (10%), BRAF (6%), ERCC4 (6%), PTPRD (6%), WETD2 (6%) and SETD2 (6%). Amplifications were found in 49% (n = 25) of all patients (15% pAS vs 84% sAS, ( p&lt; 0,01)). MYC amplifications were most common and were detected in 15% of pAS and 68% of sAS. Immune profiles of the 51 genomically characterized patients are currently under further investigation. Conclusions: We showed a clear distinction in immunological and genomic profiles between pAS and sAS. The potential benefit of ICI seems to be most promising in sAS with a T cell inflamed tumor microenvironment, frequent MYC amplifications, DDR mutations, and high mutational load, while in pAS boosting strategies to enhance susceptibility to ICI might be interesting for further investigation.

Using pan-sarcoma multiomic analysis for identifying sarcoma subtypes with immunogenic potential.

11551 Background: Immune checkpoint inhibitors (ICI) have limited efficacy for most sarcomas. Yet, responses are seen in particular sarcoma subtypes, highlighting the need for better predictive biomarkers. The T cell inflamed score (TIS), a gene expression signature reflective of an active tumor immune microenvironment, is associated with ICI response in multiple solid tumors. We evaluated the TIS across a large database of sarcomas to identify which histologic subtypes may benefit from ICI. Methods: Next generation sequencing of DNA (592 gene or whole exome)/RNA (whole transcriptome) was performed for 3605 sarcoma patient samples, representing 45 histologic subtypes (Caris Life Sciences, Phoenix, AZ). TIS (18 gene weighted coefficient composite value; Cristescu 2018) was calculated and the Microenvironment Cell Populations-counter tool (Becht 2016) was used to quantify immune cell populations. Results were compared to melanoma (n = 1255), a representative immunogenic tumor type. High TIS was defined as a score within the upper quartile of melanoma TIS (&gt; 5.5). Percentage with high TIS are reported with 95% CI. Results: Median TIS was highest in inflammatory myofibroblastic tumor (IMT), epithelioid sarcoma (EPIS), myxofibrosarcoma (MFS), well differentiated liposarcoma, and solitary fibrous tumor (SFT). These did not differ significantly from melanoma (p &gt; 0.06). Median TIS was lowest in embryonal rhabdomyosarcoma, desmoid tumor (DES), synovial sarcoma (SYNS), and Ewing sarcoma (ES). Histologic subtypes where &gt; 10% of samples had a high TIS included IMT (29.9% ± 21.7%), MFS (23.3% ± 12.6%), pleomorphic sarcoma (PLSARC) (21.9% ± 5.8%), cutaneous angiosarcoma (ANGS) (18.4% ± 13.9%), spindle cell sarcoma (17.5% ± 7.6%), liposarcoma (LPS) (17% ± 10.7%), EPIS (15.4% ± 19.6%), visceral ANGS (13.2% ± 10.7%), pleomorphic LPS (13.6% ± 14.3%), fibrosarcoma (12.5% ± 13.2%), leiomyosarcoma (11.6%± 3.4%), malignant peripheral nerve sheath tumor (MPNST) (10.2% ± 7.7%), and perivascular epithelioid cell tumor (PEComa) (10% ± 10.7%). The relative abundance of immune and stromal cell populations was highly variable across sarcoma subtypes, yet a strong positive correlation between TIS and immune cell populations was observed for most subtypes (e.g. T cells, Spearman R range: 0.56 [P = 0.08] - 0.96 [P &lt; 0.0001]). A notable exception was SFT, which had a relatively high median TIS but low abundance of CD8+ T cells and B cells. Conclusions: We found high median TIS and/or significant proportions of samples with a high TIS in sarcoma subtypes with previously demonstrated responsiveness to ICI, including MFS, PLSARC, LPS, and ANGS, while unresponsive tumor types such as RMS, DES, SYNS, and ES had low TIS. We further identified subtypes with high TIS but limited prior clinical data supporting ICI use, such as IMT, EPIS, MPNST, SFT, and PEComa. Our results warrant prospective exploration of TIS as a predictive biomarker for ICI use in sarcoma.

Surufatinib in U.S. patients with soft tissue sarcoma.

11557 Background: Surufatinib is an inhibitor of VEGFR1, 2, &amp; 3, FGFR1, and CSF-1R. A manageable safety profile, and statistically significant improvement in progression-free survival (PFS) in patients (pts) treated with surufatinib have previously been demonstrated in pts with advanced NETs of extrapancreatic (epNET) and pancreatic (pNET) origin in 2 phase 3 randomized trials conducted in China (SANET-ep; NCT02588170 &amp; SANET-p; NCT02589821). Similar safety and efficacy were demonstrated in this phase 1 study (NCT02549937) in pts with NETs. Here we report the results of surufatinib in pts with soft tissue sarcoma. Methods: This study is a phase 1, dose escalation (ESC)/expansion (EXP) study to evaluate the safety and efficacy of surufatinib in the US and Europe (EXP only). ESC previously reported the recommended phase 2 dose as 300mg once daily. Enrollment into advanced, adult, soft tissue sarcoma EXP cohorts is ongoing. The primary endpoint is PFS rate at 4 months (mo). Soft tissue sarcoma histological subtypes include: angiosarcoma (AS), epithelioid sarcoma (ES), leiomyosarcoma (LMS), pigmented villonodular synovitis (PVNS), synovial sarcoma (SS) and undifferentiated pleomorphic sarcoma (UPS). Results: 32 adults with soft tissue sarcoma were enrolled (2 each AS and ES; 10 LMS; 1 PVNS; 9 SS; 8 UPS). The median age across all subtypes was 56.5 years (range 26-77), and the majority of pts were female (68.8%). 59.3% of pts received ≥ 3 prior lines of therapy (Tx) (median lines of Tx: 3 [range 1-6]). As of 15 Nov 2021, 1 pt (PVNS) remained on Tx. The PFS rate at 4 mo was 17.5%. The median PFS was 2.56 mo (95% CI; 0.92-2.92). The median duration on treatment (mDoT) for all pts was 11.2 weeks (wks) (0.4-39.0). The mDoT for LMS pts was 11.6 wks (3.1-36.0), mDoT for SS pts was 11.9 wks (0.4-27.9), and mDoT for UPS pts was 8.2 wks (2.7-27.9). Of 29 pts with ≥ 1 post baseline assessment, 6 pts (20.7%) achieved stable disease of ≥ 8.0 wks from start of Tx. No pts achieved a partial or complete response. The safety profile of surufatinib remains consistent with previously completed trials. All pts (n = 32) reported ≥ 1 adverse event (AE), and 21 pts (65.6%) reported AEs ≥ grade 3. The most common AEs of any grade were fatigue (53.1%), hypertension (43.8%), diarrhea (40.6%), anemia (25.0%), blood bilirubin increase (25.0%), headache (21.9%), and proteinuria (21.9%). The most commonly reported AEs ≥ grade 3 in &gt; 1 pt were hypertension (21.9%), fatigue (12.5%), and anemia (9.4%). AEs leading to Tx discontinuation occurred in 9.4% of pts. Conclusions: Surufatinib demonstrated minimal antitumor activity as a single agent in heavily pretreated pts across various types of soft tissue sarcoma. The safety profile in pts with soft tissue sarcoma remains consistent with previously reported and ongoing studies with surufatinib. Clinical trials are ongoing with surufatinib globally, with active recruitment in PD-L1 combination studies. Clinical trial information: NCT02549937.

Long-term efficacy and safety of anlotinib in advanced sarcomas.

e23564 Background: Treatment of sarcomas has advanced in recent years partly because of the application of multitarget tyrosine kinase inhibitor (TKI) drugs. Anlotinib is an oral TKI with the dual effects of antiproliferation and antiangiogenesis, and it has a therapeutic effect with good tolerance and low side effects. In theory, physicians can gain long-term tumor control with anlotinib in certain advanced sarcomas. Methods: We conducted a retrospective analysis of patients with advanced sarcomas with measurable target lesions who had been treated in our ward since 2018. There were 22 patients who had taken anlotinib regularly for more than 12 months. Their general information, clinical efficacy, and toxicities were statistically analyzed. We used a swimmer plot to observe the efficacy and duration of the drugs and a waterfall plot to express the best treatment effect. Results: There were 14 male and 8 female patients, ranging in age from 14 to 75 (44.77 on average) years. The primary sarcomas were ASPS in five cases; synovial sarcoma (SS) in four cases; LMS in three cases; epithelioid sarcoma (ES) and UPS in two cases each; and clear cell sarcoma, RMS, angiosarcoma (AS), fibrosarcoma (FS), pleomorphic liposarcoma (LS), and osteosarcoma (OS) in one case each. The sites of metastasis were the lung in 15 cases, lymph nodes in 4 cases, and multiple sites in 3 cases. Therapies were as follows: first-line therapy (6 cases), second-line therapy (9 cases), third-line therapy (5 cases), and more than third-line therapy (2 cases). The current therapy protocols were nine cases with oral anlotinib alone, nine cases with combination chemotherapy, and four cases with combination immunotherapy (anti-PD1). The best clinical efficacy of this group was complete response (CR) in four cases (18.18%), partial response (PR) in five cases (22.73%), and stable disease in 13 cases (59.09%), with an overall response rate of 40.91% and the longest lasting time of 26, 16, 38 months in different response groups. The mean of progression-free survival (PFS) was 23.32 months. The main adverse effects included myelosuppression in seven cases (31.82%), hypertension in three cases (13.64%), and hand-foot syndrome and weakness in two cases (9.10%). Severe adverse effects included hypothyroidism with weakness in one case and wound ulceration with pneumothorax formation in another case. Conclusions: Anlotinib monotherapy or combination therapy can be an effective and safe choice for some advanced sarcomas with a longer maintenance time and acceptable side effects. Besides, anlotinib combined with anti-PD1 therapy has better therapeutic efficacy for specific diseases such as ASPS and ES. Anlotinib combined with chemotherapy has therapeutic efficacy for SS, LMS, FS, and RMS. Clinical efficacy such as CR and PR may be a prediction of long-term PFS in some advanced sarcomas.

Phase 1/2 study of elraglusib (9-ING-41), a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, alone or with irinotecan, temozolomide/irinotecan or cyclophosphamide/topotecan in pediatric patients with refractory malignancies: Interim results.

e22015 Background: GSK-3β overexpression is associated with aggressive malignancies, treatment resistance and poor prognosis. The GSK-3β inhibitor Elraglusib induces apoptosis via NFΚB and p53 pathways and has potent anti-fibrotic and immunomodulatory activity. Adult studies of elraglusib demonstrate clinical activity in pancreatic cancer, melanoma, lymphoma and sarcoma as a single agent or in combination with cytotoxic chemotherapy. Elraglusib is active in in vivo models of neuroblastoma (NBL) and malignant glioma. This first-in-pediatrics study (NCT04239092) is evaluating the safety, pharmacokinetics (PK), and efficacy of elraglusib monotherapy and in combination with chemotherapy in patients with refractory malignancies. Methods: Elraglusib is given intravenously (IV) twice-weekly at 3 dose levels (DL) (9.3, 12.4 and 15 mg/kg) as a single agent or in combination with irinotecan, cyclophosphamide/topotecan or temozolomide/irinotecan in 21-day cycles. A cohort of pts with refractory NBL will be treated at the recommended phase 2 dose (RP2D) of elraglusib with temozolomide/irinotecan. Results: As of January 2022, 23 pts (n = 7 female, median age 14.2 years) have received at least one dose of elraglusib. Tumor types: 5 NBL, 3 diffuse midline glioma (DMG), 3 osteosarcoma (OS), 3 ependymoma (EP), 2 alveolar rhabdomyosarcoma (aRMS), 1 angiosarcoma (AS), 1 Ewing sarcoma (ES), 1 glioblastoma (GBM), 1 hepatoblastoma (HB), 1 embryonal CNS tumor NOS, 1 NUT midline carcinoma, 1 pineoblastoma (PB). Median time from diagnosis is 26 months (range: 6.7 – 156.3) and median number of lines of prior systemic therapy is 2 (range 0-14). Two DLs of single agent (6 pts) have been completed (9.3 and 12.4 mg/kg) without elraglusib-attributable severe adverse events (SAEs). Of the 15 patients on the combination arm with irinotecan or cyclophosphamide/topotecan, a single adverse event (Grade 4 hypotension/infusion reaction) was reported. Grade 1/2 elraglusib attributable-AEs include: transient visual change (n = 10), nausea (n = 7), vomiting (n = 6), fatigue (n = 2), hypotension (n = 2) and infusion reaction (n = 1). One pt with recurrent ES had a radiographic and pathologic CR after 3 cycles of elraglusib/cyclophosphamide/topotecan. 6 pts (26.1%) had SD (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). 8 pts (35%) remained on study treatment ≥ 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). Median treatment duration was 40 days (range 1 - 126). 4 pts remain on therapy. Conclusions: Elraglusib is well tolerated as a single agent and with several chemotherapy regimens in this heavily pretreated pediatric population with refractory cancers. It has encouraging antitumor activity, with 1 CR in a patient with recurrent ES. Enrollment is ongoing; a RPD2 has not been reached. Clinical trial information: NCT04239092.

Radiotherapy induced breast angiosarcoma as a rare entity : A case report

Background: Angiosarcoma(AS) is a rare vascular malignancy that originates from the vascular endothelial cells.It can arise anywhere in the body,most commonly in skin of the scalp and neck followed by breast,liver,spleen,and heart.Based on etiology,breast Angiosarcoma(BAS) can be classified into:primary(de novo) and secondary after radiotherapy.Due to its rarity,treatment of BAS is based on the experience gained from other soft tissue sarcomas management.In this paper we report a case of secondary BAS.

S1‐Guideline Cutaneous Angiosarcomas – Update 2021

S1‐Guideline Cutaneous Angiosarcomas – Update 2021

New nomograms to predict overall and cancer-specific survival of angiosarcoma.

ObjectiveThis study was designed to establish and validate promising and reliable nomograms for predicting the survival of angiosarcoma (AS) patients.MethodsThe Surveillance, Epidemiology, and End Results database was queried to collect the clinical information of 785 AS patients between 2004 and 2015. Data were split into a training cohort (n = 549) and a validation cohort (n = 236) without any preference. Univariate Cox and multivariate Cox regression analyses were performed to analyze the clinical parameters. Independent prognostic factors were then identified. Two nomograms were constructed to predict overall survival (OS) and cancer‐specific survival (CSS) at 3 and 5 years. Finally, the models were evaluated using concordance indices (C‐indices), calibration plots, and decision curve analysis (DCA).ResultsBased on the inclusion and exclusion criteria, 785 individuals were included in this analysis. Univariate and multivariate Cox regression analyses revealed that age, tumor size, and stage were prognostic factors independently associated with the OS of AS. Tumor site, tumor size, and stage were associated with the CSS of AS. Based on the statistical results and clinical significance of variables, nomograms were built. The nomograms for OS and CSS had C‐indices of 0.666 and 0.654, respectively. The calibration curves showed good agreement between the predictive values and the actual values. DCA also indicated that the nomograms were clinically useful.ConclusionWe established nomograms with good predictive ability that could provide clinicians with better predictions about the clinical outcomes of AS patients.

Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis.

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS). Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria. Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups. Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.